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 p ositive functional effects on isolated rabbit ventricular myocytes regardle ss 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 w ere obtained: (1) at baseline; (2) after the addition of H-1-[1,2,4]oxadiaz olo[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 (fmo1/100,000 myocytes) and increased p ercent shortening (Pcs, %; 4.9 +/- 0.3 vs. 5.8 +/- 0.6) and maximum rate of shortening (Rs, mu m/s; 58.7 +/- 5.7 vs. 73.6 +/- 4.9). Zaprinast signific antly increased the cyclic GMP level from 419 +/- 140 to 599 +/- 241 and de creased 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 si milar percentage compared to the non-zaprinast treated myocytes. We conclud e that in rabbit ventricular myocytes, a reduction in the level of myocyte cyclic GMP increases myocyte function independent of the initial cyclic GMP level. Copyright (C) 2000 S. Karger AG, Basel.