Impaired Vasoconstriction and Nitric Oxide-Mediated Relaxation in Pulmonary Arteries of Hypoxia- and Monocrotaline-Induced Pulmonary Hypertensive Rats

Abstract

Pulmonary hypertension (PH) is a life-threatening disease with unclear vascular mechanisms. We tested whether PH involves abnormal pulmonary vasoconstriction and impaired vasodilation. Male Sprague-Dawley rats were exposed to hypoxia (9% O 2 ) for 2 weeks or injected with single dose of monocrotaline (MCT, 60 mg/kg s.c.). Control rats were normoxic or injected with saline. After the hemodynamic measurements were performed, pulmonary and mesenteric arteries were isolated for measurement of vascular function. Hematocrit was elevated in hypoxic rats. Right ventricular systolic pressure and Fulton's Index [right/(left ϩ septum) ventricular weight] were greater in hypoxic and MCT-treated rats than in normoxic rats. Pulmonary artery contraction by phenylephrine and 96 mM KCl was less in hypoxic and MCT-treated rats than in normoxic rats. Acetylcholine-induced relaxation was less in the pulmonary arteries of hypoxic and MCT-treated rats than of normoxic rats, suggesting reduced effects of endothelium-derived vasodilators. The nitric oxide synthase inhibitor, N -nitro-L-arginine methyl ester, and the guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, inhibited acetylcholine relaxation, suggesting that it was mediated by nitric oxide (NO)-cGMP. The NO donor sodium nitroprusside caused less relaxation in the pulmonary arteries of hypoxic and MCT-treated than of normoxic rats, suggesting decreased responsiveness of vascular smooth muscle cells (VSMCs) to vasodilators. Phenylephrine and KCl contraction and acetylcholine and sodium nitroprusside relaxation were not different in the mesenteric arteries from all groups. In lung tissue sections, the wall thickness of pulmonary arterioles was greater in hypoxic and MCT-treated rats than in normoxic rats. The specific reductions in pulmonary, but not systemic, arterial vasoconstriction and vasodilation in hypoxiaand MCT-induced PH are consistent with the possibility of de-differentiation of pulmonary VSMCs to a more proliferative/ synthetic and less contractile phenotype in PH.

Improved pulmonary vascular reactivity and decreased hypertrophic remodeling during nonhypercapnic acidosis in experimental pulmonary hypertension

“…5, D and F, and Table 2). The Phe contractile response as % of maximal Phe-induced contraction and the Phe ED 50 were similar in L-NAME-and ODQ-treated pulmonary artery from normoxic rats with or without NH 4 Cl treatment (Fig. 6, A and B, and Table 2).…”

“…3C and Table 2). In comparison, parallel experiments on mesenteric arteries from the same animals demonstrated that Pheinduced maximum contraction and the Phe ED 50 did not differ among the various experimental groups (Fig. 3, B and D, and Table 2).…”

“…6, A and B, and Table 2). Although the Phe ED 50 was not significantly different in the pulmonary artery of the different experimental groups (Table 2), the Phe contractile response as % of maximum was significantly enhanced with ODQ in pulmonary artery segments of hypoxic and MCT-treated rats with (Fig. 6, D and F) or without treatment with NH 4 Cl (Fig.…”

“…The hypoxic and monocrotaline (MCT) rat models are particularly useful in the evaluation of antiproliferative and proapoptotic therapies since medial hypertrophy of the pulmonary arterioles is a key feature in these PH models (36,52,54,64). We have previously shown that chronic hypoxia and MCT treatment in rats are associated with decreased pulmonary artery reactivity and significant pulmonary arteriolar remodeling (50). We have also reported that extracellular acidosis inhibits proliferation and migration of cultured rat and mouse VSMCs (8,11,30).…”

Nitric Oxide–Dependent Feedback Loop Regulates Transient Receptor Potential Vanilloid 4 (TRPV4) Channel Cooperativity and Endothelial Function in Small Pulmonary Arteries

“…The biophysical properties, signaling targets, and endogenous regulators of TRPV4 sparklets in small PAs remain unknown. Endothelium‐derived nitric oxide (NO) is thought to be the predominant vasodilator in the pulmonary circulation 8, 9, 10, 11, 12. Increase in global Ca 2+ has long been associated with activation of endothelial nitric oxide synthase (eNOS).…”