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 for 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 (APD90) of papillary muscle were examined every 2 hrs in the 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 APD90 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 &mgr;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, APD90 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 APD90 in the LPS-treated group did not recover and remained shorter compared with that in the sham group, in which the APD90 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 &mgr;mol/L; n = 10), the APD90 could be reversed almost completely to the same value as that in the sham group (n = 14) (196.6 ± 3.5 vs. 200.2 ± 3.8 msecs;p > .05), despite glibenclamide having no effect on the APD90 in the sham group. In the LPS-treated group, NG-nitro-l-arginine methyl ester (1 mmol/L; n = 4), methylene blue (10 &mgr;mol/L; n = 5), and aminoguanidine (100 &mgr;mol/L; n = 4) significantly prolonged the shortened APD90 (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 on the APD90 in the sham group (all p > .05). Furthermore, 8-bromoguanosine-3′,5′-cyclic monophosphate (500 &mgr;mol/L; n = 5) decreased APD in intact papillary muscle (mean reduction of APD90, 13.5 ± 3.5%, n = 5;p < .05), an effect abolished by pretreatment with glibenclamide (100 &mgr;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.