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% O2) 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 + 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, Nω-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 hypoxia- and 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.
Footnotes
This work was supported in part by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants HL-65998 and HL-70659] (to R.A.K.); and the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant HD-60702] (to R.A.K.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.160119
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ABBREVIATIONS:
- PH
- pulmonary hypertension
- ACh
- acetylcholine
- EDRF
- endothelium-derived relaxing factor
- ET-1
- endothelin-1
- l-NAME
- Nω-nitro-l-arginine methyl ester
- LVSP
- left ventricular systolic pressure
- NO
- nitric oxide
- NOS
- nitric oxide synthase
- ODQ
- 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one
- PHE
- phenylephrine
- RVSP
- right ventricular systolic pressure
- SNP
- sodium nitroprusside
- VSMC
- vascular smooth muscle cell
- MCT
- monocrotaline.
- Received August 7, 2009.
- Accepted November 12, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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