title: 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.
abstract: 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.
  
  
  METHODS
  Prospective animal study with concurrent controls.
  
  
  METHODS
  University animal research laboratory.
  
  
  METHODS
  Adult Hartley guinea pigs, weighing 300-400 g.
  
  
  METHODS
  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.
  
  
  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 micromol/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 +/- 52 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 micromol/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 micromol/L; n = 5), and aminoguanidine (100 micromol/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 micromol/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 micromol/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.
authors.affiliation: Department of Medicine, Show Chwan Memorial Hospital, Chang-Hwa, Taiwan.
authors.forename: C C
authors.initials: CC
authors.lastname: Chen
authors.forename: Y C
authors.initials: YC
authors.lastname: Lin
authors.forename: S A
authors.initials: SA
authors.lastname: Chen
authors.forename: H N
authors.initials: HN
authors.lastname: Luk
authors.forename: P Y
authors.initials: PY
authors.lastname: Ding
authors.forename: M S
authors.initials: MS
authors.lastname: Chang
authors.forename: C E
authors.initials: CE
authors.lastname: Chiang
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D006152:Cyclic GMP / Q000032:analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006168:Guinea Pigs; D008070:Lipopolysaccharides; D008751:Methylene Blue / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D010210:Papillary Muscles / Q000737:chemistry; D015221:Potassium Channels / Q000502:physiology*; D012772:Shock, Septic / Q000503:physiopathology*; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D008070:Lipopolysaccharides; D015221:Potassium Channels; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D006152:Cyclic GMP; C004479:pimagedine; D005905:Glyburide; D008751:Methylene Blue; D019331:NG-Nitroarginine Methyl Ester