Development of the dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase as the antihypertensive drugs

1998 Fiscal Year Final Research Report Summary

• Project/Area Number: 09557209
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 展開研究
• Research Field: 応用薬理学・医療系薬学
• Research Institution: Tohoku University
• Principal Investigator: SATOH Susumu Tohoku University, Faculty of Pharmaceutical Sciences, Department of Pharmacoloigy, Professor, 薬学部, 教授 (80004604)
• Co-Investigator(Kenkyū-buntansha): SAKAMOTO Takao Tohoku University, Faculty of Pharmaceutical Sciences, Department of Heterocycli, 薬学部, 教授 (00006347) ; YOSHIDA Makoto Tohoku university, Faculty of Pharmaceutical Sciences, Department of Pharmacolog, 薬学部, 助手 (90201011) ; SUZUKI Mizue (KUSABA Miz) Tohoku University, Faculty of Pharmaceutical Sciences, Department of Pharmacolog, 薬学部, 助手 (50175311) ; HISA Hiroaki Tohoku University, Faculty of Pharmaceutical Sciences, Department of Pharmacolog, 薬学部, 助教授 (60192712) ; KOGI Kentaro TOA EIYO Ltd., Fukushima Laboratory, Drug Research Department Director of Fukush
• Project Period (FY): 1997 – 1998
• Keywords: angiotensin-converting enzyme / neutral endopeptidase / dual inhibitor / BMS-182657 / atrial natriuretic peptide / mean blood pressure / urine flow rate / urinary sodium excretion

Research Abstract

BMS-182657 (BMS), a combined inhibitor of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), was administered bolus intravenously (1.5, 5, 15 mg/kg) followed by continuous intavenous infusion (1.5, 5, 15 mg/kg/h) in several kinds of conscious hypertensive model rats. In the two kidney-one clip hypertensive rats, BMS decreased mean arterial pressure (MAP) without affecting urine flow rate (UV) or urinary sodium excretion (UNaV), whereas it increased urinary cGMP excretion (UcGMPV) and plasma cGMP level (PcGMP). In spontaneously hypertensive rats, the decrease in MAP was smaller but the increase in UNaV was greater than those observed in other models of hypertension. These changes were accompanied by slight increases in UcGMPV and PcGMP.In Dhal salt-sensitive rats, BMS decreased MAP and increased UV and UNaV in a dose dependent manner. These changes were accompanied by great increases in UcGMPV and PcGMP.Pretreatment with HS-142-1, an atrial natriuretic peptide antagonist, suppressed the decrease in MAP and the increases in UV, UNaV and UcGMPV induced by BMS.In Dahl salt-resistant rats, BMS had little influence on UV, UNaV and UcGMPV.Therefore, these hypertensive models may have different sensitivity to ACE or NEP inhibition. These results suggest that BMS is an effective antihypertensive agent across a spectrum of rat hypertension models.