Margulies K B, Barclay P L, Burnett J C
Section of Cardiology, Temple University School of Medicine, Philadelphia, Pa 19140.
Circulation. 1995 Apr 1;91(7):2036-42. doi: 10.1161/01.cir.91.7.2036.
Recent studies suggest that neurohumoral mechanisms including decreased renal responses to increases in atrial natriuretic factor (ANF) play a central role in the progression from asymptomatic cardiac dysfunction to advanced congestive heart failure (CHF) with sodium retention, vasoconstriction, and reduced exercise tolerance. Recognizing that neutral endopeptidase 24.11 degrades ANF and may be enhanced in CHF, we hypothesized that chronic neutral endopeptidase inhibition (NEP-I) would potentiate renal responses to exogenous ANF and alter the temporal evolution of sodium retention in evolving CHF by potentiation of increased endogenous ANF.
We studied 13 conscious dogs with evolving CHF produced by rapid ventricular pacing at 250 beats per minute. Six of these dogs received NEP-I with candoxatril, 10 mg/kg PO BID, throughout evolving CHF. Responses to exogenous ANF, 10 micrograms/kg IV bolus, were assessed at baseline and after 6 days of CHF. Daily metabolic studies during evolving CHF with chronic NEP-I showed increased sodium excretion and renal cGMP generation consistent with enhanced renal activity of endogenous ANF compared with untreated controls. In addition, renal natriuretic and cGMP responses to exogenous ANF were intact in CHF with chronic NEP-I in contrast to markedly attenuated renal responses to exogenous ANF in untreated CHF. Despite enhanced ANF responsiveness and improved sodium balance in evolving CHF, a moderate degree of sodium retention was observed during chronic NEP-I in evolving CHF.
Enzymatic degradation by neutral endopeptidase limits local renal responses to increases in endogenous and exogenous ANF in CHF independent of changes in systemic hemodynamics or augmented plasma concentrations of ANF. The moderate sodium retention observed during evolving CHF despite chronic NEP-I probably reflects the antinatriuretic effects of hemodynamic and humoral factors independent of ANF activity.
近期研究表明，神经体液机制，包括肾脏对心房利钠因子（ANF）升高的反应性降低，在从无症状性心脏功能不全进展为伴有钠潴留、血管收缩和运动耐量降低的晚期充血性心力衰竭（CHF）过程中起核心作用。鉴于中性内肽酶24.11可降解ANF且在CHF中可能增强，我们推测慢性中性内肽酶抑制（NEP - I）会增强肾脏对外源性ANF的反应，并通过增强内源性ANF的作用来改变CHF进展过程中钠潴留的时间演变。
我们研究了13只通过每分钟250次快速心室起搏诱导出进行性CHF的清醒犬。其中6只犬在整个CHF进展过程中口服坎多沙坦进行NEP - I治疗，剂量为10 mg/kg，每日两次。在基线期和CHF发生6天后评估对外源性ANF（10微克/千克静脉推注）的反应。与未治疗的对照组相比，在CHF进展过程中进行慢性NEP - I治疗的每日代谢研究显示钠排泄增加和肾脏cGMP生成增加，这与内源性ANF的肾脏活性增强一致。此外，与未治疗的CHF对外源性ANF的肾脏反应明显减弱相反，在进行慢性NEP - I治疗的CHF中，肾脏对 外源性ANF的利钠和cGMP反应是完整的。尽管在CHF进展过程中ANF反应性增强且钠平衡改善，但在进行慢性NEP - I治疗的CHF进展过程中仍观察到中度的钠潴留。
中性内肽酶的酶促降解限制了CHF中肾脏对内源性和外源性ANF升高的局部反应，这与全身血流动力学变化或ANF血浆浓度升高无关。尽管进行了慢性NEP - I治疗，但在CHF进展过程中观察到的中度钠潴留可能反映了独立于ANF活性的血流动力学和体液因素的抗利钠作用。
