Pharmacological analysis of endotoxin-induced cardiovascular dysfunction

1995 Fiscal Year Final Research Report Summary

• Project/Area Number: 06672273
• Research Category: Grant-in-Aid for General Scientific Research (C)
• Allocation Type: Single-year Grants
• Research Field: 応用薬理学・医療系薬学
• Research Institution: Osaka City University
• Principal Investigator: MIURA Katsuyuki Osaka City University, Medical School, Lecturer, 医学部, 講師 (00183624)
• Project Period (FY): 1994 – 1995
• Keywords: Endotoxin / Shock / Cardiac output / Platelet-activating factor / Prostaglandin / Thromboxane / Adrenomedullin

Research Abstract

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.

Research Products

• [Publications] Ebara,T.,Miura,K.,Okumura,M.,Matsuura,T.,Kim,s.,Yukimura,T and Iwao,H.: "Effect of adrenomedullin on renal hemodynamics and functions in dogs" Eur J Pharmacol. 263. 69-73 (1994)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Miura,K.,Ebara,T.,Okumura,M.,Matsuura,T.,Kim,s.,Yukimura,T and Iwao,H.: "Attenuation of adrenomedullin-induced renal vasodilatation byN^G-nitro L-arginine but not benclamide" Br J Pharmacol. 115. 917-924
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Ebara, T., Miura, K., Okumura, M., Matsuura, T., Kim, S., Yukimura, T.& Iwao, H: "Effects of adrenomedullin on renal hemodynamics and functions in dogs." Eur J Pharmacol. 263. 69-73 (1994)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Miura, K., Ebara, T., Okumura, M., Matsuura, T., Kim, S., Yukimura, T.& Iwao, H.: "Attenuation of adrenomedullin-induced renal vasodilatation by N^G-nitro L-arginine but not glybenclamide" Br J Pharmacol. 115. 917-924 (1995)
  • Description: 「研究成果報告書概要(欧文)」より