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(Circulation. 1996;94:102-107.)
© 1996 American Heart Association, Inc.
Articles |
Physiological and Biochemical Evidence for Coordinate Increases in Muscarinic Receptors and Gi During Pacing-Induced Heart Failure
From the Departments of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, and Massachusetts General Hospital, Boston, and the New England Regional Primate Research Center, Southborough, Mass.
Correspondence to Dorothy E. Vatner, MD, New England Regional Primate Research Center, 1 Pine Hill Dr, PO Box 9102, Southborough, MA 01772-9102.
Background It is not clear whether the increase in the myocardial guanylyl nucleotide inhibitory protein (Gi), frequently observed in heart failure, is associated with any functional effects.
Methods and Results Eight sham-operated dogs and 10
dogs were studied with pacing-induced heart failure (240 bpm for 4
to 7 weeks), characterized by reduced (P<.05) left
ventricular dP/dt (from 2926±99 to 1303±126 mm Hg/s). The
muscarinic agonist acetylcholine (10 µg/kg IV) in the presence of
ganglionic blockade reduced left ventricular dP/dt more
(P<.05) in heart failure (-23±2%) than before heart
failure (-8±2%), despite lesser reductions in
arterial pressure.
Gi
2 was increased by 55% in
heart failure. Dose-response curves for carbachol
(10-8 to
10-3 mol/L) inhibition of
isoproterenol-stimulated adenylyl cyclase demonstrated
significantly greater (P<.05) inhibition in heart failure
compared with sham-operated dogs. These changes were associated
with a coordinate increase in muscarinic receptor density, determined
by antagonist binding with 3H-quinuclidinyl
benzilate, in heart failure (153±6.2 fmol/mg protein) compared with
sham-operated dogs (124±7.4 fmol/mg protein). Agonist binding with
carbachol also revealed an increase in total muscarinic receptors in
heart failure without a change in fraction of high- and
low-affinity receptors.
Conclusions These data, in the aggregate, provide physiological and biochemical evidence to support the concept that the coordinate increases in muscarinic receptor number and Gi levels in heart failure are coupled to increased inhibition of adenylyl cyclase activity and an increased inhibition of myocardial contractility.
Key Words: receptors • proteins • heart failure • nervous system, autonomic • signal transduction
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