Direct inotropic effects of exogenous and endogenous urotensin-II: divergent actions in failing and nonfailing human myocardium.
Direct inotropic effects of exogenous and endogenous urotensin-II: divergent actions in failing and nonfailing human myocardium.
复制标题
外源性和内源性尿素蛋白II的直接肌力作用：失败和非失败的人心肌的不同作用。
DOI：
10.1161/circheartfailure.107.748343
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发表时间：
2009-01
影响因子：
9.7
通讯作者：
Margulies, Kenneth B.
中科院分区：
文献类型：
--
作者：
Quaile, Michael P.;Kubo, Hajime;Kimbrough, Carie L.;Douglas, Stephen A.;Margulies, Kenneth B.
Urotensin-II (U-II) is an endogenous peptide upregulated in failing hearts. To date, insights into the myocardial actions of U-II have been obscured by its potent vasoconstrictor effects and interspecies differences in physiological responses to U-II. We examined the direct effects of exogenous U-II on in vitro contractility in nonfailing and failing human myocardial trabeculae (n=47). Rapid cooling contractures (RCC) were used to examine SR Ca2+ load. In nonfailing myocardium, exogenous U-II increased developed force (DF), rates of force generation and decline and RCC amplitude suggesting increased SR Ca2+ load. In isolated myocyte suspensions from nonfailing hearts, U-II increased phospholamban phosphorylation. In failing myocardium, exogenous U-II reduced DF and rates of force generation and decline without a significant change in RCC amplitude in trabeculae or a change in phospholamban phosphorylation in myocytes. To examine the effects of endogenous U-II, we administered the peptidic U-II receptor antagonist (UT-A) GSK248451A to isolated trabeculae. UT-A induced a decrease in DF in nonfailing myocardium and an increase in DF in failing myocardium. UT-A increased RCC amplitude slightly in both nonfailing and failing myocardium. During ongoing UT-A, exogenous U-II had little effect on DF and RCC amplitude, confirming effective receptor blockade. U-II modulates contractility independent of vasoconstriction with opposite effects in failing and nonfailing hearts. Positive inotropic responses to UT-A alone suggests that increased endogenous U-II constrains contractility in failing hearts via an autocrine and/or paracrine mechanism. These findings support a potential therapeutic role for UT-A in heart failure.
