Seymour A A, Asaad M M, Abboa-Offei B E, Smith P L, Rogers W L, Dorso C R
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey, USA.
J Pharmacol Exp Ther. 1996 Feb;276(2):708-13.
Simultaneous inhibition of neutral endopeptidase EC 3.4.24.11 (NEP) and angiotensin converting enzyme (ACE) by equimolar doses (100 mumol/kg i.v.) of SQ 28603 (N-[2-(mercaptomethyl)-1-oxo-3- phenylpropyl]-beta-alanine) and captopril increased sodium excretion by 888 +/- 377 microEq/3 hr and significantly lowered blood pressure by -6 +/- 2 mm Hg in conscious cynomolgus monkeys. This rate of sodium excretion was not significantly different from that elicited by 100 mumol/kg i.v. of SQ 28603 alone (1453 +/- 315 microEq/3 hr). In addition, the natriuretic response to captopril plus SQ 28603 was potentiated by infusion of 10 pmol/kg/min of human atrial natriuretic peptide (hANP 99-126) despite a reduction in renal perfusion pressure from 100 +/- 2 to 86 +/- 2 mm Hg. Lower doses (0.3 to 3 mumol/kg i.v.) of SQ 28603 that had no effect on blood pressure or renal function potentiated the natriuretic, urinary cyclic guanosine monophosphate and atrial natriuretic peptide responses without affecting the depressor activity of 0.3 nmol/kg i.v. of hANP 99-126. The potentiation of the natriuretic activity of 0.3 nmol/kg of hANP 99-126 by 1 or 3 mumol/kg of SQ 28603 was not significantly affected by the addition of equimolar doses of captopril. These results confirmed that the renal responses to the combined inhibitors resulted from NEP inhibition. In contrast, the depressor activity of the combined inhibitors was dependent on the level of ACE inhibition and was not significantly affected by either infusion of hANP 99-126 or prior sodium loading. Therefore, the vascular responses to combined NEP and ACE inhibitors did not necessarily depend upon increases in circulating atrial natriuretic peptide or reductions in angiotensin II levels. The unique profile of renal and vascular responses to combined NEP and ACE inhibition suggested that dual NEP/ACE inhibitors may be useful for the treatment of cardiovascular disorders.
等摩尔剂量（100 μmol/kg静脉注射）的SQ 28603（N-[2-(巯基甲基)-1-氧代-3-苯基丙基]-β-丙氨酸）和卡托普利同时抑制中性内肽酶EC 3.4.24.11（NEP）和血管紧张素转换酶（ACE），可使清醒食蟹猴的钠排泄量增加888±377微当量/3小时，并使血压显著降低6±2毫米汞柱。这种钠排泄率与单独静脉注射100 μmol/kg的SQ 28603所引起的排泄率（1453±315微当量/3小时）无显著差异。此外，尽管肾灌注压从100±2降至86±2毫米汞柱，但静脉输注10 pmol/kg/分钟的人心房利钠肽（hANP 99 - 126）可增强对卡托普利加SQ 28603的利钠反应。较低剂量（0.3至3 μmol/kg静脉注射）的SQ 28603对血压或肾功能无影响，但可增强利钠、尿中环磷酸鸟苷和心房利钠肽反应，而不影响静脉注射0.3 nmol/kg的hANP 99 - 126的降压活性。1或3 μmol/kg的SQ 28603对0.3 nmol/kg的hANP 99 - 126利钠活性的增强作用，在加入等摩尔剂量的卡托普利后无显著影响。这些结果证实，对联合抑制剂的肾脏反应是由NEP抑制引起的。相反，联合抑制剂的降压活性取决于ACE抑制水平，不受hANP 99 - 126输注或先前钠负荷的显著影响。因此，对联合NEP和ACE抑制剂的血管反应不一定依赖于循环心房利钠肽的增加或血管紧张素II水平的降低。联合NEP和ACE抑制的独特肾脏和血管反应特征表明，双重NEP/ACE抑制剂可能对治疗心血管疾病有用。
