Shortening of cardiac action potentials in endotoxic shock in guinea pigs is caused by an increase in nitric oxide activity and activation of the adenosine triphosphate-sensitive potassium channel

Objective: To investigate the roles of nitric oxide and adenosine triphosphate (ATP)-sensitive potassium channels (KATP) in the shortening of cardiac action potential in endotoxic shock. Design: Prospective animal study with concurrent controls. Setting: University animal research laboratory. Subjects: Adult Hartley guinea pigs, weighing 300-400 g. Interventions: Guinea pigs were anesthetized and mechanically ventilated far 6 hrs. Lipopolysaccharide (LPS) or saline (sham group) were given intravenously. Drug effects were examined at the end of 6 hrs. Measurements and Main Results:Plasma nitrate concentration was measured hourly, while guanosine 3',5'-cyclic monophosphate (cGMP) content and action potential duration at 90% of repolarization (APD(90)) of papillary muscle were examined every 2 hrs in Be 6-hr endotoxemia in both the sham and the LPS-treated groups. The basal levels of these three variables showed no difference in the two groups. In the sham group, these variables did not change significantly (n = 14 for plasma nitrate determination; n = 5 for cGMP content measurement; n = 5-14 for APD(90) measurement; all p > .05). But in the LPS-treated group, both plasma nitrate concentration and cGMP content of papillary muscle showed time-dependent increases and they were significantly higher than those in the sham group (at the 6th hr, plasma nitrate: 42.6 +/- 7.7 vs. 21.8 +/- 3.1 mu mol/L, both n = 14, p < .01; cGMP: 1.52 +/- 0.15 vs. 0.73 +/- 0.08 pmol/mg protein, both n = 5, p < .01). In contrast APD(90) revealed a time-dependent decrease compared with that in the sham group (at the 6th hr, 137.1 +/- 5.2 vs. 188.2 +/- 4.8 msecs, both n = 14, p < .001). In the following 60-min in vitro recording of action potentials after the end of 6-hr endotoxemia, the shortened APD(90) in the LPS-heated group did not recover and remained shorter compared with that in the sham group, in which the APD(90) showed no significant changes (at the 60th min, 165.1 +/- 5.7 vs. 200.2 +/- 3.8 msecs, each n = 14 p < .01). However, in the presence of glibenclamide, a specific KATP blocker (100 mu mol/L; n = 10), the APD(90) could be reversed almost completely to the same value as that in the sham group (n = 14) (196.6 +/- 3.5 vs. 200.2 +/- 38 msecs; p > .05), despite glibenclamide having no effect on the APD(90) in the sham group. In the LPS-treated group, NG-nitro-L-arginine methyl ester (1 mmol/L; n = 4), methylene blue (10 mu mol/L; n = 5), and aminoguanidine (100 mu mol/L; n = 4) significantly prolonged the shortened APD(90) (192.5 +/- 3.1, 195.0 +/- 3.3, and 176.5 +/- 3.3 msecs, respectively; p < .01, p < .01, and p < .05, respectively, compared with that without these agents, 165.1 +/- 5.7 msecs, n = 14). These agents had negligible effects an the APD(90) in the sham group (all p > .05). Furthermore, 8-bromoguanosine-3',5'-cyclic monophosphate (500 mu mol/L; n = 5) decreased APD in intact papillary muscle (mean reduction of APD(90), 13.5 +/- 3.5%, n = 5; p < .05), an effect abolished by pretreatment with glibenclamide (100 mu mol/L; n = 5) that did not have an effect by itself. Conclusions: In this experimental model, we provide reasonably convincing evidence to suggest that in endotoxic shock, an increase in nitric oxide activity may activate KATP, which plays a major role in the shortening of APD, presumably through a cGMP-dependent pathway.