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Clinical Science (1999) 96, (261–270) (Printed in Great Britain)

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Angiotensin II increases the release of endothelin-1 from human cultured endothelial cells but does not regulate its circulating levels

Claudio FERRI, Giovambattista DESIDERI, Roberta BALDONCINI, Cesare BELLINI*, Marco VALENTI†, Anna SANTUCCI† and Giancarlo DE MATTIA

University of Rome 'La Sapienza', Andrea Cesalpino Foundation, Rome 00161, Italy, *Department of Experimental Medicine, University of L'Aquila, L'Aquila 67100, Italy, and †Department of Internal Medicine, University of L'Aquila, L'Aquila 67100, Italy

Abbreviations: ALDO, aldosterone; ANG II, angiotensin II; AVP, arginine vasopressin; ET-1, endothelin-1; HUVECs, human umbilical vascular endothelial cells; PRA, plasma renin activity.

Correspondence: Dr C. Ferri.

We investigated the effect of angiotensin II on endothelin-1 secretion in vitro and in vivo. In vivo, angiotensin II was given intravenously to 23 essential hypertensive and 8 control subjects according to different protocols: Study A, 1.0 ng·min^-1·kg^-1 and 3.0 ng·min^-1·kg^-1 angiotensin II for 30 min each; Study B, 1.0 ng·min^-1·kg^-1 and 3.0 ng·min^-1·kg^-1 angiotensin II for 120 min each; Study C, 3.0 ng·min^-1·kg^-1 angiotensin II for 30 min followed by a dose increment of 3.0 ng·min^-1·kg^-1 every 30 min until mean blood pressure levels increased by 25 mmHg; Study D, 1.0 ng·min^-1·kg^-1 followed by 3.0 ng·min^-1·kg^-1 angiotensin II for 60 min each on two different NaCl diets (either 20 mmol NaCl/day or 220 mmol NaCl/day, both for 1 week). In all in vivo studies neither plasma nor urine endothelin-1 levels changed with angiotensin II infusion. In contrast, angiotensin II (10^-9, 10^-8, 10^-7 mol/l) stimulated endothelin-1 secretion from cultured human vascular endothelial cells derived from umbilical cord veins in a time- and dose-dependent manner. The in vitro angiotensin II effects were abolished by candesartan cilexetil, an inhibitor of the membrane-bound AT₁ receptor, and also by actinomycin D, an RNA synthesis inhibitor, and cycloheximide, a protein synthesis inhibitor, indicating that endothelin-1 release depended on AT₁ receptor subtype and de novo protein synthesis. Our findings indicate that angiotensin II regulates endothelin-1 release by cultured endothelial cells through an AT₁ receptor-dependent pathway, but does not influence circulating endothelin-1 levels in vivo.

Received 20 May 1998/3 September 1998; accepted 7 October 1998

The Biochemical Society and the Medical Research Society © 1999