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

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Abstract
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. Giα2 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 ...