Physiological and Biochemical Evidence for Coordinate Increases in Muscarinic Receptors and G i During Pacing-Induced Heart Failure

Abstract

Background It is not clear whether the increase in the myocardial guanylyl nucleotide inhibitory protein (G i ), 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. G i α 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 3 H-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 G i levels in heart failure are coupled to increased inhibition of adenylyl cyclase activity and an increased inhibition of myocardial contractility.