Although many reviews on histamine receptors have been published (Marone et al., 2014; Panula et al., 2015; Marino and Levi 2018; Zhang et al., 2018), few up-to-date reviews have focused on cardiac histamine receptors. Moreover, the most recent review was published by Hattori et al., in 2017. The present work reviews the most recent works on this topic in the relevant literature.

The “histamine” molecule was named by Fühner (1912) based on its chemical structure, which is β-imidazolyl-amin(e). The term histamine was derived from the Greek words for tissue (“histos” or΄ΙΣΤΟΣ) and “amine” (a nitrogen containing alkyl-derivate), which translate as the amine in the tissue. Histamine was first synthesised by two chemists from Freiburg im Breisgau using a battery of structurally similar compounds (Windaus and Vogt 1907) without studying their presence or function in animals. Later, Ackermann (also in Freiburg, Germany) found that bacteria could produce histamine from histidine, proving that histamine could be produced in nature and not only in the test tube (Ackermann 1910; Ackermann and Kutscher 1910). Previously, histamine was shown to increase the cardiac force of contraction, to increase the beating rate of the heart and to induce arrhythmias. Indeed, in early studies, synthetic histamine was found to exert a positive inotropic effect (PIE) and a positive chronotropic effect (PCE) in isolated perfused hearts (Ackermann and Kutscher 1910; Dale and Laidlaw 1910, 1911; Einis 1913). Histamine-induced arrhythmias were also reported in these early papers. For example, histamine led to asystole or third-degree atrioventricular block in isolated buffer-perfused spontaneously beating frog hearts (Einis 1913).

Over time, interest in cardiac histamine receptors has varied, depending on the development of new methods. In the early years (1910–1930), whole animal experiments were predominant. Then H₁-histamine receptor (H₁R) antagonists became available, which were used to treat anaphylactic shock. From the 1950s to 1980, electrophysiological experiments in multicellular cardiac preparations and then on isolated cardiomyocytes in animals and humans became feasible, and they were used in cardiac histamine research. In 1972, a paper on H₂-histamine receptor (H₂R) antagonists was published (Black et al., 1972). These H₂R antagonists were quickly used to differentiate between H₁R- and H₂R-mediated cardiac functions. H₂R antagonists were used in whole animal experiments, in experiments using atrial or ventricular multicellular preparations, and in isolated muscle cell studies. From 1970 to 1980, signal transductions of histamine receptors were studied using biochemical methods (adenylyl cyclase, 3′,5′-cyclic adenosine monophosphate [cAMP], and inositol trisphosphate [IP₃] measurements). When histamine receptors were cloned in the 1990s, molecular studies and mutational studies on H₁- and H₂-histamine receptors became feasible. The next steps were performed in genetic studies using adenoviral constructs or in studies on mice using gene deletion methods and gene overexpression methods to examined H₂-histamine receptors. Around 1980, a surge in clinical studies on H₂R agonists appeared, which did not lead to clinical application because of side effects. The use of these H₂R agonists could have been impaired by side effects such as acid production in the stomach (Felix et al., 1991a, 1995) or the assumption that all cAMP-increasing agents induce cardiac arrhythmias. At that time, a seminal paper was published showing that cAMP-increasing agents such as the phosphodiesterase III inhibitor milrinone or β-adrenoceptor agonists increased the ejection fraction of the left cardiac ventricle of patients with severe chronic heart failure. However, more patients died in the milrinone group than in the control group, mainly of fatal arrhythmias (Packer et al., 1991). Tariq and Aronow (2015) published a review on several cAMP-increasing agents in patients. Subsequently, the use of H₂R antagonists has been the subject of clinical studies and trials aimed at changing the therapy for heart failure.

In the present review study, we distinguish four histamine receptors that, based on their chronology of detection, are called H₁-, H₂-, H₃- and H₄-histamine receptors. They belong to the large family of heptahelical receptors that are thought to be located mainly in the sarcolemma. These histamine receptors couple via at least two pathways to elicit cardiac effects. First, the histamine receptors act via well-described guanosine-tri-phosphate (GTP)-binding proteins (G-proteins). Second, as shown in Figure 1A,B, the histamine receptors use β-arrestins to couple to intracellular signal transduction pathways (Hill et al., 1997; Seifert et al., 2013; Panula et al., 2015). All four histamine receptors are present in the mammalian heart (Panula et al., 2015; Hattori et al., 2017). However, only H₁- and H₂-histamine receptors couple directly to force contraction or beating rate in the mammalian heart (Hattori et al., 2017). In contrast to H₃- and H₄-histamine receptors, H₁- and H₂-histamine receptors are located on the cardiomyocyte (Hattori et al., 2017). The present review study focuses on H₂-histamine receptors because they are relevant for the positive inotropic and positive chronotropic effects of histamine in the human heart. There is still controversy in the field about whether H₁-histamine receptors increase or decrease the force of contraction in the human heart (Guo et al., 1984; Sanders et al., 1996). However, there is agreement that H₁-histamine receptors probably slow the intrinsic heart rate and the propagation of the heartbeat via the conduction system in the mammalian heart, including the human heart (Hattori et al., 2017). H₃- and H₄-histamine receptors are present on neuronal cell structures in the mammalian heart, but not on cardiomyocytes. H₃- and H₄-histamine receptors can inhibit the release of noradrenaline (NE) from storage sites (ganglia) in the human heart (Hattori et al., 2017).

The human H₂R consists of 359 amino acids (Gantz et al., 1991a, 1991b; Panula et al., 2015) and is located on chromosome 5 (Hill et al., 1997; Dy and Schneider 2004; Jutel et al., 2009). There are pharmacological and genetic tools to study H₂-histamine receptors in the heart. Genetic tools for studying the H₂R in more detail include a strain of general, constitutive knockout (KO = deletion of a gene in a mouse) mice for H₂R, a floxed H₂R mouse and one mouse line with cardiac specific overexpression of H₂R (Kobayashi et al., 2000; Gergs et al., 2019; Meng et al., 2021). Genetically modified mice with a floxed H₂R gene (Meng et al., 2021) can be used to generate cell-specific removal or at least reduce the expression of H₂R. Floxed mice have recently been used to delete H₂R in endothelial cells (EC) (Meng et al., 2021). Theoretically, the floxed mouse could be used for genetic deletion of H₂R in adult mouse cardiomyocytes. However, this experiment is not expected to be useful to reveal the exact function of H₂R in adult cardiomyocytes in patients because adult mouse cardiomyocytes do not express functional H₂R (Gergs et al., 2019). In adult mouse cardiomyocytes, histamine does not increase the mechanical function of the cell, and histamine has no positive inotropic effect on wild-type mouse hearts (Gergs et al., 2019). Hence, the deletion of the H₂R in adult mouse heart or adult mouse cardiomyocytes is not likely to reveal any new information. Please note that we specify adult mouse cardiomyocytes, as foetal mouse cardiomyocytes might respond to histamine by an increase in contractility, which, to the best of our knowledge, has not yet been studied. The contractile effect of histamine in the mammalian heart is clearly age dependent, but it differs in different parts or regions of the mammalian heart, and it is species dependent (see also Histamine and cAMP in the Heart: Age- and Species-Dependent Presence of Cardiac Histamine Receptors).

Other tools used to study histamine receptors are receptor agonists and receptor antagonists. These tools, similar to the genetic tools described above, also have limitations, which must be considered in planning experiments. Typical, but not necessarily specific or selective agonists of H₂R, are listed in Table 1. Obviously, histamine itself is an agonist of all four known histamine receptors. Histamine is therefore also an agonist of H₂-histamine receptors. It might be of physiological relevance that the affinity of histamine for the four histamine receptors is the lowest for H₂R. Indeed, histamine has a higher affinity for H₁-, especially for H₃- and H₄-histamine receptors, than for H₂-histamine receptors (Panula et al., 2015). However, these observations clearly show that histamine is not a specific agonist of H₂-histamine receptors. If contractile effects of histamine are detected in the mammalian heart, which histamine receptor is involved remains unknown. Specific histamine receptor antagonists must be used to classify the contractile effect of histamine and link it to, for instance, a H₁-or and H₂-histamine receptor.

The agonists listed in Table 1 are of comparable potency, or, compared with histamine, they are much more potent agonists of H₂-histamine receptors. The first agonist that was found to act on H₂R but not on H₁R was dimaprit (Table 1). Later, in addition to the previously cloned H₁- and H₂-histamine receptors, novel H₃- and H₄-histamine receptors were cloned. It was found that dimaprit, indeed, did not stimulate cloned H₁R but stimulated cloned H₂R. However, dimaprit was shown to stimulate H₃-and H₄-histamine receptors even more potently than H₂-histamine receptors (Panula et al., 2015). Currently, a molecule called compound 16 is known to be one of the most potent agonists of H₂-histamine receptors (Table 1). Interestingly, in Langendorff-perfused guinea pig hearts, a derivative of dimaprit, called apromidine, exerted a positive inotropic effect, which occurred without changing the heart rate (Felix et al., 1991a, 1995). Two dually fluorinated apromidine derivatives, which are known H₂R agonists (BU-E-75 and BU-E-76), not only induced a positive inotropic effect but also reduced heart rate in Langendorff-perfused guinea pig hearts or living anaesthetised guinea pigs (Felix et al., 1991a, 1995). The lack of a positive chronotropic effect is puzzling: in isolated spontaneously beating guinea pig right atria, BU-E-75 and BU-E-76 exerted potent positive chronotropic effects: pD₂-values of 8.12 and 8.05 were compared with pD₂-values for a positive inotropic effect in isolated paced guinea pig papillary muscles at 7.90 and 7.91, respectively (Buschauer and Baumann 1991). These results clearly showed that BU-E-75 and BU-E-76 are potent agonists of H₂-histamine receptors in the guinea pig sinus node (SA). However, in another study, the same group reported that the efficacy of inducing a positive chronotropic effect, that is, an absolute increase in the number of heartbeats in Langendorff-perfused guinea pig heart, was less than that induced by impromidine, another dimaprit derivative (Felix et al., 1991a). Similarly, BU-E-75 and BU-E-76 were more effective in inducing a positive inotropic effect on guinea pig ventricle compared with impromidine (Felix et al., 1991a). These authors speculated that in vivo, in anaesthetised guinea pig and Langendorff-perfused guinea pig heart, additional effects of BU-E-75 and BU-E-76, such as vagal stimulation, must exist, which explained their negative chronotropic effects (NCE) (Felix et al., 1991a, 1995). They also reported that BU-E-75 and BU-E-76 were virtually non-arrhythmogenic (Felix et al., 1991a).

A caveat is in order at this stage. Even if one uses a specific H₂R agonist that does not have any measurable affinity for the other three histamine receptors, control experiments are necessary to prove that the histamine receptor agonist does not act on other sarcolemmal receptors that alter cardiac contractility. A sound precaution could be to test a new H₂R agonist to determine whether one of the well-characterised H₂R antagonists, such as cimetidine or famotidine (Table 2), abrogates its cardiovascular effects. In Table 2, we have deliberately listed only one H₂R antagonist, burimamide, which is now only of historical value. Burimamide was the first H₂R antagonist to be described (Black et al., 1972). Because of its short half-life and poor oral bioavailability, it has never been clinically applied. However, it has been used in many seminal studies to identify cardiac H₂-histamine receptors. The other H₂R antagonists shown in Table 2 are still used clinically, and they have been used as substitutes for burimamide to study the functional role of H₂-histamine receptors in the heart. In Table 2, we present mainly data on affinity derived from cell culture studies in which the authors used human H₂-histamine receptors to measure affinity. Such data are difficult to obtain in studies on isolated human organs, but, under identical conditions, they should allow for comparisons between several frequently used H₂R antagonists in cardiovascular research. Figure 1A shows the generally known H₂R-initiated pathways and the current putative signal transduction steps in the mammalian heart.

H₂R can heterodimerise with H₁R (Figure 2), which was observed after receptor stimulation in U937 cells (i.e., a macrophage cell line, which per se expresses both receptors) and H₂R transfected Chinese hamster ovary (CHO) cells, leading to the desensitisation and internalisation of H₂-histamine receptors in endosomes (Alonso et al., 2013). A functional interaction was produced as follows: in cell culture, H₁-histamine receptors were stimulated for 60 min. Dimaprit evoked a smaller increase in cAMP (Figure 1A) in these cells than under control conditions. Conversely, dimaprit pre-treatment led to a reduced H₁R-mediated IP₃-increase (Figure 1B), indicating functional cross-talk, which was not due to receptor phosphorylation by kinases (Alonso et al., 2013). Whether this kind of heterodimerisation occurs in the heart, particularly in the human heart, and has functional consequences has not yet been studied. However, it could be addressed because both receptors are present on, for instance, guinea pig cardiomyocytes, which was shown in histological results (Matsuda et al., 2004). Many G-protein coupled receptors are known to heterodimerise. Hence, it is conceivable, but unknown, whether H₂R dimerises with other receptors in addition to H₁R. Diverse functional, but not necessarily structural, interactions between histamine acting via H₂-histamine receptors and other cAMP-changing agents have been studied (Table 3). Therefore, the following question arises: What are the results of the interaction of H₂-histamine receptors with other receptors? One way to address this question, which is also (patho)physiologically relevant, is the following: in isolated Langendorff-perfused heart, histamine was given initially, which increased the force of contraction in the left ventricle. It was also found to increase the current through Ca²⁺ channels in the sarcolemma (Belevych et al., 2004). Adenosine (or carbachol, a stable derivate of acetylcholine and an unspecific agonist at muscarinic receptors) was then applied, which reduced the force of contraction in the heart. This functional inhibition has usually been explained as follows (Figure 2): H₂R stimulation increases adenylyl cyclase activity (Figure 1A), which is then reduced by the stimulation of A₁-adenosine receptors or M₂-muscarinic receptors (Table 3) (Baumann et al., 1981a). The situation is somewhat different in experiments on preparations from the right human or canine atrium, where the positive inotropic effects of histamine and dimaprit, mediated by H₂R, are also reduced by adenosine or carbachol (Endoh, 1979; Baumann et al., 1981a). However, the mechanism of the action of adenosine is not clear. As the ventricle of guinea pig, adenylyl cyclases might be involved. Thus, alternatively strong lines of evidence (Behnke et al., 1990; Böhm et al., 1986; Böhm et al., 1988a; Gupta et al., 1993; Neumann et al., 1994; Herzig et al., 1995; Neumann et al., 1995) have shown that the effects of A₁-adenosine receptor stimulation or M₂-muscarinic receptor stimulation occur via subunits of GTP-binding proteins, which leads to the opening of atrial potassium channels without the involvement of cAMP. Thus, a reduction in the action potential (AP) duration and a subsequent negative inotropic effect (NIE) will ensue (Figure 2; Table 3). Because adenosine is released in ischaemia, this functional interaction might be regarded as an antihistaminergic effect of adenosine (Genovese et al., 1988). The opposite interaction was noted, at least under certain conditions: the current in sarcolemma or the force of contraction, both of which were stimulated by β-adrenoceptor agonists, was reduced by the additional application of histamine (Belevych et al., 2004; Gross et al., 1984). These results indicate that H₂-histamine receptors couple in the heart not only via stimulatory GTP-binding proteins to activate adenylyl cyclase but also via inhibitory GTP-binding proteins to inhibit the activity of adenylyl cyclase (Figure 2). This behaviour is not without precedence, and it is well known in the β₂-adrenoceptor. Similarly, the mode of interaction between H₂-histamine receptors and other receptors, such as purinoceptors, may depend upon the signal pathway involved. An adenosine triphosphate (ATP)-induced increase in arachidonic acid in H₂R transfected cells was inhibited by the additional application of histamine, but the ATP-induced increase in Ca²⁺ was not affected by the application of histamine (Traiffort et al., 1992). This ATP-based interaction has not been studied in the heart. Further evidence indicates that the order of drug application is important for H₂-histamine receptors and other receptors that are coupled to the activity of adenylyl cyclase. For example, if the cardiac serotonin 4 (5-HT₄) receptor (i.e., the receptor mediating the positive inotropic effect of serotonin in the human heart) was first stimulated, then H₂R activation decreased the force of contraction but not vice versa (Neumann et al., 2019; Neumann et al., 2021d). These data are in line with the assumption that H₂-histamine receptors are coupled via inhibitory and stimulatory G-proteins with the activity of adenylyl cyclase in the heart.

Figure 3 and Table 4 show overviews of the functional actions of histamine in the hearts of several species and in different cardiac regions (Figure 3). Table 4 shows regional differences in the presence and role of H₂-histamine receptors, which must be considered in planning studies. For comparison, animals that are seldom used in experimental medicine were included in Table 4; for example, H₂-histamine receptors are used in the python heart. Perhaps it could be concluded that histamine receptors occurred late in the evolution of the animal kingdom. Some aspects of human H₂R pharmacology are better studied in guinea pigs, and others are better studied in pigs and dogs (Table 4).

Several types of cardiomyocytes conduct the heart beat in the different regions in the heart. Sinus node cells act as a cardiac pacemaker, and atrial cardiomyocytes form the main bulk of atrial muscle. Specialised ventricular cardiomyocytes form the path of the conducting system, which propagates depolarisation starting at the sinus node via specialised cells in the atrium (Bachmann bundles) via the atrioventricular node cells, the His-bundle, the Tawara branches, and the Purkinje fibres in the ventricle walls (Figures 3, 4). However, few histological studies have been conducted to examine histamine receptors. A seminal study that used semiquantitative immunohistochemistry revealed a high density of H₁-histamine receptors on sinoatrial nodal cells and cells in the atrioventricular node but less expression in the surrounding atrial or ventricular myocardium of guinea pig (Matsuda et al., 2004). These authors detected H₂-histamine receptors immunologically mainly in the working myocardium of the right atrium and the ventricular cells in proximity to the atrioventricular cells in guinea pigs (Matsuda et al., 2004). There are no published comparative studies on the histology of the human heart; therefore, this topic warrants future research. Alterations of H₂-histamine receptors in cells in this pathway are expected to be of huge clinical relevance, as they can certainly lead to various cardiac arrhythmias. Alterations of H₂R expression might be relevant for not only primary arrhythmias because of inborn errors but also secondary arrhythmias upon ischaemia, hypertrophy, drug treatment, and perhaps ageing. However, further research in this regard needs to be undertaken.

Concerning the expression (Figures 1, 3, 4 and Table 5) and the cellular heterogeneity of H₂-histamine receptors in the heart, H₂-histamine receptors have long been known to be present and functional in blood cells. These blood cells are pumped into the heart and continuously removed by circulation. Specifically, H₂R is expressed on leucocytes, macrophages, mast cells (Marquardt et al., 1994), neutrophils (Fredholm et al., 1999), thrombocytes, and erythrocytes (Table 5). In histological studies with antibodies, the specificity of which is poor and a research need (Seifert et al., 2013) or messenger ribonucleic acid (mRNA) detection), H₂-histamine receptors have been identified in blood containing cardiac tissue section samples or cardiac homogenates. However, measurements of H₂-histamine receptors in cardiac homogenates reveal their expression in all cell types present in the heart. It could be assumed that bands thought to be specific to H₂R in Western blots, which are made from whole heart homogenates, mainly arise from cardiomyocytes. This assumption, however, does not necessarily hold true unless it is repeated with homogenates from purified cardiomyocytes (Gergs et al., 2019; and own unpublished observations). Hence, some data in the literature on cellular expression of H₂R proteins await confirmation.

The signal transduction (Figure 1A) of H₂R in general also involves binding to stimulatory G-proteins (Gs-proteins) in peripheral tissues (Table 6). When generated, cAMP then activates a cAMP-dependent protein kinase (PKA), which then phosphorylates typical targets in the heart (Figure 1A). Some of these targets are still hypothetical substrates, such as the ryanodine receptor, whereas others have been shown in transgenic mice (phospholamban, phosphatase inhibitor 1) (Gergs et al., 2019, 2020, 2021b; Neumann et al., 2021d). Moreover, H₂R stimulation can increase the phosphorylation state of the inhibitory subunit of troponin (TnI) and the myocardial C-protein. Observations in H₂-TG (transgenic mice with heart-specific overexpression of the H₂R) have remained unpublished. In the isolated human atrium, H₂R stimulation increased cAMP content (Sanders et al., 1996), the activity of PKA (Sanders et al., 1996), the phosphorylation state of phospholamban on serine 16 (Neumann et al., 2021a), which is phosphorylated by PKA, and the phosphorylation state of phospholamban on threonine 17 (Neumann et al., 2021a), which is phosphorylated by a Ca²⁺ calmodulin-dependent protein kinase (CaMKII). The phosphorylation of phosphatase inhibitor 1 (Gergs et al., 2019) was observed to activate this protein, which then inhibited protein phosphatase 1, a major cardiac phosphatase (Figure 1A) (Herzig and Neumann 2000), thus amplifying and possibly prolonging the effect of PKA on protein phosphorylation in the heart. Phosphatase 1 showed a highly complicated compartmentalisation in the heart (Herzig and Neumann 2000; Liu, 2021), and thus histamine pathways might be fine-tuned. H₂-histamine receptors not only increased phosphorylation via PKA but also via β-arrestin (Figure 1A) and other transducers, which finally increased the phosphorylation state and activity of downstream kinases, such as extracellular regulated receptor kinase 1/2 (ERK1/2) (Figure 1A) (Luo et al., 2013) and death-associated protein kinase 2 (DAPK2) in neonatal rat cardiomyocytes (Figure 1A) (Luo et al., 2013). As ERK1/2 phosphorylation and DAPK2 phosphorylation can mediate apoptosis, they may explain which H₂-histamine receptors in the heart can induce apoptosis (Luo et al., 2013; Zeng et al., 2014). Apoptosis could be initiated by a H₂R-mediated increase in the protein expression of calcineurin (=protein phosphatase 2B) in neonatal rat fibroblasts (Zeng et al., 2014). This calcineurin also increased proliferation in neonatal rat fibroblasts (Zeng et al., 2014). In neonatal rat fibroblasts, the stimulation of H₂-histamine receptors by amthamine increased the translocation of the nuclear factor of activated T-cells c3 (NFATc3) to the nuclear fraction of these cells, as well as the expression of α-smooth muscle actin (αSMA) (Zeng et al., 2014). Similarly, the stimulation of H₂-histamine receptors in neonatal rat cardiomyocytes could also increase the protein levels of the proapoptotic caspase 3 (in Western blotting), which could also contribute to H₂R-mediated cardiac apoptosis (Figure 5) (Zeng et al., 2014). The stimulation of neonatal rat cardiomyocytes for 24 h with histamine increased the protein expression of the proapoptotic protein Bax (=homolog of Bcl-2, an apoptosis activator) and the translocation of Bax to mitochondria in these cells, where Bax may have contributed to mitochondrial-initiated apoptosis (Luo et al., 2013; Zeng et al., 2014). Moreover, H₂-histamine receptors can lead to the release of proteins like atrial natriuretic peptide(s) (ANP) from neonatal rat cardiomyocytes (Luo et al., 2013). Whether these signal transduction pathways are used in adult hearts or even in human hearts remains an open question that should be addressed in future research.

H₂R couples not only through stimulatory G-proteins in the heart but also via inhibitory G-proteins (Figure 2) (Kilts et al., 2000; Belevych et al., 2004) and via so-called Gq proteins (Figure 2) (Wellner-Kienitz et al., 2003). Similarly, H₂-histamine receptors couple not only to cardiac L-type Ca²⁺ channels but also to potassium channels (Figure 1A) in the sarcolemma (Wellner-Kienitz et al., 2003).

As mentioned above, published data have shown that in the human cardiac right atrium, H₂R stimulation also increases the level of 3′, 5′-cyclic guanosine monophosphate (cGMP) (Figure 1) (Sanders et al., 1996). These authors speculated (Figure 1A) that H₂R may be responsible for the production of nitric oxide (NO) in cardiomyocytes or in endothelial cells. This NO may lead to an increase in cGMP via the activation of guanylyl cyclase (Figures 1B, 3) (Sanders et al., 1996). The produced cGMP can inhibit the activity of phosphodiesterase III (Figures 1B, 3) (Sanders et al., 1996). This inhibition would raise cAMP levels in the cells, which would contribute to a positive inotropic effect of H₂R in the human heart (Figure 1B, 3) (Sanders et al., 1996). This interesting hypothesis (Sanders et al., 1996) has apparently never been tested experimentally. Moreover, although it could be shown that the H₂R increases the force of contraction in the human right and left ventricles in vitro (Ginsburg et al., 1980; Bristow et al., 1982b) and activates ventricular adenylyl cyclase (Bristow et al., 1982a; 1982b), to the best of our knowledge, an effect of H₂-histamine receptors on cAMP levels or phospholamban phosphorylation in the human cardiac ventricle has never been reported, which warrants future research.

The signal transduction of H₁R (Figure 1B) differs from the signal transduction of H₂R in the heart. Some previous studies claimed that the positive inotropic effect of H₁R stimulation on rabbit heart was due to an increase in IP₃ content in the heart because H₁R stimulation was accompanied by an increase in cardiac IP₃ levels (Figure 1B) (Sakuma et al., 1988). However, the positive inotropic effect of H₁R stimulation was still observed in rabbit heart in the presence of inhibitors of IP₃-generation (Hattori et al., 1989). Thus, it might be concluded that an increase in cardiac IP₃-content does not cause the positive inotropic effect of histamine in rabbit heart. Subsequently, it was reported that the positive inotropic effect of histamine on guinea pig atrium led via H₁R to the tyrosine phosphorylation of regulatory cardiac proteins. This increase in the phosphorylation of the amino acid tyrosine of currently unidentified proteins of apparent molecular weights of 25, 35, 65, and 150 kDa may have caused a positive inotropic effect via the H₁-histamine receptors, as pre-treatment with a tyrosine kinase inhibitor abolished any positive inotropic effect of histamine in guinea pig atrium (Akaishi et al., 2000). It was suggested that the tyrosine phosphorylation of, for instance, myofilaments might have led to an increase in the Ca²⁺ sensitivity of the myofilaments, which may have caused the positive inotropic effect on histamine in the left atrium of guinea pig (Akaishi et al., 2000).

To better understand the mechanism of the inotropic, chronotropic and pro-arrhythmogenic effects of histamine on the human heart, it is necessary to review the electrophysiological effects of histamine on the heart of laboratory animals and human surgical samples (see Table 7). The stimulation of both H₁- and H₂-histamine receptors can affect cardiac ionic currents. Thus, in guinea pig atrial cells, histamine enhanced the slow delayed rectifier potassium current (I_Ks), the slow component of the repolarising current I_K, via H₁R and via protein kinase C (PKC) with an EC₅₀-value (=half maximal effective concentration values) of 0.7 µM (Matsumoto et al., 1999). On the rapid component of I_K, I_Kr (=rapid delayed rectifier potassium current), histamine exerted an inhibitory effect via H₁-histamine receptors with an EC₅₀-value of 0.3 µM in a PKC-independent manner (Matsumoto et al., 1999). The overall effect of the stimulation of H₁-histamine receptors in atrial cardiomyocytes is the prolongation of the AP (Amerini et al., 1982; Borchard and Hafner 1986; Hattori et al., 1988b), which might result from a higher contribution of the I_Kr component, lower EC₅₀ for I_Kr (inhibition) or from additional effects, such as the inhibition of I_{K. ACh} (=G-protein gated potassium channel (Tohse et al., 1995). However, the effects of H₁R stimulation may depend on the density of I_Kr, I_Ks, and the cell type. The reason is that in ventricular guinea pig cardiomyocytes, a shortening of the AP was observed (Valenzuela and Zhou 1992). The stimulation of the H₂R in guinea pig ventricular cardiomyocytes increased the repolarising current I_K with an EC₅₀ of 38 nM via the cAMP-PKA pathway, which could explain the shortening of the AP (Yazawa and Abiko 1993).

In the past, slow APs were used as a surrogate for the Ca²⁺ carried slow inward current and for testing the effects of calcium antagonistic drugs. These slow potentials were elicited by histamine (1–10 µM) in K⁺ (20–30 mM) depolarised papillary muscles (e.g., Barbieri et al., 1991). They, however, indicated a possible direct or indirect effect of histamine on the cardiac L-type Ca²⁺ channel current (I_Ca.L), which is in line with the finding that histamine can elicit spontaneous APls in Purkinje fibres in sheep (Cerbai et al., 1990). Accordingly, in guinea pig atrial myocytes, histamine enhanced the intracellular Ca²⁺-concentration measured by Indo-1 (a calcium indicator) fluorescence via H₁-histamine receptors in a nifedipine-sensible way (Yoshimoto et al., 1998). Although it could be assumed that this could indicate the stimulation of I_Ca.L, it was shown that this effect of histamine on the Ca²⁺ current was an indirect effect by prolonging the AP duration, due to the inhibition of the outward potassium current, thereby extending the time window for the influx of I_Ca.L and Ca²⁺ ([Ca²⁺]_i) (Yoshimoto et al., 1998). Whole cell voltage clamp experiments showed that histamine did not directly alter I_Ca.L (Yoshimoto et al., 1998). However, in guinea pig ventricular cells, H₂R stimulation enhanced the amplitude of the slow Ca²⁺-current. This effect was mimicked by GDP_ϒS (=in gamma position sulphur substituted guanosine triphosphate) (Hescheler et al., 1987).

Also modulated by histamine was the pacemaker current I(f) (=the hyperpolarisation-activated inward current (formerly known as I [h] and now as I [f]), which was enhanced via the stimulation of H₂-histamine receptors in rabbit sinoatrial nodal cells (Satoh 1993). In addition, it was shown by the overexpression of H₂-histamine receptors in rat atrial cells that histamine—in this experimental situation—inhibited I_{K. ACh} (Wellner-Kienitz et al., 2003), which was previously shown in earlier guinea pig atrial cells (Tohse et al., 1995). Thus, the increase in heart rate following histamine administration may be attributable to a combined effect that includes the stimulation of I(f), the enhancement of I_Ca.L, the increase in [Ca²⁺]_i and at least partial inhibition of I_{K. ACh}.

Combined, the effects of histamine on the electrophysiology of the heart depend on the amount and subtype of histamine receptors (H₁R; H₂R), on the density of the target channels and currents (I_Kr; I_Ks; I_{K. ACh}; I_f; I_Ca.L) and the area of the heart under investigation (i.e., the sino-atrial node, atrioventricular (AV) node, the conduction system and the ventricle), which varies among species. An overview is provided in Table 7.

The results shown in Tables 4, 7 indicate that the electrophysiological effects of histamine were recorded only in species where inotropic effects of histamine were detectable. The involvement of H₂-histamine receptors usually leads to electrophysiological effects that are opposite those of the involvement of H₁-histamine receptors. Table 7 also shows mechanisms for the arrhythmogenic effects of histamine. The term “slow APs” indicates the effect of histamine on partially depolarised cardiac tissue when calcium cations, not sodium cations, carry the sarcolemmal current.

The first investigators in the field of histamine pharmacology noted a histamine-induced positive inotropic effect in the hearts of experimental mammals (Dale and Laidlaw 1910). These early researchers noted that histamine was also active in the human cardiovascular system, which paved the way for future research (Dale and Laidlaw 1910). As shown in Table 8, a positive inotropic effect or a positive chronotropic effect of histamine or its derivatives was observed in humans and in several laboratory animals. However, in some frequently used laboratory animals, histamine did not act on the force of contraction via histamine receptors but by the release of noradrenaline (Table 8) in mice (Gergs et al., 2019) and rats (Laher and McNeill 1980a). Animals such as wild-type mouse, rat and cat are not useful as model systems of the human heart. Mice with the overexpression of H₂-histamine receptors may be a better choice (Gergs et al., 2019, 2020). They have been successfully used to predict the effects of H₂-histamine receptor agonists or H₂-histamine receptor antagonists on human hearts (Neumann et al., 2021b,c).

The involvement of adenylyl cyclase in the positive inotropic effect of histamine (Figures 1A,B) was initially suggested by Pöch and Kukovetz (1967) and later tested directly by measuring cardiac adenylyl cyclase activity and by measuring cAMP levels in isolated freeze-clamped cardiac preparations. It was tested indirectly by inhibiting the degradation of cAMP by treatment of cardiac preparations with phosphodiesterase inhibitors (Kukovetz et al., 1973). Klein and Levey (1971) were the first to report that histamine could stimulate the activity of adenylyl cyclase in broken cell preparations from guinea pig hearts, one human heart and cat hearts. The data on kitten cardiac membranes (Klein and Levey 1971) are probably doubtful, as the cat has no functional H₂-histamine receptors (Table 4) (Laher and McNeil 1980c). Because these early researchers had no H₂R antagonist at their disposal, they could only block the activity of adenylyl cyclases with very high concentrations of promethazine, which were at lower concentrations a H₁R antagonist but at higher concentrations in an H₂R antagonist (Klein and Levey 1971). In contrast, other researchers reported that the histamine-induced stimulation of guinea pig membrane-bound adenylyl cyclase was not inhibitable by promethazine at concentrations that were specific for H₁-histamine receptors (McNeill and Muschek 1972), that is, in concentrations that were so high that, as we now know, promethazine also blocked H₂-histamine receptors. However, they later obtained samples of burimamide (the first reported H₂R antagonist) (Black et al., 1972). They showed that burimamide antagonised the histamine-stimulated activity of adenylyl cyclase in guinea pig cardiac membranes (Verma and McNeill 1974). Over time, it became apparent that histamine increased the potency and effectiveness of the activity of guinea pig cardiac adenylyl cyclases if guanylnucleotides were added to the incubation medium, which was the first indication of the involvement of GTP-binding proteins in this process (Figures 1A,B). Under these experimental conditions, dimaprit, N^α-methylhistamine, and 4-methylhistamine were partial agonists, and PEA (now regarded as a H₁R agonist) was ineffective in increasing the activity of adenylyl cyclase in guinea pig cardiac membranes (Johnson et al., 1979) (Table 1) in agonists often used in cardiac pharmacology. The stimulatory effects of histamine on guinea pig adenylyl cyclase in cardiac membranes were also antagonised by clinically relevant antagonists, such as cimetidine (see Table 2 for a list of commonly used antagonists) and were thus regarded as H₂R-mediated (Johnson et al., 1979; Kanof and Greengard 1979). However, other cardiovascular drugs, such as clonidine, stimulated cardiac adenylyl cyclase via H₂-histamine receptors (Kanof and Greengard 1979). Clonidine is currently used as an antihypertensive agent because of its stimulatory action on central α₂-adrenoceptors. Whether the stimulatory effect of clonidine is species specific is unclear. Therefore, future research should be conducted to determine whether clonidine also stimulates human H₂-histamine receptors in cardiac preparations, which is currently unknown, but it might be clinically relevant.

Another potentially relevant antagonistic action in cardiac H₂-histamine receptors has been known for many years. The stimulatory effects of histamine on the activity of adenylyl cyclase in guinea pig ventricular preparations were inhibited in a competitive fashion by antidepressant and neuroleptic drugs (Kanof and Greengard 1979) (Table 2, lower part). In isolated guinea pig Langendorff-perfused hearts, high concentrations of promethazine reduced histamine-induced increases in contractility and reduced histamine-stimulated cardiac cAMP content (McNeill and Verma 1974a), extending the biochemical data to functional data.

A study on adenylyl cyclases in human ventricles that were obtained during surgery from failing and non-failing human hearts revealed findings similar to guinea pig cardiac adenylyl cyclases. Histamine concentration dependently increased adenylyl cyclase activity, which was more effective in the presence of a non-hydrolysable GTP derivative, suggesting the involvement of G-proteins (Figure 1A) in the human heart as well (Bristow et al., 1982b). Impromidine and dimaprit (Table 1) were less effective than histamine in increasing adenylyl cyclase activity in membranes of human ventricles (Bristow et al., 1982b). However, the stimulatory effects of histamine on adenylyl cyclase activity in human ventricle membranes were cimetidine sensitive and thus were probably H₂R-mediated (Bristow et al., 1982b). Other studies, in contrast, found that dimaprit and impromidine were as effective as histamine in stimulating the activity of adenylyl cyclase in membranes prepared from human papillary muscles (Baumann et al., 1981b). However, Bristow et al. (1982b) data were in line with functional data. In performing contraction experiments in isolated human left ventricular preparations, they found that impromidine was less effective than histamine. Moreover, impromidine antagonised the positive inotropic effects of histamine; thus, impromidine acted as a partial agonist of cardiac human H₂-histamine receptors (English et al., 1986; Felix et al., 1995).

Based on the foregoing studies on promethazine in the heart and adenylyl cyclases isolated in guinea pig brain, drugs used in psychiatry were noted to inhibit the histamine-stimulated activity of cerebral adenylyl cyclases. Notably, amitriptyline and nortriptyline, doxepin, haloperidol, clozapine, chlorpromazine, thioridazine, and mianserin inhibited the histamine-stimulated activity of cerebral adenylyl cyclases (Green and Maayani 1977; Kanof and Greengard 1978; Dam Trung Tuong et al., 1980). The authors speculated that the inhibition of brain H₂-histamine receptors might underlie the clinical effects of these drugs (Green and Maayani 1977; Kanof and Greengard 1978; Dam Trung Tuong et al., 1980). However, that view has been disputed (Kanba and Richelson 1983), and it is currently not the preferred explanation of the clinical effects of these psychiatric drugs. However, such data indicate that these psychiatric drugs could clinically interfere with cardiac H₂-histamine receptors. Based on these reports, amitriptyline was recently shown to antagonise the effects of histamine on the force of contraction in isolated atrial preparations from human hearts, indicating that old data on psychiatric drugs are still clinically relevant, and they have not been considered seriously in the past (Neumann et al., 2021b).

Early data showed that histamine increased the force of contraction and the beating rate in prenatal whole human heart, right atrium, or paced ventricular preparations (Wollemann and Papp 1979). These inotropic data on human prenatal hearts were accompanied by measuring the histamine-stimulated activity of adenylyl cyclase in foetal human hearts, which was antagonised by cimetidine and therefore H₂R-mediated (Wollemann and Papp 1979).

It is likely that the first reports that histamine increased the cAMP content in whole heart were based on isolated spontaneously beating guinea pig heart (Kukovetz et al., 1973). They reported that theophylline could potentiate the positive inotropic effects of histamine in Langendorff-perfused guinea pig hearts. Theophylline was used as a phosphodiesterase (PDE) inhibitor (Kukovetz et al., 1973). Furthermore, they reported that in rapidly frozen isolated guinea pig hearts, the positive inotropic effect of histamine was accompanied and even pre-ceded by increases in cAMP content (Kukovetz et al., 1973). Data on the use of subtype-specific PDE inhibitors, such as EHNA (=erythro-9-(2-hydroxy-3-nonyl) adenine) for PDE II, cilostamide for PDE III and rolipram for PDE IV have been confirmed and extended to left atrial preparations of mice overexpressing human H₂-histamine receptors (Neumann et al., 2021c). In mice, PDE II and IV were found to be particularly relevant for degrading cAMP formed by the stimulation of H₂-histamine receptors, which is not necessarily true in the human heart, but it needs to be elucidated (Neumann et al., 2021c). Kukovetz et al. (1973) data were confirmed and extended by other researchers who blocked the histamine-induced increase in cAMP content using burimamide (the first H₂R antagonist, Table 2) in contracting and rapidly frozen isolated guinea pig cardiac preparations (McNeill and Verma 1974b).

Other researchers included papaverine in their atrial preparations (Reinhardt et al., 1977). They used papaverine as a PDE inhibitor (Reinhardt et al., 1977). Papaverine shifted the effect of histamine on the force of contraction and cAMP content in guinea pig papillary muscles to lower concentrations of histamine (Reinhardt et al., 1977). Their findings also suggested that H₂-histamine receptors are coupled with the generation of cAMP, at least in guinea pig papillary muscle (Reinhardt et al., 1977). Similarly, the positive chronotropic effect of histamine in spontaneously beating guinea pig right atrial preparations could be potentiated by papaverine (Reinhardt et al., 1977). This result suggested that cAMP was formed in the sinus node, which caused an increase in the beating rate of isolated right atrial preparations from guinea pigs (Reinhardt et al., 1977). In contrast to the results shown in the guinea pig ventricle, histamine did not increase cAMP content in isolated electrically stimulated preparations from the left atrial in guinea pigs. Moreover, the inotropic effect of histamine in isolated electrically stimulated preparations from the left atrial of guinea pigs was neither potentiated by papaverine (Reinhardt et al., 1977) nor antagonised by burimamide (Verma and McNeill 1977). These results suggest that H₂-histamine receptors and cAMP were not involved in the effect of histamine in the guinea pig left atrial preparations but only in the guinea pig right atrium preparations (Verma and McNeill 1977). These findings are summarised in Table 4. However, the positive inotropic effect of histamine in the left atrium of guinea pigs was antagonised by the H₁R antagonist mepyramine (Wilson and Broadley 1980), which provided evidence that the positive inotropic effects of histamine in the left atrium of guinea pigs are H₁R-mediated. Thus, histamine can use different receptors and different second messengers in different regions of the mammalian heart (see Brief Notes on H2R Biochemistry and Table 4 for synopses of these findings).

Early indirect evidence suggested that the positive inotropic effect of H₂R stimulation was mediated by the activation of L-type Ca²⁺ channels, but not the positive inotropic effect of H₁-histamine receptors. For instance, in isolated guinea pig left atria that contained only H₁-histamine receptors (Table 4), under potassium-induced depolarised conditions, histamine was unable to increase the force of contraction, whereas in isolated right ventricular guinea pig muscle that contained both H₁- and H₂-histamine receptors (Table 4), histamine elicited an increase in the force of contraction (Hattori and Kanno 1985). These findings can be explained as follows: under partial depolarisation with high potassium, the L-type Ca²⁺ channel is activated by cAMP-increasing pathways, such as the pathway initiated by H₂-histamine receptors. However, pathways that do not use cAMP, such as H₁R, are unable to activate the L-type Ca²⁺ channel; thus, under these conditions, they cannot generate force. The same mechanism was also measured in the isolated electrically stimulated left atrium of H₂R overexpressing mice, where histamine elicited an increase in force under potassium depolarisation (Gergs et al., 2021a). These findings support the notion that in guinea pig atria, H₂R stimulation increases the force of contraction by first opening L-type Ca ²⁺ channels, which leads to an increase in cytosolic free Ca ²⁺, thereby finally increasing force (Figures 1A,B) (Gergs et al., 2021a).

Regarding time parameters, H₁R stimulation by applying the H₁R agonist PEA in the additional presence of the H₂R antagonist cimetidine increased the time to peak tension and the relaxation time in isolated guinea pig right ventricular strips. The positive inotropic effect was more pronounced at a stimulation rate of 1 Hz than at higher stimulation rates (Mantelli et al., 1982). In contrast, the H₂R-mediated effect elicited by 4-methylhistamine led to the shortening of mechanical contraction parameters (Mantelli et al., 1982). Moreover, 4-methylhistamine was able to elicit a contraction in potassium depolarised isolated guinea pig right ventricular strips, which again suggested Ca²⁺ channel activation by H₂-histamine receptors but not by H₁-histamine receptors (Mantelli et al., 1982).

In samples of human left or right ventricular papillary muscles obtained during open heart surgery in non-failing hearts with mitral valve lesions, histamine and dimaprit (dimaprit being less potent than histamine) exerted concentration-dependent positive inotropic effects that were accompanied by a reduction in time to peak tension and time of relaxation (Eckel et al., 1982) (Tables 4, 8). Similar changes in the time parameters of contraction were later reported in transgenic mice with the cardiac overexpression of human H₂-histamine receptors (Gergs et al., 2019). These contractile effects were antagonised by cimetidine but not by propranolol, suggesting the involvement of H₂-histamine receptors (Eckel et al., 1982). Noradrenaline was more potent and effective than histamine in increasing the force of contraction (Eckel et al., 1982). These contractile data were later confirmed qualitatively by other researchers in isolated muscle strips from human ventricles (e.g., Du et al., 1993). However, in their studies, noradrenaline was shown to be as effective as histamine, a discrepancy that likely resulted from the fact that they used non-failing human hearts in their contraction study (Du et al., 1993). In spontaneously beating human right atrial pectinate preparations, histamine exerted a concentration-dependent positive chronotropic and inotropic effect (Guo et al., 1984) (Tables 4, 8, Figure 1). In the additional presence of cimetidine (or ranitidine in therapeutically relevant concentrations), increasing concentrations of histamine first decreased the force of contraction, and at higher histamine concentrations, increased the force of contraction (Guo et al., 1984). This result was interpreted as a transient negative inotropic effect because low concentrations of histamine-stimulated H₁-histamine receptors that had an innate negative inotropic effect (Guo et al., 1984 (Figure 1B). In line with that hypothesis, histamine was more potent in the presence of the H₁R antagonist pyrilamine than when only histamine was given. The inotropic effects of histamine were not due to the release of noradrenaline and the subsequent stimulation of β-adrenoceptors, because pindolol (an unselective β₁-and β₂-adrenoceptor antagonist) did not affect the contractile effects of histamine (Guo et al., 1984). The negative inotropic effect of the mixed H₁R and H₂R agonist 2-(2-thiazolyl)-ethylamine (ThEA) in the presence of cimetidine was more pronounced than the negative inotropic effect of histamine, which supported a negative inotropic effect of H₁R stimulation (Guo et al., 1984). Moreover, in spontaneously beating musculi pectinati in the human right atrium, the H₁R antagonist pyrilamine increased the concentration-dependent positive chronotropic effect of histamine (Genovese et al., 1988). This result was interpreted as evidence for a H₁R-mediated negative chronotropic effect on the beating rate of the human heart (Genovese et al., 1988) (Figure 3). This conclusion was supported by the observation that the efficacy of A₁-adenosine receptor stimulation or M₂-muscarinic receptor stimulation to reduce the positive chronotropic effect of histamine was attenuated by the addition of pyrilamine (Genovese et al., 1988). For anatomical reasons, the effects of histamine on the human sinus node, the physiological pacemaker, were not investigated in that study. Therefore, the role of H₁-histamine receptors compared with H₂-histamine receptors in the human sinus node requires in vitro research. The authors were concerned that the inotropic effects of histamine on these preparations could have been indirect because in the human atrium, an increase in beating rate (even without receptor activation) leads to an increase in the force of contraction. Hence, the authors repeated their experiments using paced right atrial muscle strips and obtained qualitatively similar results (Guo et al., 1984), which indicated the direct negative inotropic effect of H₁-histamine receptors.

When H₃-histamine receptors and H₄-histamine receptors were cloned or identified, respectively, it became possible to develop specific agonists and specific antagonists for H₃- and H₄-histamine receptors. It then became feasible to study both receptors in fine detail, which led to the reclassification of hitherto known H₁R and H₂R agonists, some of which were found to be good agonists or antagonists of H₃-histamine receptors and H₄-histamine receptors (Panula et al., 2015). Hence, some older studies in the literature may require new interpretations concerning histamine receptor specificity. Here, we address a controversy regarding the positive inotropic effects (Sanders et al., 1996) and negative inotropic effects (Guo et al., 1984) of histamine, which were observed in isolated right atrial or left atrial preparations of the human heart obtained during cardiac surgery. The contrasting findings from the two well-regarded groups are difficult to reconcile. The fact that in both studies, human atrial samples were obtained during surgery makes it difficult to identify the physiological functions of histamine in the atrium in healthy subjects. At least two publications reported a H₁R-mediated effect in the human atrium: Guo et al. (1984) and Genovese et al. (1988). These effects might have resulted from the inhibition of the activity of cardiac adenylyl cyclase. Our laboratories have recently generated a transgenic mouse with the heart-specific overexpression of human H₁R, which should help us to see here more clearly what the role of H₁R in cardiac myocytes is. The positive inotropic effect of H₁R stimulation on the human heart (Figure 1B, Sanders et al., 1996) was tentatively explained as follows: H₁-histamine receptors residing in non-muscle cells or muscle cells generated NO, which was diffused in the cell or neighbouring cells, where it stimulated soluble guanylate cyclase, generating cGMP (which they measured as increased). This cGMP inhibited phosphodiesterase III, and thus cAMP levels increased, generating more force (Figure 1B) (Sanders et al., 1996). Other researchers argued that the positive inotropic effect, such as in rabbit heart and potentially in human heart, of H₁R stimulation might be due to the coupling to phospholipase C (PLC) and the generation of IP₃, which then binds to IP₃-receptors in the sarcoplasmic reticulum (SR). Subsequently, cytosolic Ca²⁺ increases, and thus force increases, which Sakuma et al. (1988) showed in rabbit atrium (Figures 1A,B). Other researchers claimed that not PLC but tyrosine phosphorylation is involved. Thus, the activation of tyrosine kinases or the inhibition of tyrosine phosphatases should be involved (Akaishi et al., 2000).

However, convincing data have shown that histamine exerts a positive inotropic effect in human right and left atrial preparations obtained from prospective organ donors (Ginsburg et al., 1980; Kaliner et al., 1981). However, the possible involvement of H₁-histamine receptors has not been extensively examined. Even non-failing donor hearts underwent drug treatment before and during cardiac explantation surgery, which might have altered the cardiac effects of histamine to some extent and might have contributed to conflicting contractile data on the role of H₁-histamine receptors. For instance, data have shown that PDE inhibitors used to treat asthmatics or heart failure patients in desperate need potentiated the contractile function of H₂R stimulation (Pöch and Kukovetz 1967; Neumann et al., 2021c). It cannot be excluded that such drugs have been taken by some patients. Therefore, data on healthy volunteers subjected to invasive cardiac catheterisation are of special value. Moreover, currently they are probably the best proof that histamine exerts stimulatory contractile effects on healthy human cardiac ventricles in vivo (Vigorito et al., 1983; 1986a; 1986b).

How does the efficacy of histamine compare with other inotropic interventions? In other words, how relevant is histamine in the human heart? These questions are relevant because histamine is of equal potency but of double efficacy compared with serotonin (acting via 5-HT₄ receptors). Histamine also has 75% of the efficacy of maximum β-adrenergic stimulation (Zerkowski et al., 1993). In the human ventricle, histamine might be less important than in the human atrium because the maximum positive inotropic effect of histamine (i.e., its efficacy) is only half of that in the human atrium (Zerkowski et al., 1993). This finding is in contrast to earlier research on human cardiac explants, which showed that the positive inotropic effect of histamine on the left ventricle and right atrium were superimposable (Ginsburg et al., 1980). These differences might have been due to unreported differences in clinical data on patients, such as time from operating theatre to laboratory, slight differences in the preparation of buffer composition, age and gender, or drug therapy. Moreover, in the human atrium, some effects of histamine were propranolol-sensitive and thus probably due to a release of noradrenaline from cardiac storage sites (Ginsburg et al., 1980). The finding that at high single doses, histamine might release cardiac noradrenaline and thence indirectly increase force is not without precedence (Table 4). Thus, in the next section, we return to the animal model.

Figures 3–5 are referred to in Roles of Histamine and Histamine Receptors in Cardiac Disease.

Currently, the involvement of histamine and its receptors in the genesis, maintenance and prevention of chronic heart failure is insufficiently understood. The following sections give an overview of the possible implications of histamine and histamine receptors for different kinds of heart failure in animal models and in humans. To illustrate, Figures 3, 5 show potentially involved signalling pathways.

Over decades of research, there has been consensus that in septic shock, histamine levels in plasma increase. An example is a hundred-fold increase in the plasma of rabbits, as reported in a review by Matsuda et al. (2002). In a rat model of septic shock, the mortality of the animals was lowered by administering both H₁R and H₂R antagonists (Brackett et al., 1985). In HDC KO mice, the injection of lipopolysaccharide (LPS), a model of sepsis, in living mice led to lower increases in IL-6 in serum or liver (heart was not reported) than in WT (Horvath et al., 2002). In septic mice subjected to LPS treatment to induce sepsis, the prior application of a drug (amodaiquine) that inhibits the activity of histamine-methyl transferase (an enzyme that inactivates histamine), increased tissue levels of histamine in the liver, and reduced sepsis-induced mortality in mice, which was explained, in part, by the measured reduction in the tumour necrosis factor alpha (Yokoyama et al., 2007). In a rabbit model of sepsis, sepsis-induced tachycardia was blunted by a H₂R antagonist (Matsuda et al., 2002). Sepsis increased mRNA levels of H₂- and H₁- histamine receptors in the atrium and ventricle of septic rabbits (Matsuda et al., 2002). If lipopolysaccharides were used to induce sepsis in mice, the role of histamine and H₂-histamine receptors was corroborated. In H₂R KO mice and HDC KO mice, sepsis was more lethal than in WT mice (Yokoyama et al., 2004). The beneficial effects of H₂R stimulation have been explained by the fact that in H₂R null mice, LPS injection in the animals led to higher levels of cytokines and histologically confirmed liver damage. However, the heart was not examined (Masaki et al., 2005). In isolated human monocytes, LPS increased the expression of adhesion molecules, which was mediated by H₂-histamine receptors (Morichika et al., 2003). This result led to the suggestion that sepsis therapy could be improved by the application of H₂R antagonists (Takahashi et al., 2004). Similarly, mice with cardiac overexpression of H₂R were more susceptible to the detrimental effect of LPS in the left ventricular ejection fraction compared with littermate WT control mice (Gergs et al., 2020).

The data on this relationship are limited; hence, further research is warranted. The H₂R-induced relaxation of isolated aortic strips using dimaprit as an agonist was greatly attenuated in mature rabbits (6–7 months of age) compared to young rabbits (6 weeks of age) (Holl and Mokler 1982). A contrasting finding was reported in strips isolated from coronary arteries in dogs. In older beagle dogs (2 years and 12 years), H₂R-induced relaxation was more potent and effective than in young beagle dogs (80–110 days of age) (Toda et al., 1987). Neonatal and adult animal models are discussed in Age-Dependent Histamine Effects.

In human subjects aged from 20 to 81 years, the vasodilatory effects of histamine via H₂-histamine receptors diminished with increasing age, while the vasodilatory effects of H₁-histamine receptors did not change during aging (Bedarida et al., 1995). In this study, the effects of the intravenous infusion of histamine (2–136 ng histamine/min in the absence or presence of 49 μg/min of the H₂R antagonist cimetidine or 530 ng/min of the H₁R antagonist brompheniramine on the diameter of the dorsal hand veins) were studied (Bedarida et al., 1995).

In healthy male subjects undergoing exercise by cycling, an increase in plasma histamine levels was observed (Doh et al., 2016). After a longer duration (more than 15 min) of skeletal muscle exercise, both H₁- and H₂-histamine receptors mediated post-exercise hyperaemia (Doh et al., 2016). Post-exercise systemic vascular pressure was reduced in both men and women, and these reductions were attenuated when 300 mg ranitidine (Table 2) per os or a combination of 540 mg fexofenadine and 300 mg ranitidine per os were administered (McCord et al., 2006a; McCord and Halliwill, 2006b). The beneficial effects of H₁R and H₂R antagonism were accompanied by and conceivably mediated by an increase in skeletal muscle perfusion in humans (Van der Stede et al., 2021). In patients with high normal hypertension (systolic blood pressure 120–139 mmHg in males aged 20–27 years), the effects of the blockade of H₁- and H₂-histamine receptors on post-exercise hemodynamics were lower than in normotensive subjects (Naylor et al., 2020). These results suggested that under pathological conditions (higher blood pressure), the vasodilatory effects of H₁-histamine receptors on endothelial cells and of H₂-histamine receptors on smooth muscle cells in the vessels of the skeletal musculature might be blunted (Naylor et al., 2020). Another interpretation of these data might be that hypertension is in part due to the functional impairment of H₂- and H₁-histamine receptors.

From a mechanistic point of view, a real (not only virtual) crystal structure of human H₂R at a good spatial resolution is crucial to better understand the receptor. The next logical step is the generation of crystal structures using histamine or dimaprit. Thereafter, crystal structures with binding proteins, such as stimulatory or inhibitory GTP-binding proteins and other signal transduction proteins, would be important. The subcellular localisation of human H₂R should be studied in much more detail. It might not be confined to the sarcolemma, which would have functional implications that are still unknown. The improved knowledge of the regulation of the promoter of human H₂R should be another research goal. Another important step forward involves the production and characterisation of a reliable antibody for detecting human H₂R in Western blots. This antibody would enable research on diseases that alter the expression of human H₂R on the protein level, such as ischaemia, which would enable the development of a therapeutic intervention. Another step is the development of cell-type specific agonists and antagonists of human H₂R, which might be achieved by the typical synthesis of new small molecules. Alternatively, a virus that has a cell type-specific promoter could be developed to code receptors. Novel cell type-specific agonists might make it possible, for example, to increase the force of contraction without acting on the sinus node. In other words, a positive inotropic effect that did not require high oxygen expenditure by simultaneously increasing the beating rate might be achieved by these novel compounds. Conversely, using smooth muscle specific H₂R agonists, blood pressure could be reduced without increasing the force of contraction. An open question remains regarding the role of histamine in arrhythmogenesis in humans. Finally, although they would be expensive, clinical trials conducted to test the usefulness of H₂R therapy in treating various forms of congestive heart failure would contribute to not only the literature but also the efficacious treatment of patients with this disease.