POTENTIAL MECHANISMS BY WHICH NONSTEROIDAL ANTIINFLAMMATORY DRUGS ELEVATE BLOOD-PRESSURE - THE ROLE OF ENDOTHELIN-1

To determine whether endothelin-l (ET-1) contributes to hypertension a ssociated with non-steroidal anti-inflammatory drug (NSAID) usage in h ealthy, elderly, normotensive individuals a randomised, double-blind, placebo-controlled, crossover trial of indomethacin was undertaken in 41 healthy, elderly individuals with stable normotension or controlled hypertension (blood pressure (BP) less than or equal to 160/90 mm Hg) . The main outcome measures were systolic and diastolic BP, heart rate , cardiac output, weight, creatinine clearance, plasma renin activity, aldosterone, endothelin-l and arginine vasopressin concentrations and 24 h urinary endothelin-l and 6 keto prostaglandin F-1 alpha outputs. Analysis of covariance was used to evaluate the effect of indomethaci n on BP and related parameters. Indomethacin treatment for 1 month inc reased systolic (+/- s.e.m.: 4.1 +/- 2.2 mm Hg; 95% confidence interva l 0 to 8.3 mm Hg) and diastolic BP (2.7 +/- 1.1 mm Hg; 0.4 to 4.9 mm H g) without altering cardiac output (P = 0.59), implying an increase in total peripheral resistance. Indomethacin treatment produced a small increase in weight (1.4 +/- 0.4 kg; 0.6 to 2.2 kg), a small reduction in renal function (creatinine clearance: 6.8 +/- 1.8 mls/min; 3.3 to 1 0.3 mls/min) but a significant (83%) increase in daily urinary endothe lin-l production (13.1 +/- 3.4 ng/ml; 6.4 to 19.8 ng/ml) without alter ing plasma ET-1 concentration, suggesting increased renal synthesis. I n conclusion, renal paracrine effcts of ET-1 may contribute to NSAID-i nduced blood pressure elevation in humans.