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 metabolic 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 (one-kidney, one-clip, 1K1C) cardiac hypertrophic rabbits. By using isolated cardiac myocytes from control and 1K1C rabbits, oxygen consumption (Mvo2; O2 nl/ min/10(5) cells), cyclic GMP (fmol/10(5) cells), and cell shortening (percentage) data were collected (a) at baseline; (b) with cyclic GMP protein kinase inhibitors KT5823 (10(-6) M) or Rp8-pCPT-cGMP (5 x 10(-6) M); (c) with the cyclic GMP phosphodiesterase 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 similar in control versus 1K1C myocytes (62 +/- 10 vs. 66 +/- 17 pmol/10(5) myocytes). Zaprinast produced a dose-dependent increase in cyclic GMP in both control and 1K1C myocytes. The addition of KT5823 did not significantly affect cyclic GMP levels. Zaprinast significantly and dose dependently decreased Mvo2, and KT5823 partially restored it in control and 1K1C. Zaprinast also significantly decreased percentage shortening, and KT5823 partially restored it in control. Similar results were obtained with Rp-8pCPT-cGMP, although neither inhibitor was effective without zaprinast. The hypertrophied myocytes demonstrated comparable responses to all agents. These data suggest that the cyclic GMP protein kinase activity was not significant under basal conditions; however, the importance of cyclic GMP protein kinase in control and 1K1C myocytes was significant under conditions of increased intracellular cyclic GMP.
Straznicka
M
M
Department of Physiology & Biophysics and Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway 08854-5635, USA.
Gong
G
G
Yan
L
L
Scholz
P M
PM
Weiss
H R
HR
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D002227:Carbazoles; D006332:Cardiomegaly / Q000503:physiopathology*; D006152:Cyclic GMP / Q000032:analysis / Q000502:physiology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology*; D007211:Indoles; D009206:Myocardium / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D011688:Purinones / Q000494:pharmacology; D011817:Rabbits
D000470:Alkaloids; D002227:Carbazoles; D007211:Indoles; D011688:Purinones; C073601:KT 5823; D017869:Cyclic GMP-Dependent Protein Kinases; C011145:zaprinast; D006152:Cyclic GMP