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

血管紧张素转换酶和中性内肽酶双重抑制剂降压药的研制

• 批准号: 09557209
• 负责人: SATOH Susumu
• 金额: $ 7.68万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09557209/
• 关键词: angiotensin-converting enzyme; neutral endopeptidase; dual inhibitor; BMS-182657; atrial natriuretic peptide; mean blood pressure; urine flow rate; urinary sodium excretion

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.

血管紧张素转换酶(ACE)和中性内肽酶(NEP)的联合抑制剂BMS-182657(BMS)先静脉推注(1.5、5、15 mg/kg)，然后持续静脉注射(1.5、5、15 mg/kg/h)。在两肾一夹高血压大鼠中，BMS降低平均动脉压(MAP)而不影响尿流率(UV)和尿钠排泄量(UNaV)，但增加尿cGMP排泄量(UcGMPV)和血浆cGMP水平(PcGMP)。自发性高血压大鼠的MAP下降幅度较小，而UNaV的上升幅度大于其他高血压模型。这些变化伴随着UcGMPV和PcGMP的轻微升高。在达哈尔盐敏感大鼠，BMS以剂量依赖的方式降低MAP，增加UV和UNaV。心钠素拮抗剂HS-142-1可抑制BMS引起的MAP下降及UV、UNaV和UcGMPV的升高。在Dahl耐盐大鼠，BMS对UV、UNaV和UcGMPV的影响不大，提示这些高血压模型对ACE或NEP抑制的敏感性不同。这些结果表明，BMS是一种有效的降压剂，在各种大鼠高血压模型中都是如此。