Endothelin Contributes to Blunted Renal Autoregulation Observed

46 Autoregulation of renal blood flow (RBF) is an essential function of the renal 47 microcirculation that has been previously shown to be blunted by excessive dietary salt. 48 Endogenous endothelin 1 (ET-1) is increased following a high salt (HS) diet and 49 contributes to the control of RBF but the differential effects of ET-1 on renal microvessel 50 autoregulation in response to HS remain to be established. We hypothesized that a HS 51 diet increases endothelin receptor activation in normal Sprague-Dawley rats and blunts 52 autoregulation of RBF. The role of ET-1 in the blunted autoregulation produced by a HS 53 diet was assessed in vitro and in vivo using the blood-perfused juxtamedullary nephron 54 preparation and anesthetized rats, respectively. Using highly selective antagonists, we 55 observed that blockade of either ETA or ETB receptors was sufficient to restore normal 56 autoregulatory behavior in afferent arterioles from HS fed rats. Additionally, normal 57 autoregulatory behavior was restored in vivo in HS fed rats by simultaneous ETA and 58 ETB receptor blockade whereas blockade of ETB receptors alone showed significant 59 improvement of normal autoregulation of RBF. Consistent with this observation, 60 autoregulation of RBF in ETB receptor deficient rats fed HS was similar to both ETB61 deficient rats and transgenic control rats on NS diets. These data support the 62 hypothesis that endogenous ET-1, working through ETB and possibly ETA receptors, 63 contributes to the blunted renal autoregulatory behavior in rats fed a HS diet. 64