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Role of Endothelin in the Control of Peripheral Vascular Tone in Human Hypertension

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Abstract

Endothelins are potent 21 amino acid vasoconstrictor isopeptides produced in different vascular tissues, including vascular endothelium. Endothelin-1 is the main endothelin generated by the endothelium and probably the most important in the cardiovascular system. Endothelin-1 acts through specific receptors termed ETA, represented only on smooth muscle cells and having the function of growth promotion and mediating contractions, and ETB, located both on smooth muscle cells, where they evoke contractions, and on endothelial cells, inducing relaxation by production of the endothelium-derived relaxing factor nitric oxide. In physiological conditions endothelin-1 administration causes vasodilation and vasoconstriction at low and high concentrations, respectively. However, administration of mixed ETA/B receptor antagonists causes slight or absent vasodilation, indicating that the direct vasoconstrictor effect of the peptide is probably masked by ETB-induced NO-dependent vasodilation. In essential hypertensive patients, the activity of exogenous endothelin-1 is either increased, similar or decreased as compared to normotensive subjects, depending on which vascular district or scheme of administration is considered. But although available evidence does not indicate increased endothelin-1 plasma levels in patients with essential hypertension, simultaneous antagonism of ETA/B receptors causes a greater degree of vasodilation in hypertensives than in normotensive subjects. Moreover administration of a selective ETB receptor antagonist causes vasoconstriction in normotensive subjects and vasodilation in essential hypertensive patients. Finally, the vasodilating effect of a mixed ETA/B receptor antagonist is inversely related to NO availability. Taken together these findings suggest that essential hypertension is characterized by increased endothelin-1 vasoconstrictor tone. This alteration seems to be dependent on decreased endothelial ETB-mediated NO production attributable to impaired NO availability. In such conditions endothelial ETB-induced vasodilation no longer compensates for the direct classical endothelin vasoconstrictor effect mediated by smooth muscle cell ETA and ETB receptors. Therefore endothelin-1 could potentially be involved in the pathogenesis of essential hypertension or of its complications, and blockade of this system is a fascinating new target for therapeutic intervention in this disease.

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Authors and Affiliations

  1. Department of Internal Medicine, University of Pisa, Pisa, Italy

    Stefano Taddei, Agostino Virdis, Lorenzo Ghiadoni, Isabella Sudano, Armando Magagna & Antonio Salvetti

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  1. Stefano Taddei
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  2. Agostino Virdis
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  3. Lorenzo Ghiadoni
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  4. Isabella Sudano
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  5. Armando Magagna
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  6. Antonio Salvetti
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Taddei, S., Virdis, A., Ghiadoni, L. et al. Role of Endothelin in the Control of Peripheral Vascular Tone in Human Hypertension. Heart Fail Rev 6, 277–285 (2001). https://doi.org/10.1023/A:1011400124060

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