Inotropic effects of alpha 1-adrenergic agonists in myocardium from rats with postinfarction heart failure.
In clinical and experimental heart failure, the inotropic response to beta-adrenergic receptor stimulation is depressed. Therefore, non-beta-adrenergic mechanisms may assume increasing importance for summoning inotropic reserve in the failing heart. To test the integrity of the inotropic pathway mediated by alpha 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 +/- 4 vs. 125 +/- 7% of baseline) and peak rate of tension rise (125 +/- 4 vs. 140 +/- 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 alpha 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 +/- 5 vs. 53 +/- 4 fmol/mg protein). These data indicate that the positive inotropic effect of alpha-agonists may be preserved in chronic ischemic heart failure. In both normal and failing myocardium, the inotropic effects of alpha 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.
Litwin
S E
SE
Charles A. Dana Research Institute, Boston, Massachusetts, USA.
Vatner
D E
DE
Morgan
J P
JP
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002303:Cardiac Output, Low / Q000209:etiology* / Q000503:physiopathology; D006321:Heart / Q000187:drug effects*; D007425:Intracellular Membranes / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009203:Myocardial Infarction / Q000150:complications*; D009206:Myocardium / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values
D000316:Adrenergic alpha-Agonists; D010656:Phenylephrine; D002118:Calcium