Clarifying endothelin type B receptor function.

Endothelin (ET) receptors have become the targets for the treatment of a variety of cardiovascular disorders and a mixed ET type A (ETA)/ET type B (ETB) receptor antagonist, bosentan, is currently being used to effectively treat pulmonary hypertension. An ongoing debate has revolved around the question of whether selective ETA receptor blockade would be preferable to using the mixed antagonist. The functional role of ET-1 is complicated by the opposing actions of the ETA and ETB receptor in the vasculature, as well as the kidney. ETB receptor function is further complicated by the presence of vasoconstrictor ETB receptors on vascular smooth muscle in some vascular beds, whereas ETB receptors on endothelium and renal tubules have vasodilator and natriuretic activities. ETB receptors also serve to clear ET-1 from the circulation and, thus, minimize vasoconstrictor activity. Despite the well-recognized effects of ETB receptors to oppose ETAmediated actions, it is not clear whether blocking both ETA and ETB receptors at the same time is detrimental or advantageous compared with selective ETA blockade. Indeed, ETA selective antagonists are also expected to soon receive approval for treatment of pulmonary hypertension. Although this may indicate that both strategies work in pulmonary hypertension, the pros and cons of selective versus mixed antagonists are much less clear in arterial hypertension and heart and kidney failure. Previous studies have shown that pharmacological blockade or genetic deficiency of ETB receptors results in salt-sensitive hypertension in rats.1,2 More recent studies have now provided information on the location(s) of the ETB receptors responsible for this effect. Ahn et al3 demonstrated salt-sensitive hypertension in mice where ET-1 expression was selectively knocked out in the renal collecting duct. It was not clear, however, whether ET-1 originating from the collecting duct acts on ETB receptors of vascular elements within the renal medulla or in an autocrine fashion on ETB receptors of collecting duct cells. In the current issue of Hypertension, Bagnall et al4 report that selective deletion of the ETB receptor from endothelial cells in mice has no affect on blood pressure or salt sensitivity despite reduced endothelial-dependent relaxation. The authors conclude that ET-1 more likely acts in an autocrine fashion on collecting duct cells, as opposed to activating endothelial ETB receptors on vasa recta, which could facilitate sodium excretion through an increase in medullary perfusion. This conclusion is further supported by reports that ETB receptors inhibit electrolyte reabsorption in vitro.5–7 Strictly speaking, a role for increased medullary perfusion in the renal response to a high-salt diet mediated by the ETB receptor cannot be completely ruled out yet. It is conceivable that activation of ETB receptors on tubular cells causes vasa recta to dilate through a “tubulovascular crosstalk” mechanism similar to that described previously for buffering angiotensin II–mediated vasoconstriction in the renal medulla and mediated by NO.8 Although some questions do remain about the precise mechanisms, the studies by Bagnall et al,4 together with previous results from other groups, indicate a major role for renal tubular ETB receptors in mediating ET-1–induced natriuresis.3,4,7 In addition to giving new insight into the renal mechanisms, the current study also seems to dramatically reduce the likelihood of vascular endothelial ETB receptors mediating saltsensitive hypertension during systemic ETB receptor blockade. Interestingly, previous cross-transplantation experiments in ETB receptor–deficient rats showed that salt sensitivity in this model depended on the deletion of extrarenal ETB receptors.9 This raises the possibility that a yet-unidentified extrarenal ETB receptor may have a protective effect against salt-sensitive hypertension, in addition to the ETB receptor on renal tubular cells. Although it has been assumed for quite some time that the endothelial ETB receptor is responsible for clearing circulating ET-1, the functional ramifications of this concept have been difficult to discern with other models in rats, such as pharmacological ETB receptor blockade or ETB receptor deficiency.1,2 Endothelial-specific ETB knockout mice have elevated levels of circulating ET-1, which provide even more definitive evidence for a role of ETB receptors on endothelium in clearing ET-1 from the circulation. However, it is now also important to realize that the resulting elevations in circulating ET-1 do not account for the hypertension produced by pharmacological or genetic disruption of the ETB receptor as documented previously.1,2 Several laboratories have shown that hypertension produced by ETB receptor blockade or high-salt intake in ETB receptor–deficient rats can be blocked by ETA receptor antagonism.2,10,11 Although an obvious argument is that a lack of ETB receptors displaces ET-1 to produce greater ETA receptor–dependent vasoconstriction, this cannot account for the hypertension in these models given these new findings. Just because ETA receptor blockade reduces blood pressure in a model of hypertension does not signify that the hypertension was produced by increased ETA receptor activation. It is also not clear how a shift of ET-1 from the ETB to the ETA receptor could explain the salt dependence of these models. Again, these new results favor a renal mechanism for the salt-sensitive hypertension observed with ETB receptor blockade or genetic deficiency of ETB receptors. Although this study represents an important advance in our understanding of how ET-1 controls blood pressure, there are a number of questions about ETB receptor function that remain. It should be noted that control mice in the current study were salt sensitive, and so it will be important to establish that a lack of The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Vascular Biology Center, Medical College of Georgia, Augusta. Correspondence to David M. Pollock, Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912-2500. E-mail [email protected] (Hypertension. 2006;48:1-2.) © 2006 American Heart Association, Inc.