In clinical and experimental heart failure, the inotropic response to a-adrenergic receptor stimulation is depressed. Therefore, non-a-adrenergic mechanisms may assume increasing importance for summoning inotropic reserve in the failing heart. To test the integrity of the inotropic pathway mediated by `1-adrenergic receptor stimulation in a model of chronic ischemic heart failure, we administered phenylephrine to noninfarcted left ventricular papillary muscles isolated from sham-operated rats (n = 10) and rats with large (>40% left ventricular circumference) anterior myocardial infarctions (n = 9). Isometric force was monitored, and intracellular Ca2+ (Cai2+) transients were recorded with the bioluminescent protein aequorin. Compared with muscles from sham-operated rats, contractility of muscles from rats with postinfarction heart failure was depressed at extracellular Ca2+ concentrations between 0.5 and 3.0 mM. Phenylephrine produced comparable dose-dependent increases in developed tension (126 q 4 vs. 125 q 7% of baseline) and peak rate of tension rise (125 q 4 vs. 140 q 9% of baseline) in muscles from sham and infarcted rats, respectively. There was no significant change in the time course of the isometric twitch or in the time course or amplitude of the Cai2+ transient after phenylephrine administration in muscles from either group. No evidence of Cai2+ overload, as defined by spontaneous Ca2+ release, was observed during phenylephrine administration in muscles from normal or failing hearts. The density of `1-adrenoceptors measured with [3H]prazosin binding in crude membranes isolated from noninfarcted left ventricular tissue was not different in control and infarcted hearts ( 48 q 5 vs. 53 q 4 fmol/mg protein). These data indicate that the positive inotropic effect of `-agonists may be preserved in chronic ischemic heart failure. In both normal and failing myocardium, the inotropic effects of `1-adrenergic stimulation occurred with little or no increase in Cai2+ availability and no apparent adverse effects on myocardial relaxation. Therefore, agents that act by similar mechanisms may have certain therapeutic advantages over traditional inotropic agents in patients with heart failure. ?
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