Pharmacological analysis of endotoxin-induced cardiovascular dysfunction

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Following endotoxin administration, a number of biologically active substances are induced that elicit various cardiovascular actions. Among those, adrenomedullin is a vasodepressor peptide recently discovered. In the present research project, I first examine the mode and mechanisms of action of this peptide on the kidney, one of the target organ of endotoxin-induced organ dysfunction. The results suggest that this peptide elicits nitric oxide-mediated renal vasodilation and diuresis, suggesting the possible protective role of adrenomedullin in endotoxin-induced renal insult.Next, I examine the sequences of systemic hemodynamics following endotoxin administration. In the experiment, I used TCV-309 (a PAF receptor antagonist), ibuprofen (a cyclooxygenase inhibitor) and S-1452 (a thromboxane A2/prostaglandin H2 receptor antagonist) and elucidated the sites of action of endogenous PAF and cyclooxygenase metabolites in experimental rat endotoxic shock. I found that all of these drugs attenuated endotoxin-induced decrease in cardiac output and increase in hematocrit. Thus, it was suggested that PAF and cyclooxygenase products, particularly thromboxane A2 elicited the reduction in cardiac output in rat endotoxic shock. Both ibuprofen and S-1452 attenuated hypotension only shortly after endotoxin administration whereas TCV-309 attenuated it only 3 hr after endotoxin. Total vascular resistance was increased by endotoxin that was attenuated by these three drugs, suggesting these drugs improve endotoxin-induced hemodynamic deterioration by blocking reduction in cardiac output and improving peripheral hemodynamics. In addtion, it was found that prostanoid other than thromboxane A2 is involved in the endotxin-induced tachycardia.