Contractile effects of angiotensin and endothelin in failing and non-failing human hearts

Background: Angiotensin 11 (Ang 11) and endothelin-1 (ET-1) share their effects on growth of myocardial cells but have been shown to elicit different effects on myocardial function. However, these effects vary markedly among species, cardiac regions (atrium or ventricle) and failing or non-failing myocardium. We therefore investigated the effects of both peptides on contractile function of isolated human myocytes from failing and non-failing hearts. Methods and results: Cardiomyocytes were enzymatically isolated and electrically stimulated (15 V, 0.2 Hz). Ang 11 elicited a positive inotropic effect (PIE) mediated by activation of protein kinase C (PKC) in atrial but no effect in ventricular myocytes. ET-I (10(-8) M) increased cell-shortening by 146 +/- 9.3% (p < 0.05) in atrial myocytes, by 99.1 +/- 16.5% (p < 0.05) in non-failing ventricular but only by 40.5 +/- 6.4% (p < 0.05) in failing ventricular myocytes. The PIE of ET-1 in failing myocytes was more pronounced at low extracellular pH (+112.6 +/- 27% at pH 7.0 vs. + 40.5 +/- 6.4% at pH 7.4, p < 0.05). Amiloride, a sodium-hydrogen-exchange inhibitor, inhibited two thirds of the PIE of ET-I in failing myocytes. The PKC-inhibitor decreased the PIE by 50% from 113% to 64% in ventricular myocytes under acidotic conditions. Conclusion: Ang 11 and ET-I elicited PIE in atrial myocytes, whereas in ventricular myocytes Ang 11 did not induce PIE in contrast to ET-1. The PIE of ET-I was markedly attenuated in failing myocytes. Under acidotic conditions, the PIE of ET-I was more pronounced in failing myocytes, indicating that ET-I may activate signaling processes in failing myocytes, which are not activated in normal myocytes. (c) 2006 Elsevier Ireland Ltd. All rights reserved.