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CLINICAL STUDY

Increased activity of endogenous endothelin in patients with hypercholesterolemia

^a Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA

Manuscript received March 15, 2000; revised manuscript received April 19, 2000, accepted June 26, 2000.

Reprint requests and correspondence: Dr. Julio A. Panza, Cardiology Branch, National Institutes of Health, 10 Center Dr, MSC 1650, Building 10, Room 7B-15, Bethesda, Maryland 20892-1650
panzaj{at}nih.gov

OBJECTIVE

We sought to assess the activity of endogenous endothelin-1 (ET-1) in hypercholesterolemic patients using antagonists of ET-1 receptors.

BACKGROUND

Endothelial dysfunction in hypercholesterolemic patients may contribute to their risk of premature atherosclerosis. Endothelin, a peptide released by endothelial cells, may be involved in this process by activating smooth muscle cell mitogenesis and leukocyte adhesion.

METHODS

Forearm blood flow (FBF) responses (strain-gauge plethysmography) to intra-arterial infusion of a selective blocker of ETA receptors (BQ-123) and, on a separate occasion, to ET-1 were measured in 12 hypercholesterolemic patients and 12 normal control subjects. In addition, on a different day, six hypercholesterolemic patients received co-infusion of BQ-123 and BQ-788 (a selective blocker of ETB receptors).

RESULTS

In normal subjects, BQ-123 did not significantly modify FBF from baseline (p = 0.78); however, in hypercholesterolemic patients, BQ-123 administration resulted in a significant vasodilator response (p < 0.001). Administration of exogenous ET-1 resulted in similar vasoconstrictor responses in patients (37%) and control subjects (35%) (p = 0.83). In hypercholesterolemic patients, the vasodilator response to selective ETA blockade was reversed by nonselective blockade of ET-1 receptors obtained by co-infusion of BQ-123 and BQ-788.

CONCLUSIONS

The vascular activity of endogenous ET-1 is enhanced in hypercholesterolemic patients, whereas their sensitivity to exogenous ET-1 is unchanged. These findings suggest increased production of ET-1, which may participate in the pathophysiology of vascular disease characteristic of hypercholesterolemia.

Abbreviations and Acronyms   BP = blood pressure   ET-1 = endothelin-1   FBF = forearm blood flow   NHLBI = National Heart, Lung, and Blood Institute   NO = nitric oxide

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