Endothelin receptors and calcium signaling ¹

Abstract

Endothelin (ET) is a potent vasoactive peptide produced by endothelial cells that elicits prolonged constriction in most smooth muscle preparations and dilation in others. Of three isopeptides, ET-1 is the only form constitutively released and may modulate vascular tone via binding to one of several receptor subtypes in smooth muscle. Activation of the ETA receptor is associated with pronounced vasoconstriction whereas ETB receptor occupation is linked to vasodilation. In addition, other subtypes of the ETB receptor exist, one mediating vasodilation (ETB1) and the other eliciting constriction (ETB2). An additional receptor subtype, ETC, has been identified although its physiological significance is uncertain. Distribution of these receptors varies between species and among tissue types, although it has been generally observed that ETA receptors predominate in arterial vessels whereas ETB receptors predominate on the low pressure side of the circulation. In vascular smooth muscle, an increase in intracellular Ca2+ is a common feature occurring after activation of all receptor subtypes. Upon binding of ET-1 to ETA, phospholipase C is activated and inositol triphosphate is generated. Ca2+ is then released from intracellular stores accompanied by the influx of extracellular Ca2+ and activation of the contractile machinery. The precise mechanism by which ET-1 affects intracellular Ca2+ regulation is not fully understood, but most likely involves multiple ion channels, protein kinases, and other intracellular mediators. The events coupled to non-ETA receptor signaling are poorly understood.

Phosphorylation and Desensitization of Human Endothelin A and B Receptors

“…Whereas ET-R-promoted phospholipase C activity desensitizes rapidly, ET-R-promoted phospholipase D activity (2) may desensitize much more slowly, as has been observed for the AT 1A -R (18,49). Furthermore, the attenuating effect of nitric oxide on ET-1-stimulated signaling (39), which may facilitate ET-1 signal termination in vivo, may be unphysiologically deficient in experimental systems demonstrating sustained ET-1-promoted activity (1,48).…”

Rosiglitazone prevents the progression of renal injury in DOCA-salt hypertensive rats

“…21 The function of ET B R appears to be more complex, as it is located on a variety of cell types. 22 ET B R is particularly abundant in the renal medullary epithelium, where it appears to influence tubular sodium and water reabsorption, accounting for the natriuretic and diuretic actions of ET-1. 23 The selective blockade of ET B R resulted in increased blood pressure and increased sodium and water retention in DOCA-salt rats.…”

Acute blockade by endothelin-1 of haemodynamic insulin action in rats

“…Therefore results might have been more dramatic if endothelin-1 had been infused at a higher rate or as a bolus prior to insulin infusion. However, once endothelin-1 concentrations plateau, the actions are marked and long lasting [11]. Therefore, this model is more representative of a disease state in which plasma concentrations are high, such as during diabetes or hypertension.…”

“…Endothelin-1 is also thought to be involved in the redistribution of flow seen during exercise, causing con-striction in the gut and non-working muscles [8,9]. Although plasma endothelin-1 has a short half-life of approximately 3.6 min [10] and is cleared rapidly from circulation by the pulmonary, splanchnic and renal systems, endothelin-1 has long-lasting and potent vasoconstrictor effects [11].…”