Abstract
Background: Hypoxia represents both an outcome of cardiopulmonary diseases and a trigger for severe pulmonary complications as pulmonary hypertension. Because nitric oxide (NO) is a critical mediator in the development of pulmonary hypertension, the modulators of its downstream function may become target of pharmacological interventions aimed at alleviating the impact of this condition. Here, we investigate the effects of an early administration of phosphodiesterase-5 inhibitor in rats where pulmonary artery hypertension was induced by chronic exposure to hypoxia.Methods: Rats were divided into three groups: normoxic control, hypoxic with no treatments (2 weeks breathing an atmosphere containing 10% oxygen), and hypoxic treated with sildenafil (1.4 mg/Kg per day in 0.3 mL i.p.). After sacrifice, hearts and lungs were removed and harvested for analyses.Results: Sildenafil reduced hypoxia-induced right ventricle hypertrophy without effects in lung hypertrophy, and blunted the increase in right ventricle pressure without effects on left ventricle pressure. Furthermore, the NO-producing systems (i.e., the phosphorylation of the endothelial isoforms of NO synthase that was measured in both myocardial and lung tissues), and the blood NO stores (i.e., the plasma level of nitrates and nitrites) were up-regulated by sildenafil. We did not find significant effects of sildenafil on weight and hemoglobin concentration. Morphological analysis in lung biopsies revealed that 2-week hypoxia increased the frequency of small pulmonary vessels leaving large vessels unaffected. Finally, ultrastructural analysis showed that sildenafil down-regulated the hypoxia-induced increase in the thickness of the pulmonary basal lamina.Conclusions: In this model of pulmonary hypertension, sildenafil contrasts the negative effects of hypoxia on pulmonary vascular and right ventricle remodeling. This action does not only encompass the canonical vasomodulatory effect, but involves several biochemical pathways. Although the human pathological model is certainly more complex than that described here (for example, the inflammatory issue), the potential role of phosphodiesterase-5 for long-term treatment, and perhaps prevention, of pulmonary hypertension is worthy of investigation.
Highlights
Pulmonary hypertension (PH), a devastating complication of several cardiopulmonary diseases such as chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD), arises from the progressive narrowing or destruction of the arteries that carry blood from the heart to the lungs
The raise in pulmonary arteries pressure strains the right ventricle (RV) causing hypertrophy and eventually leading to right heart failure. This pathobiology is complicated by hypoxia, which is at the same time an outcome of pulmonary diseases and an established trigger for PH as it was reported, for example, in rats breathing 10% O2 for 2 weeks, which develop marked signs of RV hypertrophy (Milano et al, 2011)
nitric oxide (NO) is believed to modulate the vascular function through stimulation of smooth muscle cell soluble guanylate cyclase that catalyzes the conversion of guanosine triphosphate into cyclic guanosine monophosphate, which lowers cytoplasmic Ca2+ and mediates smooth muscle cell relaxation
Summary
Pulmonary hypertension (PH), a devastating complication of several cardiopulmonary diseases such as chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD), arises from the progressive narrowing or destruction of the arteries that carry blood from the heart to the lungs. The raise in pulmonary arteries pressure strains the right ventricle (RV) causing hypertrophy and eventually leading to right heart failure This pathobiology is complicated by hypoxia, which is at the same time an outcome of pulmonary diseases and an established trigger for PH as it was reported, for example, in rats breathing 10% O2 for 2 weeks, which develop marked signs of RV hypertrophy (Milano et al, 2011). NO is believed to modulate the vascular function through stimulation of smooth muscle cell soluble guanylate cyclase that catalyzes the conversion of guanosine triphosphate into cyclic guanosine monophosphate (cGMP), which lowers cytoplasmic Ca2+ and mediates smooth muscle cell relaxation This effect can be made more persistent and intense by selective inhibitors of phosphodiesterase type 5 (PDE5), an enzyme that degrades cGMP into inactive 5′GMP. We investigate the effects of an early administration of phosphodiesterase-5 inhibitor in rats where pulmonary artery hypertension was induced by chronic exposure to hypoxia
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