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Modulation of NO signaling as a target to reverse hypoxia-induced right ventricular hypertrophy and pulmonary hypertension

English title Modulation of NO signaling as a target to reverse hypoxia-induced right ventricular hypertrophy and pulmonary hypertension
Applicant Milano Giuseppina
Number 110058
Funding scheme Project funding (Div. I-III)
Research institution Service de Chirurgie Cardio-Vasculaire Département de chirurgie - CHUV
Institution of higher education University of Lausanne - LA
Main discipline Pathophysiology
Start/End 01.10.2005 - 30.09.2008
Approved amount 227'000.00
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All Disciplines (2)

Discipline
Pathophysiology
Biochemistry

Keywords (5)

L-arginine; sildenafil; chronic hypoxia; pulmonary hypertension; cardiac hypertrophy

Lay Summary (English)

Lead
Lay summary
SECOND YEAR: OCTOBER-MARCH 2007Chronic exposure to hypoxia (CH), a common adverse consequence of most pulmonary disorders, can lead to a sustained increase in pulmonary arterial pressure (PAP), right ventricular hypertrophy and is, therefore, closely associated with heart failure and increased mortality. We recently have demonstrated that Sildenafil treatment during CH reduces cardiac hypertrophy and right systolic ventricular pressure, presumably via increased phosphorylation of eNOS, irrespectively of 2 and 4-weeks of exposure to hypoxia. The purpose of this study was to test the effects of Sildenafil (Viagra®) on pulmonary hypertrophy after 2 and 4 weeks of exposure to CH. In additional, although several studies have showed that Sildenafil induces preconditioning-like protective effects against ischemia/reperfusion (I/R) injury in different animal models and it attenuates necrosis as well as apoptosis in adult cardiomyocytes subjected to simulated ischemia/reoxygenation, the effects in chronic hypoxia are less defined. Therefore we hypothesized that a similar protection against I/R would be possible if PDE-5 inhibitor (Sildenafil) was administered during exposure to chronic hypoxia. Male 5-week old Sprague-Dawley rats were placed in hypoxic chambers and were randomly divided into following groups: Normoxia (N), chronic hypoxia (CH) and CH treated Sildenafil (CH+S). Hypoxia (10% O2) was maintained for 2-4 weeks. Normoxic rats breathing room air in the same chambers used for hypoxia served as control. Sildenafil was given daily to N+S and CH+S rats (1.4 mg/kg, i.p.). For the first time, we demonstrate that treatment with Sildenafil result in cardioprotection from exposure to chronic hypoxia. More specifically, our data illustrate the capacity of Sildenafil in attenuation of myocardial apoptosis and improve tolerance to MI/R. In additional, Sildenafil attenuates the increase in number of pulmonary arteries irrespectively of duration of hypoxia.APRIL-SEPTEMBER 2007Endothelium-dependent nitric oxide-mediated vasodilatation is impaired in rats with pulmonary hypertension induced by CH. We therefore investigated whether the prolonged administration of both L-Arginine, the substrate for endothelial nitric oxide synthase (eNOS) or the NOS inhibitor N6-nitro-l-arginine methyl ester (L-NAME) would alleviated pulmonary hypertension.Rats were placed in hypoxic chambers (see above) and were randomly divided into the following groups: N, N+L-Arginine, N+L-NAME, CH, CH+L-Arginine and CH+L-NAME. Both L-Arginine (500 mg/Kg, ip) and L-NAME (20mg/Kg, ip) were given daily for 2 weeks. We have shown that exposure to chronic continuous hypoxia for 2 weeks induces pulmonary and right cardiac hypertrophy, an increase in numbers of right and left pulmonary arteries, in right ventricular systolic pressure and in plasma nitrates/nitrites levels. These changes are attenuated by chronic treatment of both L-Arginine or L-NAME, expect for pulmonary hypertrophy. Therefore, NO plays a significant role in right ventricular hypertrophy but not in pulmonary hypertrophy induced by chronic hypoxia.
Direct link to Lay Summary Last update: 21.02.2013

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