Improvement in organ blood flow by inhibition of thromboxane synthetase during experimental endotoxic shock in the rat.
Endotoxic shock is associated with increased metabolism of arachidonic acid to thromboxane (Tx) and prostaglandins. This investigation examined the effects of two structurally dissimilar inhibitors of (Tx) synthetase on Salmonella enteritidis endotoxin (LPS) (15 mg/kg)-induced alterations in cardiac output and organ blood flow in Long-Evans rats. An imidazole derivative, 7(1-imidazolyl) heptanoic acid (7-IHA), and sodium -(E)-3-[4-(3-pyridyl-methyl)phenyl]-2-methacrylate (OKY-1581) were injected intravenously at 30 and 5 mg/kg, respectively, 30 min before injection with endotoxin. Cardiovascular function was assessed 30 min post-LPS with Sr-85 labeled microspheres under light ether anesthesia. Injection of endotoxin caused a 60% decrease in cardiac output (34.0 +/- 2.7 ml/min/100 g body weight in control rats) and a 38.9% decrease in systolic arterial pressure. Both Tx synthetase inhibitors significantly (p less than 0.05) attenuated the decrease in cardiac output, although only 7-IHA improved blood pressure. Pretreatment with 7-IHA or OKY-1581 significantly (p less than 0.05) attenuated the LPS-induced decrease in renal perfusion. Lung nutrient blood flow (1.1 +/- 0.2 ml/min/g lung) decreased nearly 70% in shock. Both Tx synthetase inhibitors prevented this reduction. LPS shock resulted in approximately a 30% decrease in brain blood flow. 7-IHA significantly (p less than 0.05) improved flow, while OKY-1581 was without apparent effect. Splanchnic blood flow was likewise improved by 7-IHA and OKY-1581. Liver blood flow, 55% less than values of the control group in shock (p less than 0.05), was returned to values of the controls by both inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)
D000179:Acrylates / Q000494:pharmacology*; D000818:Animals; D004731:Endotoxins / Q000037:antagonists & inhibitors; D006439:Hemodynamics / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D008689:Methacrylates / Q000494:pharmacology*; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects; D012477:Salmonella enteritidis; D012772:Shock, Septic / Q000503:physiopathology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D000179:Acrylates; D004731:Endotoxins; D007093:Imidazoles; D008689:Methacrylates; C024335:1-(7-carboxyhexyl)imidazole; C031517:2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic acid; D013930:Thromboxane-A Synthase