Decreasing cyclic GMP exerts similar positive functional effects on cardiac myocytes regardless of initial level

We tested the hypothesis that lowering the level of cyclic GMP would have positive functional effects on isolated rabbit ventricular myocytes regardless of the basal cyclic GMP level. Cell shortening data were collected with a video detector; O(2) consumption data were obtained with a Clark electrode; intracellular cyclic GMP levels were obtained by radioimmunoassay. Data were obtained: (1) at baseline; (2) after the addition of 1H-[1,2,4]oxadiazolo[4, 3-alpha]quinoxaline-1-one (ODQ) 10(-6) and 10(-4) mol/l, a selective soluble guanylyl cyclase inhibitor, and (3) after zaprinast 10(-6) mol/l, a cyclic GMP phosphodiesterase inhibitor, followed by ODQ 10(-6) and 10(-4) mol/l. We found that ODQ 10(-4) mol/l significantly decreased the cyclic GMP level from 493 +/- 75 to 301 +/- 78 (fmol/100,000 myocytes) and increased percent shortening (Pcs, %; 4.9 +/- 0.3 vs. 5.8 +/- 0.6) and maximum rate of shortening (Rs, microm/s; 58.7 +/- 5.7 vs. 73.6 +/- 4.9). Zaprinast significantly increased the cyclic GMP level from 419 +/- 140 to 599 +/- 241 and decreased Pcs (6.2 +/- 0.5 vs. 4.4 +/- 0.4) and Rs (65.5 +/- 5.3 vs. 49.6 +/- 4.3). After zaprinast, ODQ 10(-4) mol/l decreased the cyclic GMP level to 439 +/- 139 and increased percent shortening and rate of shortening by a similar percentage compared to the non-zaprinast treated myocytes. We conclude that in rabbit ventricular myocytes, a reduction in the level of myocyte cyclic GMP increases myocyte function independent of the initial cyclic GMP level.