Urotensin II acutely increases myocardial length and distensibility: potential implications for diastolic function and ventricular remodeling.
Urotensin II (U-II) is a cyclic peptide that may be involved in cardiovascular dysfunction. In the present study, the acute effects of U-II on diastolic properties of the myocardium were investigated. Increasing concentrations of U-II (10(-8) to 10(-6) M) were added to rabbit papillary muscles in the absence (n = 15) or presence of: (1) damaged endocardial endothelium (EE; n = 9); (2) U-II receptor antagonist, urantide (10(-5) M; n = 7); (3) nitric oxide (NO) synthase inhibitor, N(G)-Nitro-L-Arginine (10(-5) M; n = 9); (4) cyclooxygenase inhibitor, indomethacin (10(-5) M; n = 8); (5) NO synthase and cyclooxygenase inhibitors, N(G)-Nitro-L-Arginine (10(-5) M) and indomethacin (10(-5) M), respectively, (n = 8); or (6) protein kinase C (PKC) inhibitor, chelerythrine (10(-5) M; n = 9). Passive length-tension relations were constructed before and after a single concentration of U-II (10(-6) M; n = 3). U-II concentration dependently decreased inotropy and increased resting muscle length (RL). At 10(-6) M, active tension decreased 13.8 +/- 5.4%, and RL increased to 1.007 +/- 0.001 L/L (max). Correcting RL to its initial value resulted in an 18.1 +/- 3.0% decrease in resting tension, indicating decreased muscle stiffness, which was also suggested by the down and rightward shift of the passive length-tension relation. This effect remained unaffected by EE damage and PKC inhibition. In contrast, the presence of urantide and NO inhibition abolished the effects of U-II on myocardial stiffness, while cyclooxygenase inhibition significantly attenuated them. U-II decreases myocardial stiffness, an effect that is mediated by the urotensin-II receptor, NO, and prostaglandins. This represents a novel mechanism of acute neurohumoral modulation of diastolic function, suggesting that U-II is an important regulator of cardiac filling.
Fontes-Sousa
Ana Patrícia
AP
Department of Physiology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.
Brás-Silva
Carmen
C
Pires
Ana Luísa
AL
Monteiro-Sousa
Daniela
D
Leite-Moreira
Adelino F
AF
D000704:Analysis of Variance; D000818:Animals; D003971:Diastole / Q000187:drug effects; D004548:Elasticity; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D011453:Prostaglandins / Q000502:physiology; D011817:Rabbits; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D014579:Urotensins / Q000494:pharmacology / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000187:drug effects
D011453:Prostaglandins; D043562:Receptors, G-Protein-Coupled; C121697:UTS2R protein, human; D014579:Urotensins; D014662:Vasoconstrictor Agents; D009569:Nitric Oxide; C029677:urotensin II
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