Role of epithelial sodium channels in the renal myogenic response?

Letters to the Editor will be published, if suitable, as space permits. They should not exceed 1000 words (typed double-spaced) in length and may be subject to editing or abridgment. The recent publication by Guan et al 1 and the accompanying editorial in a recent issue of Hypertension 2 both state that the findings of Guan et al 1 contradict the observations that we published previously concerning the effects of benzamil and amiloride on the myogenic response of the renal afferent arte-riole. 3 We argue that much of the data in the 2 studies are, in fact, complementary. In Guan et al 1 and in our study, benzamil and amiloride did not inhibit the afferent arteriolar myogenic response at concentrations Յ1 ␮mol/L. We observed no affect of 3 ␮mol/L of amiloride, whereas Guan et al 1 found 5 ␮mol/L of amiloride to fully block myogenic responses. It is important to note that the original studies implicating epithelial sodium channels (ENaCs) in myogenic signaling reported inhibition at 0.1 ␮mol/L of benzamil and 1 ␮mol/L of amiloride, and concentration dependency for the inhibition was clearly demonstrated (see Reference 4). The specificity of pharmacological probes invariably depends on concentration. This is particularly true of amiloride and its derivatives. These agents inhibit ENaC at submicromolar concentrations. Higher levels affect nearly all of the sodium transporters and alter the function of a wide variety of ion channels and enzymes (reviewed in Reference 5). Benzamil blocks ENaC with an IC 50 of Ϸ10 nmol/L (Ϸ10 times lower than that of amiloride 5) and the Na ϩ /Ca 2ϩ exchanger with an IC 50 of 100 nmol/L. Studies directly evaluating the blockade of ENaC currents routinely demonstrate that 1 ␮mol/L of amiloride and benzamil block ENaC by Ϸ80% and 90% to 100%, respectively. Accordingly, we interpret the observations made by both our laboratory 3 and Guan et al 1 that, at 1 ␮mol/L, neither benzamil nor amiloride inhibits the myogenic response of the afferent arteriole as suggesting that ENaC plays little if any role in myogenic signaling in this vessel. On observing no effects at 1 ␮mol/L, Guan et al 1 examined the effects of 10 ␮mol/L of benzamil and observed full inhibition. They interpreted this action as being attributed to ENaC blockade. The comprehensive review by Kleyman and Cragoe, 5 written Ͼ2 decades ago, strongly warns against such interpretations , emphasizing the broad range of protein …