Endogenous endothelins and the response to electrical renal nerve stimulation in anaesthetized rabbits

The influence of endogenous endothelins on the neural control of renal function is poorly understood. We therefore studied the effects of endothelin blockade (combined ET_A and ET_B receptor antagonism using TAK-044) on the acute and prolonged effects of renal nerve stimulation in rabbits, measuring renal blood flow, glomerular filtration rate (GFR), urine flow and sodium excretion. Brief (3 min) stimulation over 0.5-8 Hz produced frequency-dependent reductions in total renal blood flow, cortical blood flow and, less markedly, medullary blood flow. TAK-044 did not significantly alter basal total renal blood flow or cortical blood flow, or their responses to nerve stimulation, but significantly increased basal medullary blood flow (P < 0.01) and increased the slope of the stimulation frequency-medullary blood flow relationship (P < 0.05). Prolonged (20 min) stimulation at 0, 0.5 and 2 Hz produced frequency-dependent reductions in total renal blood flow, GFR, urine flow and sodium excretion, but not medullary blood flow. Pretreatment with TAK-044 did not significantly alter these responses. Thus, endogenous endothelins do not appear to either augment or lessen the effects of renal nerve activation on total renal blood flow, cortical blood flow, GFR or sodium excretion. The apparent ability of TAK-044 to enhance medullary blood flow responses to renal nerve stimulation may reflect an action of endogenous endothelins to blunt neurally mediated vasoconstriction in the medullary circulation. Alternatively, it may simply be secondary to the effects of endogenous endothelins on basal medullary blood flow.