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The xanthine derivative KMUP‐1 inhibits models of pulmonary artery hypertension via increased NO and cGMP‐dependent inhibition of RhoA/Rho kinase
Author(s) -
Chung HuiHsuan,
Dai ZenKong,
Wu BinNan,
Yeh JwuLai,
Chai CheeYin,
Chu KoungShing,
Liu ChungPin,
Chen IngJun
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.00740.x
Subject(s) - rhoa , rho associated protein kinase , enos , vasoconstriction , medicine , soluble guanylyl cyclase , phosphodiesterase , angiotensin ii , phenylephrine , endocrinology , vascular smooth muscle , nitric oxide , pharmacology , biology , chemistry , phosphorylation , nitric oxide synthase , signal transduction , biochemistry , blood pressure , smooth muscle , guanylate cyclase , enzyme
Background and purpose: KMUP‐1 is known to increase cGMP, enhance endothelial nitric oxide synthase (eNOS) and suppress Rho kinase (ROCK) expression in smooth muscle. Here, we investigated the mechanism of action of KMUP‐1 on acute and chronic pulmonary artery hypertension (PAH) in rats. Experimental approach: We measured pulmonary vascular contractility, wall thickening, eNOS immunostaining, expressions of ROCK II, RhoA activation, myosin phosphatase target subunit 1 (MYPT1) phosphorylation, eNOS, soluble guanylyl cyclase (sGC), protein kinase G (PKG) and phosphodiesterase 5A (PDE‐5A), blood oxygenation and cGMP/cAMP, and right ventricular hypertrophy (RVH) in rats. Key results: In rings of intact pulmonary artery (PA), KMUP‐1 relaxed the vasoconstriction induced by phenylephrine (10 µM) or the thromboxane A 2 ‐mimetic U46619 (0.5 µM). In endothelium‐denuded PA rings, this relaxation was reduced. In acute PAH induced by U46619 (2.5 µg·kg −1 ·min −1 , 30 min), KMUP‐1 relaxed vasoconstriction by enhancing levels of eNOS, sGC and PKG, suppressing those of PDE‐5A, RhoA/ROCK II activation and MYPT1 phosphorylation, and restoring oxygenation in blood and cGMP/cAMP in plasma. Incubating smooth muscle cells from PA (PASMCs) with KMUP‐1 inhibited thapsigargin‐induced Ca 2+ efflux and angiotensin II‐induced Ca 2+ influx. In chronic PAH model induced by monocrotaline, KMUP‐1 increased eNOS and reduced RhoA/ROCK II activation/expression, PA wall thickening, eNOS immunostaining and RVH. KMUP‐1 and sildenafil did not inhibit monocrotaline‐induced PDE‐5A expression. Conclusion and implications: KMUP‐1 decreased PAH by enhancing NO synthesis by eNOS, with consequent cGMP‐dependent inhibition of RhoA/ROCK II and Ca 2+ desensitization in PASMCs. KMUP‐1 has the potential to reduce vascular resistance, remodelling and RVH in PAH.