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

将血管紧张素转换酶（ACE）和中性内肽酶（NEP）联合抑制剂BMS-182657 （BMS）分别以1.5、5、15 mg/kg的剂量静脉给药，再以1.5、5、15 mg/kg/h的剂量静脉持续给药。在二肾一夹高血压大鼠中，BMS降低了平均动脉压（MAP），但不影响尿流率（UV）和尿钠排泄（UNaV），而增加了尿cGMP排泄（UcGMPV）和血浆cGMP水平（PcGMP）。在自发性高血压大鼠中，MAP的下降幅度较小，但UNaV的增加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Dhal盐敏感大鼠中，BMS呈剂量依赖性地降低MAP，增加UV和UNaV。这些变化伴随着UcGMPV和PcGMP的显著增加。心房利钠肽拮抗剂HS-142-1预处理可抑制BMS诱导的MAP下降和UV、UNaV、UcGMPV升高。在Dahl盐抗性大鼠中，BMS对UV、UNaV和UcGMPV的影响较小。因此，这些高血压模型可能对ACE或NEP抑制的敏感性不同。这些结果表明BMS是一种有效的抗高血压药物，适用于各种大鼠高血压模型。

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.