ABSTRACT

Although it has long been known that glucocorticoid excess is associated with hypertension, the mechanisms by which they affect blood pressure are still not well understood. Endothelin-1 is a potent vasoactive peptide involved in the maintenance of vascular tone as well as in pathophysiological states. Soon after its isolation ten years ago, it was shown that glucocorticoids increase endothelin-1 secretion in vascular smooth muscle cells (VSMC). Neither the consequences nor the mechanisms by which glucocorticoids affect endothelin-1 production have been clearly established.

We have thus sought to determine the effect of glucocorticoids on preproendothelin-1 expression in vivo and in vitro. Our data show that a single injection of dexamethasone increases preproendothelin-1 expression in rat aorta. This rise in the steady state mRNA level is rapid with a significant increase within one hour and a maximal 2.5-fold stimulation eight hours after glucocorticoid administration. Furthermore, systolic blood pressure is elevated in dexamethasone- treated rats suggesting that the increase in vascular preproendothelin-1 mRNA is responsible for the rise in blood pressure. In VSMC, we have shown that glucocorticoids stimulate preproendothelin-1 gene transcription rate (Morin C et  al. 1998, BBRC 244:583). The rise in preproendothelin-1 steady state mRNA level in VSMC is rapid and transient with a maximal three-fold stimulation within one hour of glucocorticoid treatment. Glucocorticoid effect is dose-dependent (EC₅₀ ~ 2-3 nM) and completely blocked by co-incubation with the glucocorticoid antagonist RU 38486, clearly showing that it is mediated by the glucocorticoid receptor (GR).

Conversely, we and others have previously shown that glucocorticoids decrease the binding of endothelin-1 to its vasopressor endothelin-A (ET-A) receptor in VSMC. In order to determine the mechanism(s) by which glucocorticoids exert their effect on ET-A receptor number, we have studied its expression in VSMC. Our data show that a lowering of ET-A steady state mRNA levels parallels the decrease in endothelin- 1 binding. This decline in ET-A receptor expression is maximal by 12 hours and tends to return to baseline values at 24 hours. When VSMC are incubated with the ET-A receptor antagonist BQ-123 alone, ET-A receptor expression rises and the addition of BQ-123 concomitantly with the glucocorticoid agonist RU 28362 reverses the glucocorticoid-induced decrease in ET-A receptor expression. These data suggest that the endogenous production of endothelin-1 exerts a down-regulatory action on its own receptors.

Our results show that glucocorticoids acutely increase blood pressure in rats and suggest that elevated endothelin-1 levels are involved. In addition to their transcriptional regulation of the preproendothelin- 1 gene, glucocorticoids affect ET-A receptor expression in VSMC. Together, our results suggest a novel and complex interplay between glucocorticoids and endothelin-1, its receptors and effectors in the vessel wall, which is likely to contribute to the regulation of blood pressure by corticosteroids in health and disease.