The major advantage of the use of animal models is that they allow single components of the disease to be evaluated, accurately controlling the triggering events in terms of both severity and duration, and providing homogeneous populations (Lévy et al., 2012). These models also provide an excellent opportunity to explore the underlying mechanistic pathways of HT related to OSA and their consequences under controlled conditions. Moreover, animal models have enabled the study of parameters that have proved difficult to assess in humans, particularly due to the need for organ harvesting to explore the mechanisms underlying the consequences of IH at the molecular level (Dematteis et al., 2009). Thus, studies with animal models are good tools for overcoming some confounding factors present in human studies (e.g., the presence of comorbidities, disease duration, and behavioral and environmental variables) (Badran et al., 2014), and for providing more specific information concerning the efficacy of drugs to be tested.

In 2009, Dematteis et al. used the terminology homologous (sharing the cause or pathophysiology of the human disease), predictive (responding to treatment similarly to the human disease) and isomorphic (displaying symptoms similar to those of the human disease although their cause and pathophysiology may differ) to categorize sleep apnea models (Dematteis et al., 2009). According to these categories, most sleep apnea models are only partially isomorphic, focusing on a specific aspect of the human disease. As a matter of fact, none of the currently available animal models reproduce all aspects of human sleep apnea and they present some important limitations. Nonetheless, the animal models of sleep apnea have brought out most of the available knowledge in this field and furthermore, almost all cardiovascular diseases known to be present in patients with OSA have been replicated in these models (Dumitrascu et al., 2013).

The effective use of animals to study sleep apnea implies recognition of the natural similarities and differences between animals and humans to ensure the reliability of the experimental results. For instance, as rodents are nocturnal animals, the stimulus must be applied during the sleep-dominant phase of the diurnal cycle. Moreover, in humans the circadian distribution of sleep tends to be consolidated and normally monophasic, with a daily sleep duration of 7–8 h, whereas it is polyphasic, relatively fragmented and with a duration of 12–15 h in rodents (Toth and Bhargava, 2013). Another issue is related to the fact that rodents sleep in the prone position (Golbidi et al., 2012); it is well known that supine OSA is the dominant phenotype of OSA syndrome and that the supine position favors upper airway collapse in humans (Joosten et al., 2014). Furthermore, additional care must be taken to minimize external factors (e.g., light exposure, photoperiod, noise, disruptions in the home environment, and post-surgical care in studies, for instance requiring implantation of telemetric devices) able to influence sleep in animals used in experimental research (reviewed in Toth and Bhargava, 2013).

The experimental animal models developed to mimic OSA have recently been reviewed (Dematteis et al., 2009; Golbidi et al., 2012; Davis and O'Donnell, 2013; Toth and Bhargava, 2013) and assembled taking into account the main injuries triggered by OSA. Despite attempts to use large animals (e.g., dogs, lambs, and pigs) to simulate upper airway obstruction, most research on the cardiovascular consequences of OSA has been performed in rodents. Alternative models (e.g., cell cultures incubated in specific devices that perform oxygen fluctuations mimicking sleep apnea-related IH), mainly relevant to signaling investigation (Kumar et al., 2003; Gozal et al., 2005; Ryan et al., 2005), represent a complementary approach to the most widely used sleep models. However, in spite of the recommendations to refine, reduce and replace (the 3Rs programme), these alternative models cannot replace animal models in the study of HT.

The natural models of sleep apnea include the English bulldog, the historic natural model of spontaneous obstruction (Hendricks et al., 1987), the sleep-related central apnea models [e.g., Sprague-Dawley rats (Carley et al., 2000), spontaneously hypertensive (SH) rats (Carley et al., 1998), C57BL/6J (Julien et al., 2003; Liu et al., 2010)], and the Zucker obese rat in which apnea is obesity-related (Ray et al., 2007; Lee et al., 2008; Iwasaki et al., 2012). The experimentally-induced models (e.g., the sleep deprivation model, induced airway obstruction and the CIH model) are the most widely used. Due to model limitations and lack of extensive study, we only briefly describe the induced airway obstruction model and the sleep deprivation model. Special focus will be given to the CIH model, based on the assumption that IH is the most effective paradigm to induce HT related to OSA and probably the most relevant stimulus regarding the cardiovascular sequelae of OSA.

The variety of models of IH in healthy human subjects is much less impressive than that observed for animal models of sleep apnea. In terms of the exposure time, these models are usually divided into short-term and chronic (Foster et al., 2007). In short-term IH models, generally the exposure time (20–60 min) and the duration of the hypoxia or voluntary apnea period (30 s) are very limited. The protocols of Cutler et al. and Tamisier et al. are good examples of short-term models (Cutler et al., 2004; Tamisier et al., 2009). In contrast, Foster et al. made use of a chronic model, exposing healthy human volunteers to an hour of IH (5 min hypoxia alternating with 5 min normoxia) daily for 2 weeks (Foster et al., 2005). As in the animal models of IH, only some studies have controlled the level of CO₂ (Foster et al., 2005), whereas others have not (Tamisier et al., 2009). Regardless of the protocol followed, exposing humans to CIH implies careful supervision.

In 2001, Xie et al. exposed nine healthy human subjects during wakefulness to 20 min of isocapnic hypoxia (arterial O₂ saturation, 77–87%) and 20 min of normoxic hypercapnia (end-tidal PCO₂, 15.3–8.6 Torr above eupnea) on two separate days. The subjects breathed through a leak-free nasal mask and the neurocirculatory and ventilatory responses to these two stimuli were further evaluated (Xie et al., 2001). These authors found that hypoxia induced a sympathetic activation that outlasted the chemical stimulus, whereas hypercapnia evoked a short-lived sympathetic activation (Xie et al., 2001). Years later, in a study performed with a larger sample (n = 31), Cutler et al. used a model of IH induced by voluntary apnea (30 s of hypoxic apnea every 1 min—simulating an AHI of 60/h—for 20 min) to determine if the cessation of breathing is important in prolonged sympathetic activation (Cutler et al., 2004). This study also included two other groups that were exposed to intermittent hypercapnic hypoxia and to intermittent isocapnic/hypoxia, respectively (Cutler et al., 2004). Their results support the hypothesis that short-term exposure to intermittent hypoxic apnea results in sustained elevation of post-ganglionic muscle sympathetic nerve activity and that hypoxia is the primary mediator of this response (Cutler et al., 2004). The data reported by Leuenberger et al. one year later were in line with these results (Leuenberger et al., 2005). They also found, in a study that enrolled 26 patients, a sustained sympathetic activation and also a transient elevation of BP following 30 min of voluntary end-expiratory apneas primed with a hypoxic gas mixture and lasting for 20 s in each minute (Leuenberger et al., 2005).

Foster et al. carried out three main studies in healthy human volunteers. The first aimed to determine the ventilatory, cardiovascular and cerebral tissue oxygen response to two protocols of IH (Foster et al., 2005). This study involved 18 patients randomly assigned to short-duration IH (1 h of 12% O₂ separated by 5 min of normoxia) or long-duration IH (30 min of 12% O₂). Both groups had 10 exposures over 12 days. Their findings show a rise in mean arterial blood pressure (MAP) that occurs throughout the daily exposure to short-duration IH but not during exposure to long-duration IH; moreover, they demonstrate that the vascular processes required to control blood flow and O₂ supply to cerebral tissue in a healthy human are delayed following exposure to 12 days of isocapnic IH (Foster et al., 2005). In 2009, the same group reinforced the enrollment of IH on the pathogenesis of cardiovascular and cerebrovascular disease in patients with OSA (Foster et al., 2009). They exposed 10 healthy subjects to IH (2 min of hypoxia: nadir P_ET,O2 = 45.0 mmHg, alternating with 2 min of normoxia: peak P_ET,O2 = 88.0 mmHg for 6 h) for 4 consecutive days and concluded that IH alters BP (MAP increased by 4 mmHg) and induces an increase in cerebral vascular resistance (Foster et al., 2009). More recently, Foster et al. have assessed the role of the type I angiotensin II receptor in mediating an increase in arterial pressure associated with a single 6-h IH exposure (Foster et al., 2010). For that, they exposed nine healthy subjects to sham IH, IH with placebo medication, and IH with the type I angiotensin II receptor antagonist (losartan). Their findings demonstrate a significant increase in arterial pressure after exposure to isocapnic IH (Foster et al., 2010). Furthermore, since this increase is prevented by the blockade of AT₁ receptors, these results suggest an important role for the rennin-angiotensin-aldosterone system (RAAS) in the pathophysiology of HT related to OSA (Foster et al., 2010).

Tamisier et al. have developed a novel model of nocturnal CIH in healthy humans, which represents an important step forward in the field, designed to overcome some of drawbacks and confounding factors that are present in studies of both animals and OSA patients (Tamisier et al., 2009). To investigate the effects of CIH on sleep, BP and ventilatory control, these authors make use of altitude tents to mimic the cyclical arterial oxygen desaturations-resaturations of sleep apnea. They delivered O₂ for 15 s every 2 min during sleep while subjects breathed 13% O₂ in a hypoxic tent to create 30 cycles/h of cyclic desaturation-reoxygenation (SpO₂ range: 95–85%), and exposed subjects overnight for 8–9 h/day for 2 or 4 weeks (Tamisier et al., 2009). Among other results, they show that waking normoxic arterial pressure increased significantly at 2 weeks for systolic and for diastolic at 4 weeks, that patients developed a sustained BP increase during the day and exhibited a steeper BP decrease at night compared to baseline BP values, and finally, that this model produces clinically relevant fluctuations in SaO₂ (Tamisier et al., 2009). Although undoubtedly relevant, the authors recognize the presence of several respects in which their model does not mimic sleep apnea, e.g., no negative intrathoracic pressure development, higher percentage of sleep time at <90% SaO₂ and poikilocapnia (Tamisier et al., 2009). However, some of these limitations can be overcome to achieve a pattern of IH more akin to OSA features. This model was further used by the same group in 2011 to shed light on the profile of the BP increase previously described to determine if it is sustained and to explore potential underlying physiological mechanisms. The authors found that only 2 weeks of severe IH exposure produces a sustained daytime BP increase in the setting of sympathetic activation and blunted vascular sympathic baroreflex gain in healthy volunteers (Tamisier et al., 2011).

In conclusion, to date, only a small number of studies have been conducted using healthy human models of IH and these have primarily been aimed at elucidating the role of IH in sustained sympathetic activation and cerebrovascular regulation. Only a few studies have evaluated BP outcomes (Foster et al., 2009, 2010; Tamisier et al., 2009, 2011) and none of these models have truly been used to assess the efficacy of AHDs in the treatment of HT related to OSA. In fact, in the later work of Foster et al., losartan (the angiotensin II AT₁ receptor antagonist) was used only to demonstrate a mechanistic pathway rather than to evaluate its efficacy (Foster et al., 2010). Thus, future research in this field is clearly needed.

Despite the considerable number of studies involving OSA patients, only a few have investigated the efficacy of different AHDs and in general, they tend to be individual drug studies. Moreover, most of the studies only take into account the number of drugs taken by patients to adjust this variable and are difficult to interpret as most of the patients were already under AHDs regimens. This lack of information could be attributed to the large number of possible different AHDs regimens observed in OSA patients. Table 3 summarizes the most relevant studies that have investigated the efficacy of AHDs in OSA patients.

In a study undertaken by Pelttari et al., the AH effects of four different AHDs (atenolol: a beta-blocker; isradipine: a calcium channel blocker; hydrochlorothiazide: a diuretic; spirapril: an angiotension-converting enzyme inhibitor) in obese patients with OSA and HT were compared using ambulatory blood pressure monitoring (ABPM) (Pelttari et al., 1998). This study revealed that although daytime HT was quite easily controlled by the single use of these drugs (especially with atenolol and isradipine; diuretics did not significantly lower BP) none of the AHDs were able to produce a significant decrease in nocturnal BP (Pelttari et al., 1998). Mayer et al. carried out another comparative study between cilazapril (an angiotension-converting enzyme inhibitor) and metoprolol (a beta-blocker) (Mayer et al., 1990). Their findings showed that despite the short period of therapy (1 week), both metoprolol and cilazapril lowered nighttime BP in OSA patients (Mayer et al., 1990).

A multiple crossover study examined the BP-lowering effect of the five major AHDs classes (atenolol: beta-blocker; amlodipine: calcium channel blocker; enalapril: angiotension-converting enzyme inhibitor; hydrochlorothiazide: diuretic; losartan: angiotensin receptor blocker) and showed that atenolol induced the most pronounced effect in lowering BP (Kraiczi et al., 2000). Atenolol was more efficient in reducing mean nighttime diastolic and systolic BP (measured by ABPM) compared to amlodipine, enalapril, hydrochlorothiazide, and losartan (Kraiczi et al., 2000). Salo et al. investigated the effects of four AHDs (atenolol; isradipine: a calcium channel blocker; hydrochlorothiazide; spirapril: an angiotension-converting enzyme inhibitor) on cardiovascular autonomic control and reactivity in HT OSA patients (Salo et al., 1999). This group reported that of the four drugs, only atenolol effected BP variability (Salo et al., 1999). Thus, the results of these two pilot studies are in line with those arguing the involvement of the sympathetic system in the pathophysiology of HT related to OSA, suggesting that beta-blockers, in particular atenolol, may have beneficial effects beyond BP reduction in patients with OSA. However, both studies presented low levels of causation, which could have limited the ability to detect differences between classes.

Nevertheless, it has been advanced that angiotension-converting enzyme inhibitors (ACEi) treatment could exacerbate OSA by inducing upper airway inflammation (Cicolin et al., 2006). The comparison between chronic treatments of ACEi and angiotensin AT1 receptor antagonists in terms of AH efficacy and levels of inflammatory markers has never been performed either in humans with OSA or in animal models. More recently, other study compared the effect of doxazosin (an α1- adrenergic receptor antagonist) and enalapril (an angiotensin-converting enzyme inhibitor) on nocturnal BP control and concluded that the former has a proportionally poorer effect than the latter (Zou et al., 2010). In 1994, Grote et al. performed a study aimed at assessing the effectiveness of cilazapril (an angiotension-converting enzyme inhibitor) in managing high BP in patients with OSA. Although the study comprised a small sample size, the results suggested that cilazapril is effective in reducing BP in all sleep stages (Grote et al., 1994). In another small study, Heitmann et al. evaluated the effect of nebivolol (a third generation beta-blocker) on BP reduction and sleep apnea activity in HT patients with mild to moderate OSA in comparison with valsartan (an angiotensin receptor blocker) and concluded that the effect of these AHDs were similar (Heitmann et al., 2010). Despite the same limitations, these studies highlight the role of the renin-angiotensin-aldosterone system (RAAS) in the pathophysiology of HT related to OSA.

In two past studies (Lozano et al., 2010; Litvin et al., 2013), patients either received CPAP in combination with AHDs or alternatively, the pharmacological treatment alone, allowing the evaluation of the effects of CPAP and AHDs independently or in conjunction. In the study undertaken by Lozano et al., patients were under an AHDs regimen with at least three drugs at adequate doses, including a diuretic (Lozano et al., 2010). The authors noted a significant decrease in the mean 24-h diastolic BP in patients who received CPAP in addition to conventional treatment, suggesting that resistant HT treated with both CPAP and AHDs provides greater BP reduction than AHDs alone (Lozano et al., 2010). However, in patients who used CPAP less than the average (5.6 ± 1.52 h/night) and for those treated with conventional treatment alone, there was no significant difference in the 24-h ambulatory BP values (Lozano et al., 2010). These findings are in line with those reported by Litvin et al., attained with patients who received stepped dose titration of AHDs treatment (valsartan 160 mg + amlodipine 5–10 mg + hydrochlorothiazide 25 mg) for 3 months before CPAP was added (Litvin et al., 2013). These findings seem to suggest that the best strategy to treat HT related to OSA involves the combination of OSA treatment with CPAP and the use of AHDs. This combination is likely to be more effective in lowering both daytime and nighttime BP than either treatment alone (Phillips and O'Driscoll, 2013). In addition, Pépin et al. explored RAAS inhibition using losartan in a crossover randomized control trial. In this study, the authors compared the efficacy of CPAP and valsartan in reducing BP in HT patients with OSA never treated for either condition (Pépin et al., 2009). They reported that although the BP decrease was significant with CPAP treatment, valsartan induced a four-fold higher decrease in mean 24-h BP than CPAP in this specific sample (Pépin et al., 2009).

In an earlier report, 74 of the 393 OSA patients using AH medications on a regular basis for more than 6 months were deemed to have been treated “ineffectively” (Lavie and Hoffstein, 2001), but the characterization of these medications was not reported. The same limitation is found in the study of Deleanu et al., which aimed to study the effect of medication-controlled HT on OSA patients (Deleanu et al., 2014). The authors suggested that controlled BP abates sleepiness and reduces remaining symptoms (e.g., headaches, impotence and morning fatigue). These findings could be much more interesting if the regimens responsible for these effects were revealed.

In a very recent study, Kario et al. aimed to evaluate the effects of bedtime dosing of vasodilating (nifedipine, a calcium channel blocker) vs. sympatholytic (carvedilol, a non-selective β-blocker/α₁-blocker) AH agents on the sleep BP profile in HT OSA patients (Kario et al., 2014). For this, they made use of a new BP monitoring method, the trigger sleep BP monitoring (TSP) method, which is based on the automated fixed-interval measurement function with an additional oxygen-triggered function that initiates BP measurement when oxygen desaturation falls below a set variable threshold continuously monitored by pulseoximetry (Kario et al., 2014). The BP lowering effects of nifedipine on the mean and minimum sleep systolic BP were stronger than those of carvedilol; moreover, sleep systolic BP surge (the difference between the hypoxia peak systolic BP—SBP—measured by the oxygen-triggered function and SBP within 30 min before and after the peak SBP) was only significantly reduced by carvedilol (Kario et al., 2014). Thus, both drugs are effective in decreasing sleep BP (Kario et al., 2014) but the effect of carvedilol seems to be related more specifically to the hypoxia stimuli than nifedipine.

Finally, Cichelero et al. recently published the protocol of their randomized double-blind clinical trial, which seeks to compare the efficacy of chlorthalidone (a diuretic) with amiloride (also a diuretic) vs. amlodipine (a calcium channel blocker) as a first drug option in patients older than 40 years of age with stage I HT and moderate OSA (Cichelero et al., 2014). The findings of this study have not yet been reported.

In summary, individual drug studies find that the blockade of β1-adrenergic receptors (e.g., atenolol and nebivolol) and the renin-angiotensin-aldosterone (RAA) pathway, including both ACEi and angiotensin AT1 receptor antagonists, might be helpful. Spironolactone (a mineralocorticoid receptor antagonist) has been proposed has a very useful tool in cases of resistant HT (Ziegler et al., 2011a,b), a very prevalent condition in OSA patients (Oliveras and Schmieder, 2013; Solini and Ruilope, 2013) in which aldosterone levels are generally elevated, as well as for severe OSA patients (Ziegler et al., 2011a). Moreover, a study performed by Gaddam et al. (2010) has provided preliminary evidence that treatment with this drug substantially reduces the severity of OSA and improves BP in patients with both OSA and resistant HT (Gaddam et al., 2010). These results seem promising but need to be confirmed in further larger studies. In contrast, despite volume overload appears to play a large role in the development of OSA (Owen and Reisin, 2013), diuretics, namely thiazide, have not been very effective AH agents in OSA patients without fluid retention (Ziegler et al., 2011b). Calcium channel blockers, although effective in lowering BP, seem to present an effect less related to hypoxia stimuli. Moreover, Nerbass et al. reported that the use of these drugs might impact negatively on sleep duration in HT patients with OSA (Nerbass et al., 2011). They reported that the use of calcium channel blockers was associated with significant reduction in total sleep time and lower sleep efficiency (Nerbass et al., 2011). Thus, their prescription can be questionable in these patients.

Despite the findings of these studies, they present some limitations and important data are missing. The major limitations comprise the following: the variability of subjects included in the studies as most of them were performed in non-AHDs naïve patients; the severity and chronicity of HT, which were not taken into account and consenquently the clinical relevance of BP reduction is questionable; the drug effectiveness in reducing nocturnal BP, which was not assessed in some studies; the confounding risk factors for HT that might be present in OSA patients (e.g., obesity) and were not properly addressed in most studies. Furthermore, we can point out several questions that are still unanswered, e.g., how many OSA patients are controlled under monotherapy with beta- blockers, angiotensin-converting enzyme inhibitors (ACEis), and angiotensin II receptor blockers (ARBs)? Beta-blockers or RAAS blockers are apparently effective, but should they be used alone or in combination? How many OSA patients remain uncontrolled despite the use of two or more AHDs? How do different AHDs behave when included in an AHDs regimen? In addition, the impact of these studies in clinical practice is unknown because epidemiological studies designed to investigate the AH medication profile in OSA patients are lacking. In addition, the more recent recommendations for the management of patients with OSA and HT are inconclusive regarding the use of AHDs and recognize the lack of strong evidence for the establishment of a first-line AHDs regimen for these patients (Parati et al., 2013). Other authors support the idea that as there is no clear evidence for prefering a specific class of AHDs, the selection should primarily be guided by the patient's cardiometabolic profile and associated comorbidities (e.g., obesity, metabolic syndrome, diabetes mellitus, and cardiovascular diseases) (Tsioufis et al., 2010). Moreover, these authors recommend that due to the lack of relevant trials focused on the use of associations of AHDs in OSA patients, the choice should rely on current HT guidelines and the adverse effects of AHDs also need to be considered (Tsioufis et al., 2010). The limited evidence base restricts the ability to make informed treatment choices. Thus, larger scale observational and clinical studies are needed to address these and possibly other limitations and bring new insights to the field.

Another problem concerning the studies carried out in humans is that HT is frequently not recognized in patients with OSA (Baguet et al., 2009), and it is important to highlight that patients with elevated BP who do not carry the diagnosis of HT may be misclassified as non-HT (Wang and Vasan, 2005). Consequently, aggressive control of BP must be warranted in OSA patients and an accurate method for BP measurement should be used in the early diagnosis of clinically suspected OSA patients. Taking into account the advantages and limitations of the several methods of BP measurement, 24-h ABPM seems to be superior to office BP measurement and home BP monitoring in diagnosing HT in patients with suspected OSA (for a review, see Parati et al., 2012).

As previously stated, a rather wide variety of animal models has been used to evaluate the cardiovascular consequences of OSA and to study the cause-effect mechanisms in OSA. As CIH causes a moderate increase in BP, drugs can be tested further to modulate this effect. However, studies aimed at investigating the AH effect of drugs on animal models are scarce. Table 4 summarizes the studies that have evaluated the effects of AHDs on BP in animal models of CIH.

In a study undertaken to clarify the role of renal sympathetic nerve activity and plasma renin activity (PRA) in the diurnal BP response to chronic IH, Fletcher et al. demonstrated that the pharmacological blockade of the RAAS with losartan prevented the rise in BP induced by CIH (Fletcher et al., 1999, 2002). Losartan and other angiotensin antagonists (A-779, an Ang-(1–7) antagonist; ZD7155, an AT1 antagonist; PD123319, an AT2 receptor antagonist) were further used by da Silva et al. (2011) to investigate the role of endogenous angiotensin peptides within the hypothalamic paraventricular nucleus (PVN) neurons to control BP in a rat model of CIH-induced HT. These authors concluded that endogenous angiotensin peptides acting in the PVN contribute to IH-induced increases in MAP observed in this rat model. In 2013, losartan was used once again to test the role of the brain RAAS in CIH HT (Knight et al., 2013). The work of this group provided evidence that brain RAAS contributes to CIH HT and that brain RAAS appears to be critical for the development and maintenance of the sustained HT during normoxia (Knight et al., 2013).

Other groups have found that the systemic administration of endothelin (ET) receptor antagonists in rodents prevents the increase in BP during CIH exposure (Kanagy et al., 2001; Allahdadi et al., 2008; Belaidi et al., 2009). The data provided by Allahdadi et al. showed that an endothelin receptor antagonist (ET_A: BQ-123) acutely decreased the MAP dose dependently in rats exposed to IH but not sham rats, suggesting that targeting ET_A receptors may be a selective and effective treatment of HT related to OSA (Allahdadi et al., 2008). Belaidi et al. used SH rats and bosentan, a mixed endothelin receptor antagonist (Belaidi et al., 2009). Their results showed that the administration of bosentan during chronic IH prevented the increase in BP and reinforced the idea that endothelin antagonists could be useful therapeutic tools in HT related to OSA (Belaidi et al., 2009). The same effects were reported by Kanagy et al. for PD145065, a non-selective endothelin receptor antagonist (Kanagy et al., 2001).

Soukhova-O'Hare et al., designed a study based on the assumption that ROS and altered L-Ca²⁺ channel activity may underlie the post-natal programing of exaggerated BP and cardiac remodeling (Soukhova-O'Hare et al., 2008). To test this hypothesis, these authors used nifedipine, an L-calcium channel blocker, and a superoxide dismutase mimetic (MnTMPyP pentachloride); both attenuated BP (Soukhova-O'Hare et al., 2008). Their results suggested that Ca²⁺ and reactive oxygen species-mediated signaling during IH are critical mechanisms underlying post-natal programing of an increased severity of HT in SH rats. Kumar et al. reported similar results for the same superoxide dismutase mimetic (Kumar et al., 2006). A year before, Troncoso Brindeiro et al. used another superoxide dismutase mimetic, tempol, and showed that scavenging superoxide prevents both the increase in ET-1 production and vascular ROS levels induced by CIH exposure (Troncoso Brindeiro et al., 2007). The later work of Del Rio et al., using the antioxidant ascorbic acid, showed that this substance prevented the increased plasma peroxidation and nitrotyrosine formation within the carotid body, as well as HT (Del Rio et al., 2010), supporting the essential role of oxidative stress in the generation of carotid body chemosensory potentiation and systemic cardiorespiratory alterations induced by IH (Del Rio et al., 2010).

More recently, Hung et al. tested the hypothesis that melatonin, previously shown to ameliorate oxidative injury and inflammation, could have a protective effect against IH-induced HT and endothelial dysfunction. This assumption was confirmed as melatonin promoted a decrease in systolic BP and prevented endothelial dysfunction with ameliorated levels of nitric oxide, endothelial-dependent relaxation, and expressions of eNOS and antioxidant enzymes (Hung et al., 2013).

Based on the studies described, we can conclude that most reports on CIH animal models in which drugs have been tested were not designed to respond to pharmacological issues: they have been used solely as pharmacological tools to address physiological mechanisms. The experiments evaluate prevention but not the effectiveness of treatment. They must be planned first to induce HT and then evaluate the efficacy of cumulative doses of drugs because the translation of the results to humans obtained with simultaneous induction of HT and drug administration is not relevant. Other limitations of the pharmacological approaches included in these works are the absence of dose-response curves and comparison of the effectiviness of different drugs in the same animal model. Thus, other studies must be designed to overcome these drawbacks.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.