Potentiation of renal effects of atrial natriuretic factor-(99-126) by SQ 29,072.

Abstract

Depressor and renal activities of atrial natriuretic factor-(99-126) were determined in conscious, unrestrained spontaneously hypertensive rats treated with a neutral endopeptidase inhibitor, SQ 29,amino]heptanoic acid). SQ 29,072 (100 /tmol/kg i.v.) prolonged the transient depressor effects of the peptide for as long as 2 hours. During the first hour after 3, 10, and 30 nmol/kg atrial natriuretic factor, urinary excretion of cyclic 3'5' guanosine monophosphate was significantly increased by 9.2±3.4, 13.0±2.2, and 12.7±4.2 nmol/kg/hr, respectively, in vehicle-treated rats and by 26.9±7.9, 52.1±11.1, and 46.4±12.2 nmol/kg/hr, respectively, in rats given 100 /tmol/kg SQ 29,072. During the first hour after 3 and 10 nmol/kg atrial natriuretic factor-(99-126), the sodium loss was 161±56 and 139±42 /teq/kg/hr in vehicle-treated rats and was significantly greater (694±316 and l,038±135 /teq/kg/hr) in rats given 100 /tmol/kg SQ 29,072. After administration of 3, 10, and 30 /tmol/kg SQ 29,072, the area over the curves of the depressor responses to 3 nmol/kg of the peptide increased from 297±70 to 306±108, 440±143, and 669±186 mm Hgmin, respectively, while the concurrent natriuretic responses rose from 161±56 to 250±88,332±142, 464±164, and 694±316 /teq/kg/hr. In summary, the neutral endopeptidase inhibitor SQ 29,072 increased the magnitudes and especially the durations of the depressor, natriuretic, and cyclic guanosine monophosphate responses to exogenous atria] natriuretic factor-(99-126) in conscious spontaneously hypertensive rats, presumably by inhibition of degradation of atrial natriuretic factor in vivo. In conclusion, neutral endopeptidase inhibition offers an important new technique for enhancement and prolongation of the biological lifetime of atrial natriuretic factor. (Hypertension 1989;14:87-97)

Atrial natriuretic factor-potentiating and antihypertensive activity of SCH 34826. An orally active neutral metalloendopeptidase inhibitor.

“…35 Since submission of this work, several reports on ANF-potentiating activity of neutral endopeptidase inhibitors have appeared. 36 - 38 Our results are consistent with these studies.…”

Effects of Vasopeptidase Inhibition on Renal Function and Tubuloglomerular Feedback in Spontaneously Hypertensive Rats

“…Similar findings have been reported previously in rats (31) and humans (32). The disparity between the two responses was likely due to the fact that the natriuresis is separate from the diuretic response, since the primary control of water reabsorption in the collecting ducts occurs via an antidiuretic hormone, i.e., arginine vasopressin (AVP), and not the ANP-sensitive sodium channel (33).…”

Omapatrilat Versus Lisinopril

“…9 Inhibition of NEP produces increases in plasma ANP concentrations and urine sodium and volume excretion and a decrease in blood pressure (BP) in deoxycorticosterone acetate-salt uninephrectomized rats. 10,11 NEP inhibitors, when given alone, have not been effective as long-term antihypertensive agents in humans, perhaps because of compensatory reflex renin-angiotensin-aldosterone system activation. 12,13 These limitations may be overcome by VPIs through their additional ability to inhibit ACE and to potentiate the kallikrein-kinin system, resulting in additional vasodilation.…”