Action of acetylcholine on regional myocardial work and metabolism in vivo: Association with cyclic GMP

This study was designed to test the hypothesis that in the in vivo dog heart, increases in cyclic (c) GMP and also decreases in cAMP induced by intracoronary administration of acetylcholine are associated with depressed myocardial function. In 10 open-chest anesthetized dogs, 0.5 mu g . kg(-1). min(-1) of acetylcholine was infused into the left anterior descending coronary artery. The intracoronary infusion of acetylcholine was continued simultaneously with 0.1 mu g . kg(-1). min(-1) of isoproterenol. Regional segment work was calculated as the integrated product of force (auxotonic force transducer) and segment shortening (sonomicrometry). Regional myocardial O-2 consumption was calculated from blood flow measurements and regional O-2 saturations. Competitive radioligand binding assays were used to determine the intracellular level of cAMP and cGMP in the myocardium. Local intracoronary infusion of acetylcholine significantly reduced regional segment work (from 36.7 +/- 6.5 to 19.1 +/- 3.7 x 10(-3) J/min) and O-2 consumption (from 6.4 +/- 0.8 to 3.8 +/- 0.7 mt O-2 . min(-1). 100 g(-1)). This was related to a decrease in cAMP levels (from 364 +/- 25 to 262 +/- 17 pmol/100 g) and an increase in cGMP levels (from 1.34 +/- 0.06 to 1.78 +/- 0.15 pmol/100 g). When isoproterenol (0.1 mu g . kg(-1). min(-1)) was added to the acetylcholine infusion line, cAMP levels tripled to 769 +/- 84 pmol/100 g, while O-2 consumption rose to 6.6 +/- 1.4 mt O-2 . min(-1). 100 g(-1). However, regional work was only partially restored (25.7 +/- 4.8 x 10(-3) J/min). Thus, both cAMP decrements and cGMP elevation occurred together with the negative inotropic effect of acetylcholine, and increased cAMP alone (produced by isoproterenol) did not fully overcome the acetylcholine effect. This was associated with elevated intracellular levels of cGMP.