Antishock effect of U-67,590A, methylprednisolone suleptanate, associated with restoration of lowered vascular reactivity in endotoxemic rats.
We wished to investigate the modulating effects of a glucocorticoid on mortality and sustained hypotension in endotoxemic rats in conjunction with in vitro study of responses of isolated aorta to KCl, norepinephrine (NE), and acetylcholine (ACh). Endotoxemia was induced by intravenous (i.v.) bolus injection of 50 mg/kg Escherichia coli endotoxin in rats, resulting in high mortality. Pretreatment with U-67,590A, methylprednisolone suleptanate, at a dose of 9 mg/kg resulted in 100% survival; the survival rate of saline-treated controls was 21%. Isolated rat aorta that had been treated with endotoxin for 4 h showed decreases in contractile responses to KCl and NE and in relaxing response to ACh. Similar attenuation of contractile responsiveness was observed in endothelium-denuded preparations. Addition of endotoxin to the in vitro tissue bath did not inhibit the responses in a 4-h period. Pretreatment with U-67,590A inhibited the late gradual decrease in blood pressure (BP) but not the early hypotensive response to endotoxin. The responses to KCl or NE of aorta isolated 4 h after the endotoxin injection remained suppressed in U-67,590A-treated rats but were restored in 24 h. These results suggest that endotoxemia impairs the endothelium moderately, but this does not account for either reduced reactivity of vascular smooth muscle to vasoconstrictor agents or the sustained hypotension. The steroid inhibits endotoxemia-induced mortality and sustained hypotension.
Nomura
S
S
Department of Pharmacology, Upjohn Pharmaceuticals, Tsukuba Research Laboratories, Japan.
Harasawa
Y
Y
Hayashi
S
S
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects*; D004731:Endotoxins / Q000008:administration & dosage / Q000633:toxicity*; D004926:Escherichia coli; D066298:In Vitro Techniques; D008297:Male; D008775:Methylprednisolone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011355:Prodrugs / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000188:drug therapy*; D015996:Survival Rate
D004731:Endotoxins; D011355:Prodrugs; D011189:Potassium Chloride; C052305:methylprednisolone suleptanate; D009638:Norepinephrine; D008775:Methylprednisolone