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Urotensin II acutely increases myocardial length and distensibility: potential implications for diastolic function and ventricular remodeling

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Abstract

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, NG-Nitro-l-Arginine (10−5 M; n = 9); (4) cyclooxygenase inhibitor, indomethacin (10−5 M; n = 8); (5) NO synthase and cyclooxygenase inhibitors, NG-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.

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Acknowledgments

The authors thank Doctor Maria José Prata for her assistance in data analysis.

This paper is supported by the Portuguese Foundation for Science and Technology (grant number POCI/SAU-FCT/60803/2004, partially funded by FEDER) through the Cardiovascular R&D Unit (FCT number 51/94). Ana Patrícia Fontes-Sousa is supported by a grant from the Portuguese Foundation for Science and Technology (number SFRH/BD/22590/2005).

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  1. Department of Physiology, Faculty of Medicine, University of Porto, 4200-319, Porto, Portugal

    Ana Patrícia Fontes-Sousa, Carmen Brás-Silva, Ana Luísa Pires, Daniela Monteiro-Sousa & Adelino F. Leite-Moreira

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  1. Ana Patrícia Fontes-Sousa
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  2. Carmen Brás-Silva
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Correspondence to Adelino F. Leite-Moreira.

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Fontes-Sousa, A.P., Brás-Silva, C., Pires, A.L. et al. Urotensin II acutely increases myocardial length and distensibility: potential implications for diastolic function and ventricular remodeling. Naunyn-Schmied Arch Pharmacol 376, 107–115 (2007). https://doi.org/10.1007/s00210-007-0180-8

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