Exogenous, but not endogenous, cyclic GMP reduces hepatic pyruvate kinase activity

We investigated the effects of exogenous cyclic GMP and stimulants of endogenous cyclic GMP accumulation on L-form (hepatic) pyruvate kinase (ATP: pyruvate 2-O-phosphotransferase, EC 2.7.1.40) activity in isolated rat hepatocytes. Exogenous cyclic GMP (200 muM) reduced pyruvate kinase activity, but was less potent than exogenous cyclic AMP (50 muM) (Ki congruent to 120 muM vs. 30 muM, respectively), had a slower onset of action (1.0 vs. 0.3 min, respectively) and a less rapid maximal effect (5.0 vs. 1.0 min, respectively). Similar results were noted with dibutyryl cyclic GMP or dibutyryl cyclic AMP. 1.0 muM acetylcholine increased cyclic GMP concentrations in isolated hepatocytes from 233 +/- 16 to 447 +/- 3 pmol/g cell protein (P less than 0.001), but did not alter pyruvate kinase activity. Similar results were noted with carbamylcholine, NaN3 or acetylcholine plus eserine sulfate. The results suggest a differential effect of exogenous vs. endogenous cyclic GMP on L-form pyruvate kinase activity, and question the physiological relevance of observations with exogenous cyclic GMP in this system.