Commentary on Expression of Exogenous Epithelial Sodium Channel Beta Subunit in the Mouse Middle Cerebral Artery Increases Pressure-Induced Constriction

In this issue of the American Journal of Hypertension, Nemeth et al. report important new information regarding a potential role for the epithelial sodium channel (ENaC) in pressure-induced constriction/myogenic responses.1 Although ENaC is present in the late distal convoluted tubule, the connecting tubule, and the entire collecting duct of the kidney, it is now well known that it can be found elsewhere in the body including blood vessels.2 In the present study, the investigators took advantage of ex vivo transfection technology to overexpress ENaC in mouse middle cerebral arteries. Although previous studies have looked at the possible effects of inhibition of ENaC, the present studies provide new information in that “gain of function” was examined. Such a situation occurs clinically in patients with Liddle’s syndrome who exhibit excessive distal nephron sodium reabsorption as the result of inappropriately high ENaC activity. The excessive sodium retention drives down circulating renin and aldosterone levels and renders agents that interfere with the rennin–angiotensin–aldosterone system ineffective in reducing the hypertension of these patients. Direct inhibition of ENaC with amiloride effectively lowers blood pressure in these patients. It is not clear whether vascular ENaC is overexpressed in patients with Liddle’s syndrome or other forms of inappropriately high ENaC activity and whether inhibition of vascular ENaC contributes to the antihypertensive effect of amiloride unrelated to an effect to increase urinary sodium excretion. Although amiloride is effective in lowering blood pressure in Liddle’s syndrome, this syndrome is an extremely rare genetic disorder. However, the use of amiloride together with hydrochlorothiazide is common and of great utility in combating hypertension and cardiovascular events.3 Thus, the contribution of inhibition of vascular ENaC to blood pressure lowering could potentially be of widespread clinical relevance. The present study raises many important questions about the regulation of vascular ENaC. Studies by Kornel and Smoszna-Konaszewska showed that exposure of aortic vascular smooth muscle cells to physiology concentrations of aldosterone for 7–10 days caused an increase in sodium flux, which was completely inhibited by low concentrations of amiloride.4 Angiotensin II (independent of aldosterone) directly stimulates ENaC in the cortical collecting duct.5 Likewise, vasopressin6 has been reported to stimulate ENaC, whereas endothelin7 has been reported to inhibit ENaC in the rat collecting duct. Endothelin is a vascular hormone produced by endothelial cells and is overexpressed when levels of nitric oxide are low, such as during endothelial dysfunction or endothelial nitric oxide synthase inhibition.8 Aldosterone, angiotensin II, and vasopressin may all be elevated to some degree in the hypertensive state making vascular ENaC a point of convergence of these systems and potential therapeutic target. Another interaction to consider is that between epoxyeicosatrienoic acid and ENaC. 11,12-Epoxyeicosatrienoic acid has been demonstrated to exert an inhibitory effect on ENaC function in the cortical collecting duct.9 Epoxyeicosatrienoic acid has been suggested to be an “endothelial-dependent hyperpolarizing factor” and thus is also ideally situated to modulate the effects of hormones on vascular ENaC. Studies by Finn and Arendshorst investigated the autoregulation of renal blood flow in the rat kidney using electromagnetic flow probes and found no role for either prostaglandins10 or the rennin–angiotensin system.11 Myogenic tone is thought to play a central role in renal autoregulation. However, although studies have been performed that demonstrate that ENaC inhibition with amiloride decreases myogenic tone in isolated renal vessels,12 results of whole kidney blood flow studies to investigate an effect of amiloride on autoregulation have not been reported. Interestingly studies by Fan et al.13 have shown that 20-HETE will enhance myogenic responses in renal vessels; however, unlike epoxyeicosatrienoic acid, 20-HETE has no known effects on ENaC function. Rather, 20-HETE acts through G-protein coupled receptor (GPR75) signaling to increase calcium entry into vascular smooth muscle cells and cause vasoconstriction.14 ENaC may serve as one of many vascular mechanoreceptors involved in myogenic tone, and it will be interesting to see whether the contribution of ENaC depends on the vascular bed under study or even sites within the vascular bed. Likewise, a pressure-sensitive myogenic response is thought to play a pivotal role among the multilevel mechanisms that come into play in the autoregulation of cerebral blood flow.15 The loss of autoregulatory tone in the cerebral circulation can result in bursting of vessels downstream (penetrating arterioles). Previous studies have described that the myogenic response of cerebral vessels is enhanced in hypertension.15 This adaptation is thought to protect against the bursting of vessels and the resulting cerebral hemorrhage. By interfering with the cerebral myogenic response, amiloride might thus be expected to provoke cerebral hemorrhage. However, in studies performed in my laboratory, we reported that ENaC inhibition with amiloride protected against stroke in saline-drinking stroke-prone spontaneously hypertensive rats (SHRSP),16 and in subsequent studies using more selective ENaC inhibition (benzamil), not only increased longevity but also markedly improved kidney structure and function.17 Saline-drinking SHRSP develop hemorrhagic infarcts. The primary event is cerebral ischemia and consequently pressure upstream builds up which can lead to bursting of the blood vessel. The pathologic origin of the lesions in such studies is difficult to assess as areas of ischemia may be missed on histologic inspection unless serial (consecutive) sectioning of the brain is done. Areas of hemorrhage are more likely to be seen on histological analysis. That said, angiotensin-converting enzyme inhibitors,18 AT1 receptor blockers,19 mineralocorticoid receptor antagonists,20 or adrenalectomy inhibitors21 all of which interfere with the formation or action of aldosterone, like ENaC inhibitors, are effective in protecting against hemorrhagic infarcts (and malignant nephrosclerosis) in saline-drinking SHRSP and not simply cerebral hemorrhage. Thus, the therapeutic effect of vascular ENaC modulation may be critically dependent on the underlying pathological situation. The present study sets the stage for future studies, which undoubtedly will reveal the pathologic importance of vascular ENaC. The authors declared no conflict of interest.