title: Direct inotropic effects of exogenous and endogenous urotensin-II: divergent actions in failing and nonfailing human myocardium.
abstract: 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.
  
  
  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 Ca(2+) load. In nonfailing myocardium, exogenous U-II increased developed force (DF), rates of force generation and decline and RCC amplitude suggesting increased sarcoplasmic reticulum Ca(2+) 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.
authors.affiliation: Department of Physiology, Temple University School of Medicine, Philadelphia, Pa, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Quaile
authors.forename: Hajime
authors.initials: H
authors.lastname: Kubo
authors.forename: Carie L
authors.initials: CL
authors.lastname: Kimbrough
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Douglas
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Margulies
mesh_terms: D000328:Adult; D015153:Blotting, Western; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000378:metabolism; D014579:Urotensins / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D017923:Sodium-Hydrogen Exchangers; D014579:Urotensins; C029677:urotensin II; D012964:Sodium; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester