title: Effect of potassium channel and cytochrome P450 inhibition on transient hypotension and survival during lipopolysaccharide-induced endotoxic shock in the rat.
abstract: The purpose of this study was to determine whether inhibition of potassium channels or cytochrome P450 attenuates the transient phase of hypotension during endotoxic shock in vivo, and to determine whether these interventions improve the rate of survival. Male Sprague-Dawley rats were pretreated with saline (0.2 ml, i.v.), tetraethylammonium chloride (TEA 30 mg/kg; 0.2 ml, i.v.), proadifen (SKF-525 A; 50 mg/kg, i.p.) or ketoconazole (50 mg/kg, i.p.) and challenged with lipopolysaccharide (LPS; 20 mg/kg, i.p.). Changes in heart rate, mean (MAP), systolic (SP) and diastolic (DP) arterial pressures as well as survival rate were then monitored for 45 min. Potassium channel inhibition with TEA had no effect on LPS-induced hypotension at any time point compared with saline (maximal fall in MAP of 79 +/- 18 and 80 +/- 13 mm Hg, respectively). Pretreatment with proadifen or ketoconazole, inhibitors of cytochrome P450, significantly attenuated LPS-induced hypotension compared with saline (maximal fall in MAP of 34, 26 and 63% below baseline, respectively). This effect was evident in all arterial pressures measured, MAP, SP and DP. At 45 min, the survival rate in the saline group was 66%. Pretreatment with TEA significantly reduced survival rate to 50% and pretreatment with proadifen or ketoconazole improved survival to 100% (p < 0.05). These results suggest that an arachidonic acid metabolite produced by a cytochrome P450-catalyzed reaction may contribute to the transient phase of LPS-induced hypotension. However, these effects do not appear to be mediated through potassium channel activation.
authors.affiliation: Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Boston, MA 02115, USA.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Clayton
authors.forename: Barbara W
authors.initials: BW
authors.lastname: LeDuc
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Kelly
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007022:Hypotension / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D026902:Potassium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D003577:Cytochrome P-450 Enzyme System