Phosphodiesterase-5 Inhibition Alleviates Pulmonary Hypertension and Basal Lamina Thickening in Rats Challenged by Chronic Hypoxia
Articolo
Data di Pubblicazione:
2018
Citazione:
Phosphodiesterase-5 Inhibition Alleviates Pulmonary Hypertension and Basal Lamina Thickening in Rats
Challenged by Chronic Hypoxia / C. Nydegger, C. Martinelli, F. Di Marco, G.P. Bulfamante, L. von Segesser, P. Tozzi, M. Samaja, G. Milano. - In: FRONTIERS IN PHYSIOLOGY. - ISSN 1664-042X. - 9(2018 Mar 27), pp. 289.1-289.9.
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 0.3mL 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
Nydegger et al. PDE-5 Inhibition in Cardiopulmonary Disease
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.
Tipologia IRIS:
01 - Articolo su periodico
Elenco autori:
C. Nydegger, C. Martinelli, F. Di Marco, G.P. Bulfamante, L. von Segesser, P. Tozzi, M. Samaja, G. Milano
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