Preserved inotropic effects of a1-adrenergic receptor stimulation
in myocardium from rats with post-infarction heart failure.
Litwin, Sheldon E., Dorothy E. Vatner, and James P. Morgan.
The Department of Internal Medicine (Cardiovascular Division) and
the Charles A. Dana Research Institute and the Harvard-Thorndike
Laboratory of Beth Israel Hospital, Harvard Medical School, Boston,
MA 02215, and The New England Regional Primate Research Center,
Southborough, MA
APStracts 2:0221H, 1995.
In clinical and experimental heart failure, the inotropic response to
b-adrenergic receptor stimulation is depressed. Therefore, non-b
-adrenergic mechanisms may assume increasing importance for summoning
inotropic reserve in the failing heart. To test the integrity of the
inotropic pathway mediated by a1-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 Ca2+i transients were
recorded with the bioluminescent protein aequorin. Compared to
muscles from sham-operated rats, contractility of muscles from rats
with postinfarction heart failure was depressed at extracellular
[Ca2+] between 0.5-3.0 mMol/L. 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
(mean+SEM). There was no significant change in the time course of the
isometric twitch, or in the time course or amplitude of the Ca2+i
transient following phenylephrine administration in muscles from
either group. No evidence of Ca2+i overload, as defined by
spontaneous calcium release, was observed during phenylephrine
administration in muscles from normal or failing hearts. The density
of a1-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 a
agonists may be preserved in chronic ischemic heart failure. In both
normal and failing myocardium, the inotropic effects of a1-adrenergic
stimulation occurred with little or no increase in Ca2+i 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.
Received 29 September 1994; accepted in final form 16 may 1995.
APS Manuscript Number H881-4.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 30 May 1995.