PHYSIOLOGICAL AND BIOCHEMICAL-EVIDENCE FOR COORDINATE INCREASES IN MUSCARINIC RECEPTORS AND G(I) DURING PACING-INDUCED HEART-FAILURE

Background It is not clear whether the increase in the myocardial guan ylyl nucleotide inhibitory protein (G(i)), frequently observed in hear t failure, is associated with any functional effects. Methods and Resu lts Eight sham-operated dogs and 10 dogs were studied with pacing-indu ced 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 mu g/kg IV) in the pr esence of ganglionic blockage 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. G(i alpha 2) was increased by 55% in heart failure. Dose-response curves for carbachol (10(-8) to 10(-3) mol/L) inhibition of isoproterenol-stimulated adenyl yl cyclase demonstrated Significantly greater (P < .05) inhibition in heart failure compared with sham-operated dogs. These changes were ass ociated with a coordinate increase in muscarinic receptor density, det ermined by antagonist binding with H-3-quinuclidinyl benzilate, in hea rt failure (153 +/- 6.2 fmol/mg protein) compared with sham-operated d ogs (124 +/- 7.4 fmol/mg protein). Agonist binding with carbachol also revealed an increase in total muscarinic receptors in heart failure w ithout a change in fraction of high- and low-affinity receptors. Concl usions These data, in the aggregate, provide physiological and biochem ical evidence to support the concept that the coordinate increases in muscarinic receptor number and G(i) levels in heart failure are couple d to increased inhibition of adenylyl cyclase activity and an increase d inhibition of myocardial contractility.