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

BMS-182657（BMS）是一种血管紧张素转换酶（ACE）和中性内肽酶（NEP）的联合抑制剂，静脉推注（1.5，5，15 mg/kg），然后持续静脉输注（1.5，5，15 mg/kg/h）给几种清醒高血压模型大鼠。在两肾一夹高血压大鼠中，BMS降低平均动脉压（MAP），但不影响尿流率（UV）和尿钠排泄量（UNaV），增加尿cGMP排泄量（UCGMPV）和血浆cGMP水平（PcGMP）。在自发性高血压大鼠中，MAP的下降较小，但UNaV的增加大于在其他高血压模型中观察到的。在Dhal盐敏感大鼠中，BMS呈剂量依赖性降低MAP，增加UV和UNaV。预先给予心房钠尿肽拮抗剂HS-142-1可抑制BMS引起的MAP下降和UV、UNaV和UcGMPV的升高，而BMS对Dahl盐耐受大鼠的UV、UNaV和UcGMPV的影响不大。这些结果表明，BMS是一种有效的抗高血压药物在整个频谱的大鼠高血压模型。

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.