EFFECTS OF XAMOTEROL ON INOTROPIC AND LUSITROPIC PROPERTIES OF THE HUMAN MYOCARDIUM AND ON ADENYLATE-CYCLASE ACTIVITY

The purpose of the present study was to characterize the effects of xamoterol in the human myocardium. In the presence of forskolin or milrinone, xamoterol increased isometric force of contraction, contraction velocity, and relaxation velocity in isolated, electrically driven preparations from human myocardium, but had no effect alone. There was no difference in the effect of xamoterol between right atrial myocardium and left ventricular myocardium from nonfailing (NF), moderately failing (NYHA II-III), and severely failing (NUHA IV) human hearts. The positive inotropic and lusitropic effects of isoprenaline were reduced depending on the severity of heart failure in left ventricular myocardium (i.e., NF > NYHA II-III > NYHA IV). In the presence of norepinephrine, xamoterol produced negative inotropic effects similar to those of the β-adrenoceptor antagonists pindolol and propranolol. Xamoterol alone had no effects on force of contraction, whereas pindolol and propranolol markedly reduced contractile force. In NYHA class IV, isoprenaline stimulated adenylate cyclase about twofold but xamoterol, like pindolol or propranolol, had no effect. Experiments with the β1- and β2-selective antagonists CGP 207. 12A and ICI 118.551, respectively, showed that the positive inotropic and lusitropic effects of xamoterol were mediated by β1-adrenoceptors. Consistently, xamoterol had a selectivity of 13.8 at β1-adrenoceptors as measured in radioligand binding experiments. It is concluded that xamoterol acts as a β1-adrenoceptor antagonist with a selectivity of 13.8 in human ventricular myocardium. The compound has an intrinsic sympathomimetic activity, as it produces β1-adrenoceptor-mediated positive inotropic and lusitropic effects in the presence of forskolin. The beneficial effects of xamoterol in patients with heart failure could be due to prevention of the detrimental effects of norepinephrine such as β1-adrenoceptor downregulation or an increase of Gi (inhibitory guanine-nucleotide binding protein). © 1990.