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Original Articles

Direct Inotropic Effects of Exogenous and Endogenous Urotensin-II

Divergent Actions in Failing and Nonfailing Human Myocardium

Michael P. Quaile, PhD; Hajime Kubo, PhD; Carie L. Kimbrough, MPH; Stephen A. Douglas, PhD and Kenneth B. Margulies, MD

From the Department of Physiology (M.P.Q., H.K.), Temple University School of Medicine, Philadelphia, Pa; Statistical Sciences (C.L.K.), GlaxoSmithKline, Research Triangle Park, NC; Vascular Biology and Thrombosis (S.A.D.), GlaxoSmithKline, King of Prussia, Pa; and the Cardiovascular Institute (M.P.Q., K.B.M.), University of Pennsylvania School of Medicine, Philadelphia, Pa.

Correspondence to Kenneth B. Margulies, MD, University of Pennsylvania School of Medicine, 608 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104. E-mail kenneth.margulies{at}uphs.upenn.edu

Received October 26, 2007; accepted November 6, 2008.

Background— 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.

Methods and Results— 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 sarcoplasmic reticulum Ca²⁺ load. In nonfailing myocardium, exogenous U-II increased developed force (DF), rates of force generation and decline and RCC amplitude suggesting increased sarcoplasmic reticulum 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.

Conclusions— 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 or paracrine mechanism. These findings support a potential therapeutic role for UT-A in heart failure.

Key Words: calcium • contractility • myocardial contraction • pharmacology • sarcoplasmic reticulum

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Related Article

Direct Inotropic Effects of Exogenous and Endogenous Urotensin-II: Divergent Actions in Failing and Nonfailing Human Myocardium

Michael P. Quaile, Hajime Kubo, Carie L. Kimbrough, Stephen A. Douglas, and Kenneth B. Margulies
Circ Heart Fail 2009 2: 39-46. [Abstract] [Full Text] [PDF]