INHIBITION OF NEUTRAL ENDOPEPTIDASE CAUSES VASOCONSTRICTION OF HUMAN RESISTANCE VESSELS IN-VIVO

Background-Neutral endopeptidase (NEP) degrades vasoactive peptides, i ncluding the natriuretic peptides, angiotensin II, and endothelin-1. S ystemic inhibition of NEP does not consistently lower blood pressure, even though it increases natriuretic peptide concentrations and causes natriuresis and diuresis. We therefore investigated the direct effect s of local inhibition of NEP on forearm resistance vessel tone. Method s and Results-Four separate studies were performed, each with 90-minut e drug infusions. In the first study, 10 healthy subjects received a b rachial artery infusion of the NEP inhibitor candoxatrilat (125 nmol/m in), which caused a slowly progressive forearm vasoconstriction (12+/- 2%; P=0.001). In a second two-phase study, 6 healthy subjects received , 4 hours after enalapril (20 mg) or placebo, an intra-arterial infusi on of the NEP inhibitor thiorphan (30 nmol/min). Thiorphan caused simi lar degrees of local forearm vasoconstriction (P=0.6) after pretreatme nt with both placebo (13+/-1%, P=0.006) and enalapril (17+/-6%, P=0.05 ). In a third three-phase study, 8 healthy subjects received intra-art erial thiorphan (30 nmol/min), the endothelin ETA antagonist BQ-123 (1 00 nmol/min), and both combined. Thiorphan caused local forearm vasoco nstriction (13+/-1%, P=0.0001); BQ-123 caused local vasodilatation (33 +/-3%, P=0.0001). Combined thiorphan and BQ-123 caused vasodilatation (32+/-1%, P=0.0001) similar to BQ-123 alone (P=0.98). In a fourth stud y, 6 hypertensive patients (blood pressure > 160/100 mm Hg) received i ntra-arterial thiorphan (30 nmol/min). Thiorphan caused a slowly progr essive forearm vasoconstriction (10+/-2%, P=0.0001).Conclusions-Inhibi tion of local NEP causes vasoconstriction in forearm resistance vessel s of both healthy volunteers and patients with hypertension. The lack of effect of ACE inhibition on the vasoconstriction produced by thiorp han and its absence during concomitant ETA receptor blockade suggest t hat it is mediated by endothelin-1 and not angiotensin II. These findi ngs may help to explain the failure of systemic NEP inhibition to lowe r blood pressure.