Cyclic GMP and cyclic AMP induced changes in control and hypertrophic cardiac myocyte function interact through cyclic GMP affected cyclic-AMP phosphodiesterases

We tested the hypothesis that the negative functional effects of cyclic GMP (cGMP) would be greater after increasing cyclic AMP (cAMP), because of the action of cGMP-affected cAMP phosphodiesterases in cardiac myocytes and th at this effect would be altered in left ventricular hypertrophy (LVH) produ ced by aortic valve plication. Myocyte shortening data were collected using a video edge detector, and O-2 consumption was measured by O-2 electrodes during stimulation (5 ms, 1 Hz, in 2 mM Ca2+) from control (n = 7) and LVH (n = 7) dog ventricular myocytes, cAMP and cGMP were determined by a compet itive binding assay. cAMP was increased by forskolin and milrinone (10(-6) M). cGMP was increased with zaprinast and decreased by 1H-[1,2,4]oxadiazolo [4,3-a]quinoxilin-1-(ODQ) both at 10(-6) and 10(-4) M, with and without for skolin or forskolin + milrinone. Zaprinast significantly decreased percent shortening in control (9 + 1 to 7 +/- 1%) and LVH (10 +/- 1 to 7 +/- 1%) my ocytes. It increased cGMP in control (36 +/- 5 to 52 +/- 7 fmol/10(5) myocy tes) and from the significantly higher baseline value in LVH (71 +/- 12 to 104 +/- 18 fmol/10(5) myocytes). ODQ increased myocyte function and decreas ed cGMP levels in control and LVH myocytes. Forskolin + milrinone increased cAMP levels in control (6 +/- 1 to 15 +/- 2 pmol/10(5) myocytes) and LVH ( 8 + 1 to 18 + 2 pmol/10(5) myocytes) myocytes, as did forskolin alone. They also significantly increased percent shortening. There were significant ne gative functional effects of zaprinast after forskolin + milrinone in contr ol (15 +/- 2 to 9 + 1%), which were greater than zaprinast alone, and LVH ( 12 +/- 1 to 9 +/- 1%). This was associated with an increase in cCMP and a r eduction in the increased cAMP induced by forskolin or milrinone. ODQ did n ot further increase function after forskolin or milrinone in control myocyt es, despite lowering cGMP. However, it prevented the forskolin and milrinon e induced increase in cAMP. In hypertrophy, ODQ lowered cGMP and increased function after forskolin. ODQ did not affect cAMP after forskolin and milri none in LVH. Thus, the level of cGMP was inversely correlated with myocyte function. When cAMP levels were elevated, cGMP was still inversely correlat ed with myocyte function. This was, in part, related to alterations in cAMP . The interaction between cGMP and cAMP was altered in LVH myocytes.