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(Circulation. 1995;92:106-113.)
© 1995 American Heart Association, Inc.

Articles

Role of Endogenous Endothelin-1 in Experimental Renal Hypertension in Dogs

Julian Donckier, MD, PhD; Liviu Stoleru, MD; Wataru Hayashida, MD; Henri Van Mechelen, MS; Philippe Selvais, MD; Laurence Galanti, MD; Jean-Paul Clozel, MD; Jean-Marie Ketelslegers, MD, PhD; Hubert Pouleur, MD, PhD

From the Divisions of Endocrinology and Internal Medicine (J.D., L.G.), University Hospital UCL of Mont-Godinne, Yvoir, Belgium; Departments of Physiology and Cardiology (L.S., W.H., H.V.M., H.P.) and the Unit of Diabetology and Nutrition (P.S., J.-M.K.), University of Louvain, Brussels, Belgium; and the Pharma Division (J.-P.C.), Preclinical Research, F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Correspondence to Julian Donckier, MD, PhD, Endocrinology and Internal Medicine, University Hospital of Mont-Godinne, 5530 Yvoir, Belgium.

Background Endothelin-1, a vasoconstrictive peptide released by endothelium, may be involved in the pathophysiology of hypertension. The goal of the present study was to evaluate the role of endogenous endothelin-1 in renal hypertension in dogs. The model of hypertension consisted of silk tissue wrapping of the left kidney, which produced hypertension associated with perinephritis after 6 to 8 weeks.

Methods and Results Thirty-two anesthetized open chest dogs were studied randomly: 8 dogs with perinephritic hypertension received the nonpeptidic ET_A-ET_B receptor antagonist bosentan (group 1); 8 other hypertensive dogs received the vehicle solution (group 2); 8 healthy dogs received bosentan (group 3); and 8 healthy dogs received the vehicle solution (group 4). Bosentan was injected as an intravenous bolus (3 mg/kg) followed by a 1-hour infusion at a rate of 7 mg · kg^-1 · h^-1. In hypertensive dogs, bosentan produced a similar decrease (P=.0001) of both left ventricular systolic and mean aortic pressures, which averaged 38 mm Hg (-22% and -24%, respectively). These parameters remained unchanged with the vehicle solution. Left ventricular end-diastolic and left atrial pressures also declined significantly with bosentan (P=.0005 and P<.05, respectively). Left ventricular lengths tended to decrease. The other cardiovascular parameters (heart rate, peak [+]dP/dt, time constant of relaxation, and coronary vascular resistance) did not change significantly. In healthy dogs, bosentan decreased mean aortic pressure by 19 mm Hg (P=.004). Vehicle solution had no effect. Plasma endothelin-1 levels, similar under basal conditions in healthy and hypertensive dogs, increased 30-fold with bosentan (P=.0001).

Conclusions Specific endothelin-1 receptor antagonism markedly lowers blood pressure in experimental hypertension but is less effective on blood pressure of healthy animals. This suggests that endothelin-1 plays a role in the pathophysiology of hypertension but contributes to a lesser extent to the maintenance of normal blood pressure. This role of endothelin-1 is unrelated to its plasma levels. The increase of plasma endothelin-1 with bosentan, due either to a displacement of endothelin-1 from its receptor or to a feedback mechanism, does not prevent this blood pressure reduction.

Key Words: endothelin • hypertension • kidneys

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