Cyclic GMP protein kinase mediates negative metabolic and functional effects of cyclic GMP in control and hypertrophied rabbit cardiac myocytes

We tested the hypothesis that in isolated cardiac myocytes, the negative me tabolic and functional effects of cyclic guanosine monophosphate (GMP) are mediated by cyclic GMP protein kinase activity, and that these effects are altered in renal hypertensive tone-kidney, one-clip, 1K1C) cardiac hypertro phic rabbits. By using isolated cardiac myocytes from control and 1K1C rabb its, oxygen consumption (Mvo(2); O-2 nl/ min/10(5) cells), cyclic CMP (fmol /10(5) cells), and cell shortening (percentage) data were collected (a) at baseline; tb) with cyclic GMP protein kinase inhibitors KT5823 (10(-6) M) o r Rp-8-pCPT-cGMP (5 x 10(-6) M); (c) with the cyclic GMP phos phodiesterase inhibitor zaprinast (10(-6), 10(-4) M); and (d) with zaprinast (10(-6), 10 (-4) M) and protein kinase inhibitors. Basal levels of cyclic GMP were simi lar in control versus 1K1C myocytes (62 +/- 10 vs. 66 +/- 17 pmol/10(5) myo cytes). Zaprinast produced a dose-dependent increase in cyclic GMP in both control and 1K1C myocytes. The addition of KT5823 did not significantly aff ect cyclic GMP levels. Zaprinast significantly and dose dependently decreas ed Mvo(2), and KT5823 partially restored it in control and 1K1C. Zaprinast also significantly decreased percentage shortening, and KT5823 partially re stored it in control. Similar results were obtained with Rp-8-pCPT-cGMP, al though neither inhibitor was effective without zaprinast. The hypertrophied myocytes demonstrated comparable responses to all agents. These data sugge st that the cyclic GMP protein kinase activity was not significant under ba sal conditions; however, the importance of cyclic GMP protein kinase in con trol and 1K1C myocytes was significant under conditions of increased intrac ellular cyclic GMP.