Abstract
Various animal models of pulmonary hypertension (PH) exist, among which injection of monocrotaline (MCT) and exposure to hypoxia are used most frequently. These animal models have not only been used to characterize the pathophysiology of PH and its sequelae such as right ventricular hypertrophy and failure, but also to test novel therapeutic strategies. This manuscript summarizes the available treatment studies in animal models of PH, and compares the findings to those obtained in patients with PH. The analysis shows that all approaches which have proven successful in patients, most notably prostacyclin and its analogs and endothelin receptor antagonists, are also effective in various animal models. However, the opposite it not always true. Therefore, promising results in animals have to be interpreted carefully until confirmed in clinical studies.
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Pulmonary hypertension (PH) is a serious illness, with multiple potential causes that may progressively worsen and eventually prove fatal. PH was previously classified into two categories: primary pulmonary hypertension and secondary pulmonary hypertension, depending on the absence or the presence of identifiable causes or risk factors. In 1998, during the Second World Symposium on Pulmonary Hypertension held in Evian, France, a clinical classification of PH was proposed (Fishman 2001). This scheme was modified in 2003 during the Third Symposium on Pulmonary Arterial Hypertension in Venice (Simonneau et al. 2004). The current classification consists of five categories in which PH is grouped according to specific therapeutic interventions directed at dealing with the cause: (1) pulmonary arterial hypertension (this includes idiopathic pulmonary arterial hypertension, IPAH), (2) pulmonary hypertension associated with left heart disease, (3) PH associated with lung diseases and/or hypoxemia, (4) PH due to chronic thrombotic and/or embolic disease, and (5) miscellaneous.
PH is characterized by progressive remodeling of the small pulmonary arteries, causing increased resistance to blood flow in the lung, which, in turn, can raise the pulmonary arterial pressure (PAP). As the resistance rises, the afterload on the right ventricle (RV) increases. Unrelieved PH, regardless of the underlying cause, leads to RV hypertrophy and ultimately failure. PH is difficult to diagnose and a challenge to treat.
Although the long-term prognosis for patients with PH is poor at present, there have been recent advances in our understanding of the pathophysiological mechanisms underlying the progression of PH. Accordingly, novel therapeutic approaches, which target various molecular pathways, hold promise for an improved prognosis. Most treatment studies have mainly targeted the vascular derangements (vasoconstriction, vascular remodeling) of PH. Fewer studies have addressed the RV sequelae of PH. In the following, we will briefly review the various animal models which have been used to investigate the pathophysiology of PH as well as to evaluate novel therapeutic approaches. The potential value of such models will be discussed in light of the available treatment data in humans. The most commonly used models of PH are the monocrotaline (MCT) model and the chronic hypoxia model.
Animal models
Monocrotaline injection
The MCT model was introduced more than 40 years ago (Lalich and Merkow 1961). It is based upon a single injection of MCT (typically 60 mg/kg intraperitoneally or subcutaneously) which rapidly leads to severe pulmonary vascular disease in the absence of intrinsic heart and lung disease, thus suggesting its value as an animal model of IPAH. Despite its frequent use for many decades, the basic mechanism underlying PH induction by MCT remains to be fully resolved. It is accepted that MCT is not intrinsically toxic, but must be activated to the reactive MCT pyrrole, the initial dehydrogenation product of MCT, by hepatic cytochrome P450 3A (Mattocks 1968; Segall et al. 1991; Reid et al. 1998). The pulmonary vascular endothelium is thought to be an early target of MCT intoxication, and also plays a central role in the development of human PH (Loscalzo 1992; Tuder et al. 1994). Interestingly, only the combination of MCT-injection with one-sided pneumonectomy causes the neointima formation and vascular obliteration of small pulmonary arterioles that reproduces many of the pathological features of human IPAH (Yi et al. 2000).
Major differences exist between rat strains with regard to their MCT sensitivity, and even within a given strain the inter-individual differences in time of onset and extent of toxic effects can vary markedly (Hardziyenka et al. 2006). These differences in susceptibility may relate to the pharmacokinetics of MCT, and possibly include differences in degradation and hepatic formation of the toxic MCT pyrrole or conjugation and excretion (Mattocks 1986). Thus, MCT injection is an artificial model, but mimics well the processes occurring secondary to dysfunction of the pulmonary arteries.
Chronic hypoxia
Reduction of the alveolar oxygen pressure to <70 mm Hg elicits strong pulmonary arterial vasoconstriction. Hypoxia-induced pulmonary vasoconstriction is common in mammals, but important species differences exist. Rabbits show almost no reaction to hypoxia, whereas cattle exhibit the strongest vasoconstriction; hypoxic vasoconstriction is weaker in humans than in rats (Reeve et al. 1979). There is also a great variability among humans (Naeije et al. 1982).
The pathophysiological mechanism of hypoxic pulmonary vasoconstriction is still under discussion. While a short exposure to hypoxia causes acute pulmonary vasoconstriction, prolonged hypoxia results in remodeling of the distal branches of pulmonary arteries. Experiments conducted in rats chronically exposed to hypoxia showed endothelial and myocyte hyperplasia in the walls of pulmonary arteries during the first days of continuous hypoxia (Meyrick and Read 1978, 1980; Fung and Lin 1991).
Hypoxia applied in animal experiments has been much more severe than the hypoxia that generally develops in human disease states. This could result in a different severity of vasoconstriction and remodeling. It is also possible that an episode of hypoxic pulmonary vasoconstriction in humans must last a certain time before it initiates reactions that ultimately lead to arterial-wall remodeling (Tozzi et al. 1989). Another cause of discrepancy may be related to variations in the individual susceptibility to the hypoxic stimulus (Weitzenblum and Chauat 2001). In animal models, intermittent severe hypoxia leads to the development of PH, regardless of the duration of the hypoxia/normoxia intervals. Intermittent hypoxia in humans, however, seems to exert only a small, probably clinically unimportant, effect on pulmonary hemodynamics. Thus, hypoxia is a stimulus also occurring in some forms of human PH, but the duration and severity of hypoxia may differ between the animal models and humans.
Ligation of ductus arteriosus
Persistent PH of the newborn is a clinical syndrome characterized by elevated pulmonary vascular resistance, resulting in right-to-left shunting across the foramen ovale and ductus arteriosus with severe hypoxemia (Levin et al. 1976). Chronic intrauterine PH due to ligation of the ductus arteriosus in fetal lambs mimics this condition, and causes marked elevation of intrauterine PAP, RV hypertrophy, hypertension-related structural changes in the lung, and failure to achieve the normal decline in pulmonary resistance at birth (Morin 1989; Abman et al. 1989, Belik et al. 1993). Studies of this experimental model of persistent PH of the newborn suggest that high pulmonary vascular resistance is partly due to vascular remodeling and an imbalance in production or responsiveness to vasodilator and vasoconstrictor stimuli (Murphy et al. 1981; Morin 1989; Abman et al. 1989).
Chronic embolic PH
Repeated microembolizations with Sephadex microspheres generate moderate chronic PH in dogs (Shelub et al. 1984). Based upon the size of the injected microspheres, the vascular lesions can be targeted at smaller or larger vessels. Primary vascular mechanical obstruction and vasoconstriction (Dantzker and Bower 1981) are the mechanisms of the high pulmonary vascular resistance (Shelub et al. 1984). Weimann et al. (1999) established a model of sustained PH in pigs using three repeated embolizations with polydextrane microspheres, which led to a sustained elevation in PAP. In this model, PAP was increased for at least 1 week. Models of acute pulmonary embolism using various different materials (Malik and van de Zee 1977; Bottiger et al. 1996) or autologous blood clots (Palevsky and Fishman 1990) have been used to study the pathophysiological mechanisms or drug effects within the 1st hour following the embolization.
Genetically modified animals
Genetic screening has identified a number of potentially important gene variants that may contribute to the development of PH. A heterozygous mutation of the BMPR2 gene, which encodes for the bone morphogenetic protein receptor-II, has been found in a substantial proportion of patients with IPAH (Lane et al. 2000; Deng et al. 2004), suggesting that this gene may be involved in the pathophysiology of PH. However, heterozygous BMPR2-deficient mice generally exhibit only a mild phenotype with slight increases in PAP and evidence of reduced arterial remodeling after chronic exposure to hypoxia (Beppu et al. 2000), indicating that this mouse model may not fully mimic human PH.
A role of serotonin (5-hydroxytryptamine, 5-HT) and its plasmatic membrane transporter (5-HTT) was recently reported in the pathogenesis of PH in human and experimental models. Specifically, genetically engineered mice lacking the 5-HTT exhibit attenuated hypoxia-induced PH (Eddahibi et al. 2000a,b, 2001), whereas 5-HHT overexpression can induce PH in mice (Guignabert et al. 2006).
Treatment targets in PH
Various drug classes are currently used or are under investigation for the treatment of PH, both in animal models and in patients. They include prostanoids, endothelin (ET) receptor antagonists, phosphodiesterase (PDE) 5 inhibitors, 5-HTT inhibitors, NO (for a review, see Badesch et al. 2004), other vasodilators, and statins. Among these on prostacyclin analogs, ET receptor antagonists and the PDE5 inhibitor sildenafil have internationally been registered as therapeutics for PH treatment.
Prostanoids
Prostacyclin and several of its analogs have been tested in animal models and patients with PH with good success. Their conceptual role in the treatment of PH has been confirmed using MCT-treated rats which were rescued by gene therapy with prostacyclin synthase (Nagaya et al. 2000). Repeated inhalation of iloprost also reversed both hemodynamic derangements and structural changes of the small pulmonary arteries in the MCT rat model of PH (Schermuly et al. 2005). Beraprost sodium, a stable and orally active prostacyclin congener, exhibited protective effects on the development of PH in the MCT rat model (Miyata et al. 1996). Interestingly, a combination of the PDE5 inhibitor sildenafil plus beraprost was significantly more effective than either drug alone in MCT-induced PH (Itoh et al. 2004). Recently, subcutaneous administration of the prostacyclin agonist ONO-1301 markedly attenuated PH, and improved survival in MCT-treated rats (Kataoka et al. 2005). Potential benefits of ONO-1301 as compared to prostacyclin may include its long plasma half-life, which results in long-lasting increases in plasma cAMP levels and attenuation of increases in plasma thromboxane levels. Thus, various prostacyclin receptor agonists have shown beneficial effects in the rat MCT model. Differences among the compounds may largely relate to differential pharmacokinetic properties.
In line with the consistent effective of prostacyclin and its analogs in the MCT model, such compounds have also been studied extensively in the treatment of human PH (for reviews see McLaughlin and Rich 1998; Wanstall and Jeffery 1998). The vasoprotective effects of prostacyclin include vasodilatation and inhibition of platelet aggregation and pulmonary artery smooth muscle cells (PASMC) proliferation (Rich and McLaughlin 1999). While prostacyclin can be administered intravenously or by inhalation, its pharmacokinetic properties, particularly its very short half-life, are not optimal for chronic treatment. Therefore, several prostacyclin analogs have been tested. The prostacyclin analog iloprost has vasodilatory and antithrombotic properties, and exhibits long-term beneficial effects in PH patients upon daily inhalations (Witt and Muller 1987). Inhalation of aerosolized iloprost promoted selective pulmonary vasodilatation in severe PH of both primary and secondary origin (Olschewski et al. 1996; Hoeper et al. 2000). On the other hand, the effectiveness of the prostacyclin analog beraprost sodium was limited in patients with primary and secondary PH (Saji et al. 1996; Hashida et al. 1998). Intravenous epoprostenol improves exercise capacity and survival in patients with PH (Archer and Michelakis 2006). Moreover, continuous intravenous epoprostenol treatment prior to pulmonary endarterectomy in patients with chronic thromboembolic PH produced beneficial hemodynamic and clinical effects (Bresser et al. 2004). In a direct comparative cross-over study, treprostinil had even better overall therapeutic efficacy than epoprostenol after intravenous administration in PH patients (Gomberg-Maitland et al. 2005). Of interest, according to that study treprostinil also exhibited bioequivalence, whether administered subcutaneously or intravenously, and it has a longer half-life than epoprostenol.
In conclusion, prostacyclin and its analogs have largely been tested in the MCT rat model, and the animal data—with the possible exception of beraprost—are largely in good agreement with those found in clinical studies. Therefore, the MCT rat model appears useful for studies on prostacyclin analogs. Whether beneficial long-term effects of prostanoids are due to the sustained pulmonary dilatatory effects, or whether they indicate reverse remodeling of the pulmonary vasculature, is still unclear (McLaughlin et al. 1998).
ET receptor antagonists
ET levels are elevated in PH, providing the rationale for the use of endothelin receptor antagonists (Stewart et al. 1991). BQ-123, a selective antagonist of the ETA subtype of ET receptors, was the first ET receptor antagonist to exhibit beneficial effects in animal models of PH (Miyauchi et al. 1993). BQ-123 is a peptide, and hence not orally active. It has a short duration of action, requiring continuous intravenous infusion. Medial-wall thickness and neomuscularisation were inhibited using continuous infusion of BQ-123 in a rat hypoxia model (Bonvallet et al. 1994; Di Carlo et al. 1995), the MCT rat model (Miyauchi et al. 1993), and in newborn sheep in which the ductus arteriosus was ligated (Ivy et al. 1997, 1998). It was demonstrated that inhibition of pulmonary vascular remodeling by BQ-123 is associated with concomitant reductions in PAP, but the rise in PAP was prevented completely only with the highest dose of BQ-123 (9.6 mg/day) (Di Carlo et al. 1995). Other ETA receptor antagonists, which are orally active and can be administered once daily—e.g. A 127722, LU135252, and sitaxsentan—have also been examined in various animal models of PH, where they consistently attenuated or even prevented medial thickening of pulmonary arteries (Chen et al. 1995, 1997; Prie et al. 1997; Nguyen et al. 2000; Jasmin et al. 2001; Tilton et al. 2000).
Bosentan, an antagonist of both ETA and ETB receptors, has also been examined in various animal models of PH. Similar to ETA-selective receptor antagonists, bosentan had beneficial effects on medial thickening and neomuscularisation of distal pulmonary arteries, and reduced PAP in a rat hypoxia model and rat MCT model (Chen et al. 1995; Eddahibi et al. 1995; Hill et al. 1997). In a canine model of chronic thromboembolic hypertension, treatment with bosentan not only reduced medial thickening of pulmonary arteries, but also reduced adventitial thickening and prevented intima fibrosis and peripheral neomuscularisation (Kim et al. 2000). In hypoxic models of PH, bosentan administration after PH had developed not only attenuated the remodeling of the pulmonary vessels, but actually reversed it towards values seen in normoxic animals; additionally, any further rise in PAP was either prevented or reversed (Chen et al. 1995, 1997; Tilton et al. 2000). Of note, inhibition of the remodeling in the rat MCT model required higher doses of bosentan and sitaxsentan than in the rat hypoxia model (Chen et al. 1995; Eddahibi et al. 1995; Hill et al. 1997; Tilton et al. 2000). Another mixed ETA/B antagonist, BSF420627, was effective in a hypoxia model of PH (Jasmin et al. 2001). Thus, ET receptor antagonists appear to readily inhibit remodeling associated with hypoxic exposure.The combined therapy of an oral ET receptor antagonist and the prostacyclin analogue beraprost was superior to the single use of each drug alone in PH induced by MCT injection in rats, even if started after the onset of PH (Ueno et al. 2002).
While it remains unclear whether selective ETA receptor antagonism is effective clinically, bosentan has shown therapeutic efficacy in several studies with patients with PH (for a review see Dingemanse and van Giersbergen 2004). This included significant improvement in exercise capacity, functional class, and pulmonary hemodynamics in patients with PH (Channick et al. 2001; Rubin et al. 2002). In patients with chronic thromboembolic PH, bosentan provided an alternative medical therapy to improve 6-minute walking distance, functional class, cardiac index, total pulmonary resistance, and 1-year survival (Hughes et al. 2006). Retrospective studies in children with PH (IPAH or associated with congenital heart or connective tissue diseases), suggested that bosentan, with or without concomitant prostanoid therapy, is efficacious and safe, and may improve survival (Rosenzweig et al. 2005; Maiya et al. 2006). Taken together, these data show that hypoxia-related PH models were more sensitive towards inhibition of ET receptors than other models; however, it remains unclear whether this translates into a differential sensitivity of PH patients based upon the underlying cause of their condition.
PDE5 inhibitors
The pulmonary arterial vasodilating effects of PDE5 inhibitors, which were originally developed for the management of erectile dysfunction, were discovered incidentally. Most available studies have been performed with sildenafil, but limited data with other compounds such as T-1032 (Inoue et al. 2002) suggest that the sildenafil findings may represent class effects. Chronic oral treatment of MCT-treated rats with sildenafil significantly attenuated PH despite delayed administration, i.e. commencement of treatment after PH had already developed (Schermuly et al. 2004). Sildenafil was also found to be effective in PH of newborn rats exposed to hypoxia (Ladha et al. 2005). In vitro studies suggest that this may involve beneficial effects on endothelial capillary network formation (Ladha et al. 2005), on calcium signaling in pulmonary artery smooth muscle cells from hypoxia-exposed rats—leading to a reduced vascular reactivity (Pauvert et al. 2004)—and on smooth muscle cell proliferation (Tantini et al. 2005). Moreover, sildenafil also blunted the acute hypoxia-induced vasoconstriction response in isolated lungs obtained from both wild-type mice and those genetically engineered to lack the endothelial NO synthase (Zhao et al. 2001). Interestingly, a combination of the prostanoid beraprost and sildenafil was significantly more effective than either drug alone in MCT-induced PH; plasma levels of cAMP and cGMP also increased substantially more, and remained elevated for a longer period of time, in animals treated with the combination (Itoh et al. 2004).
In humans, sildenafil can attenuate the acute pulmonary vascular response to hypoxia (Zhao et al. 2001). Hence, sildenafil was shown to be effective in treating PH in humans. This applies to high-altitude-induced transient PH in healthy volunteers (Richalet et al. 2005), as well as to patients suffering from PH (Galie et al. 2005; Wilkins et al. 2005). Moreover, sildenafil treatment of PH patients has been associated with reduction in RV mass (Wilkins et al. 2005), suggesting that PDE-5 inhibitors may have a role in the prevention or reversal of remodeling of the RV secondary to PH. Similar to the animal studies, the combination of sildenafil and beraprost has also yielded beneficial effects in PH patients (Ikeda et al. 2005). Interestingly, sildenafil has been effective in various pathophysiologically different models of PH, raising the possibility that it may be suitable for the treatment of PH patients irrespective of the underlying cause. It is also interesting to note that sildenafil exhibited its beneficial clinical effects upon once-daily dosing, despite its relatively short half-life. However, the long-term benefits of sildenafil remain to be established (Pomeranze and Bhavsar 2005).
NO and L-arginine
Within PASMCs, NO and PDE5 are part of the same signaling cascade, as inhibition of the latter potentiates effects of the former, i.e., reduced breakdown of cGMP enhances cGMP-dependent effects of NO. A possible role of NO in the management of PH has been studied using inhaled NO gas, NO donor drugs, L-arginine (the precursor of NO), and gene transfer of NO synthase. Animal and human studies have demonstrated that NO causes selective pulmonary vasodilatation, lowering PAP and pulmonary vascular resistance (Stamler et al. 1994; Das and Kumar 1995).
In animal studies, the effectiveness of NO seems to vary depending on the experimental model. In adult rats injected with MCT, inhalation of NO had no effect on remodeling (Maruyama et al. 1997; Horstman et al. 1998), but this approach was effective in newborn rats treated with MCT (Roberts et al. 2000). Treatment of both hypoxia-induced and MCT-induced PH in rats with L-arginine inhibited medial thickening and neomuscularisation, and this was associated with a reduction in PAP (Mitani et al. 1997). The beneficial effect of L-arginine in the rat MCT model was observed in studies aimed at reversing rather than preventing PH and its sequelae. Neomuscularisation was reduced, but there was no effect on medial thickening or PAP. The beneficial effect of L-arginine in the MCT model is surprising, in light of the lack of effect of NO gas in adult rats under similar conditions. A recent experimental approach for increasing NO in the pulmonary vasculature is gene transfer of NO synthase, the enzyme responsible for the production of NO from L-arginine. Using the hypoxia model in rats, the transfer by aerosol of an adenoviral vector containing the gene for inducible NO synthase was found to decrease neomuscularisation of small pulmonary arteries, and to reduce both pulmonary vascular resistance and PAP (Budts et al. 2000).
Until now, elevation of NO tone has been tested clinically only on a limited basis. In critically ill adults, NO is used as an option in the short-term management of PH, because it reduces PAP and improves oxygenation by increasing the fraction of blood flow to lung regions with a normal ventilation–perfusion ratio in acute respiratory syndrome (Rossaint et al. 1993). A possible role for NO donors or L-arginine in the chronic treatment of PH remains to be established. This also makes it difficult to compare clinical and experimental data based upon an NO approach.
Ca2+-channel blockers
In both hypoxic and MCT-treated rats, diydropyridine Ca2+-entry blockers such as nifedipine, nitrendipine and amlodipine had beneficial effects on pulmonary vascular remodeling (Takahashi et al. 1996; Jeffery and Wanstall 2001; Morel et al. 2003). Although Ca2+-entry blockers are widely used in the treatment of human PH, the clinical evidence base for such use is insufficient. As compared to other uses of this drug class, relatively high doses are needed in PH patients, possibly due to both impaired drug absorption and lower sensitivity of the pulmonary vasculature (Rich et al. 1992). It had been proposed that acute responses to such drugs may predict long-term responses, as improved survival in acute responders as compared to non-responders has been reported (Rich et al. 1992). More recent analyses, however, found that <10% of the IPAH evaluated patients exhibited long-term benefit upon Ca2+-entry blocker treatment (Sitbon et al. 2005). These authors strongly advised not to consider Ca2+-entry blockers as a routine first-line treatment for PH. While a comprehensive discussion of the benefits and risks of Ca2+-entry blockers in the treatment of PH is beyond the scope of this manuscript, these data highlight the possibility that positive data in animal models, even if shown in multiple models, do not necessarily predict clinical efficacy in PH, particularly with regard to end-points such as survival.
Statins
Based upon their anti-proliferative and anti-inflammatory cardiovascular effects in addition to cholesterol-lowering effects (Koh 2000; Kwak et al. 2000), statins have also been tested in animal models and patients with PH. Most of these studies have used simvastatin. Originally, it was reported that simvastatin was effective in the rat MCT model when administered at the time of induction of vascular injury, but had only smaller effects when given 2 weeks after the induction of PH (Nishimura et al. 2002). In a later study from the same group, using the more severe MCT/pneumonectomy rat model of fatal PH, simvastatin attenuated and reversed both PH and neointimal formation and completely abolished mortality; this was accompanied by a reversed vascular occlusion through reduced intima proliferation and increased apoptosis of pathological smooth muscle cells in pulmonary arteries (Nishimura et al. 2003). Similar results were noted in a rat model of hypoxic pulmonary hypertension (Girgis et al. 2003). A study in this issue of the journal (Guerard et al. 2006) extends findings on the use of statins in PH to pravastatin by demonstrating beneficial effects when administered at the time of PH induction by MCT. This is interesting because pravastatin differs from simvastatin and other statins due to its open lactone ring chemical structure (Hamelin and Turgeon 1998). While it is too early to determine the utility of statins in the treatment of PH, it is encouraging that simvastatin was shown to improve exercise capacity in an observational study with PH patients (Kao 2005).
5-HTT inhibitors
Perivascular inflammation, i.e., infiltration with macrophages and lymphocytes in the region of occlusive lesions, is a histopathological feature of PH (Tuder et al. 1994). It may involve endothelial dysfunction with deregulated expression of vasoactive, mitogenic and pro-inflammatory mediators (Lopes et al. 2000). These findings are the rationale to test anti-inflammatory approaches—such as immunosuppressant and cytokine antagonists—in the treatment of PH. Indeed, the immunosuppressants rapamycin and triptolide were shown to significantly reduce PAP in rats that had undergone pneumectomy and subsequent MCT injections (Faul et al. 2000; Nishimura et al. 2001). Interleukin-1 is excessively produced in the lungs of MCT-treated rats, but not in hypoxia-induced PH; accordingly, repeated injections of a recombinant interleukin-1 receptor antagonist reduced PH and RV hypertrophy in the MCT model, but not in the chronic hypoxia model (Voelkel et al. 1994). The possible implications of such findings for the treatment of PH patients are difficult to evaluate in the absence of clinical data.
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers
The effects on PH or its sequelae of drugs that prevent either the production or the action of the potent mitogen/growth factor angiotensin II have been examined in both hypoxic and MCT rat models. In chronically hypoxic rats, various ACE inhibitors have been shown to inhibit pulmonary vascular remodeling associated with the development of PH. When rats were studied for the entire hypoxic period (Zakheim et al. 1975; Van Suylen et al. 1998), medial thickening and muscularisation of the pulmonary arteries were attenuated. In one study with the ACE inhibitors cilaprazil, medial thickening of these vessels was even totally prevented (Clozel et al. 1991). The beneficial effects of ACE inhibitors were even found when treatment started 7 or 12 days after commencement of hypoxic exposure (Nong et al. 1996). On the other hand, the effects of ACE inhibitors in MCT-treated rats are not fully clear. While treatment with captopril (12 mg/kg/day for 4 weeks) had no effects on medial thickness, neomuscularisation or on PAP (Van Suylen et al. 1998), a longer treatment with a higher dose (60 mg/kg/day for 6 weeks) reduced the degree of neuromuscularisation of peripheral pulmonary arteries (Molteni et al. 1985). The role of angiotensin II in PH is further confirmed by findings with angiotensin receptor antagonists. Thus, losartan inhibited medial hypertrophy and neuromuscularisation in hypoxic rats (Zhao et al. 1996) as well as in the MCT-plus-pneumonectomy rats (Okada et al. 1998). Similarly, olmesartan medoxomil inhibited RV hypertrophy, and also inhibited increases in mRNA levels of various markers of RV dysfunction such as atrial and brain natriuretic peptides in a chronic hypoxia model of PH (Nakamoto et al. 2005). The possible implications of such findings for the treatment of PH patients are difficult to evaluate in the absence of clinical data.
Conclusion
In conclusion, a variety of therapeutic strategies have been tested in various animal models of PH, most often hypoxia- or MCT-based models. Several of these approaches were also shown to be effective in PH patients, and all clinically proven treatments also work in the animal models. However, some models may be more sensitive to certain approaches than others (e.g. the greater potency of ET receptor antagonists in hypoxia than in other models). Moreover, the clinical role of Ca2+-entry blockers remains unclear, despite their consistent beneficial effects in animal models. Therefore, promising animal data—e.g. with 5-HTT inhibitors, inhibitors of the rennin-angiotensin-system, statins or anti-inflammatory drugs—need to be interpreted with caution until confirmed in clinical studies.
Abbreviations
- ACE:
-
angiotensin converting enzyme
- ET:
-
endothelin
- IPAH:
-
idiopathic pulmonary arterial hypertension
- 5-HT:
-
(5-hydroxytryptamine); serotonin
- 5-HTT:
-
serotonin plasmatic membrane transporter
- MCT:
-
monocrotaline
- PAP:
-
pulmonary aterial pressure
- PASMCs:
-
pulmonary artery smooth muscle cells
- PDE5:
-
phosphodiesterase 5
- PH:
-
pulmonary hypertension
- RV:
-
right ventricle
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Dr. Tan was supported by the Royal Netherlands Academy of Arts and Sciences (KNAW) and the Netherlands Heart Foundation (NHS 2002B191).
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Campian, M.E., Hardziyenka, M., Michel, M.C. et al. How valid are animal models to evaluate treatments for pulmonary hypertension?. Naunyn-Schmied Arch Pharmacol 373, 391–400 (2006). https://doi.org/10.1007/s00210-006-0087-9
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DOI: https://doi.org/10.1007/s00210-006-0087-9