Cyclic GMP decreases cardiac myocyte oxygen consumption to a greater extent under conditions of increased metabolism

We tested the hypothesis that the negative effects of intracellular guanosine 3',5'-cyclic monophosphate (cyclic GMP) were more profound on cardiac myocyte oxygen consumption (VO2) during increased metabolism of the myocytes. The steady state VO2 of a suspension of single myocytes isolated from hearts of New Zealand White rabbits was measured in a glass chamber by using a Clark-type oxygen electrode, and cyclic GMP was determined by using a radioimmunoassay. The cellular cyclic GMP levels were increased either by adding 3-morpholino-sydnonimine (SIN-1), a guanylate cyclase stimulator, or zaprinast (ZAP), a cyclic GMP-phosphodiesterase inhibitor, at various doses. In 0.5 mM Ca2+ medium, average VO2 was 123 +/- 8 nl/min/100,000 cells, and cyclic GMP was 35.4 +/- 9.3 fmol/100,000 cells, and these increased significantly to 182 +/- 9 nl/min/100,000 cells and 78.2 +/- 7.3 fmol/100,000 cells in 2.0 mM Ca2+. There were dose-dependent responses of the VO2 and cellular cyclic GMP levels in responding to both SIN-1 and ZAP. An inverse relation between cellular cyclic GMP level and VO2 existed in the myocytes. The regression equations for the four treatments were log(VO2) = -0.002[cyclic GMP] + 2.19, r = 0.96 for SIN-1 in low (0.5 mM) Ca2+; log(VO2) = 0.005[cyclic GMP] + 1.80, r = 0.38 for ZAP in low Ca2+; log(VO2) = -0.001[cyclic GMP] + 2.24, r = 0.82 for SIN-1 in high (2.0 mM) Ca2+; and log(VO2) = -0.004[cyclic GMP] + 2.56, r = 0.93 for ZAP in high Ca2+. The slope of ZAP regression line was significantly more negative than that of SIN-1 with high calcium. At any given level of cyclic GMP ZAP decreased the VO2 to a greater extent than did SIN-1 although the latter caused the maximal increase in cyclic GMP level. The reduction in VO2 caused by a corresponding increase in cellular cyclic GMP was greater in myocytes incubated with high-Ca2+ medium.