HYPOTENSIVE EFFECTIVENESS OF THE INTRARENAL MEDULLARY ENDOTHELIN ETA RECEPTOR BLOCKADE IN THE TWO ANIMAL MODELS OF HYPERTENSION

Abstract

Objective: Endothelin-1 (ET-1) is involved in the pathogenesis of arterial hypertension and chronic kidney disease, however, its mechanism of action is unclear. ET-1 is known to act via ETA and ETB receptors; their activation leads, respectively, to constriction or NO-mediated dilation of the systemic and renal vasculature. ET-1 levels are elevated in experimental and in human hypertension. Here we examined the effects of ETA receptor blockade with atrasentan, administered intravenously (i.v.) or directly to the renal medullary interstitium (i.med.) in two models of rat hypertension. Design and method: In anaesthetized rats with hypertension induced by uninephrectomy followed by high-salt (4% Na w/w) diet (HS/UNX) and in spontaneously hypertensive rats (SHR) we measured mean arterial pressure (MAP), total renal blood flow (RBF, renal artery probe), renal medullary blood flow (MBF, laser-Doppler flux), and renal medullary nitric oxide (NO) signal. Atrasentan doses were: 0.6 mg/kg/h i.v. or 0.12 mg/kg/h i.med. Results: In HS/UNX intravenous atrasentan reduced MAP (142 ± 7 to 117 ± 8 mmHg, p < 0.001) and increased NO signal by 12% (p < 0.05). RBF fell from 25.6 ± 1.7 to 22.3 ± 1.6 ml/min (p < 0.03). Intramedullary atrasentan decreased MAP (127 ± 6 to 115 ± 6, p < 0.04) and increased NO signal by 9.7% (p < 0.03). RBF and MBF did not change significantly. In SHR intravenous atrasentan decreased MAP (171 ± 3 to 152 ± 9 mmHg, p < 0.03) and RBF (6.4 ± 0.5 to 5.0 ± 0.4 ml/min, p < 0.02); NO signal increased by 9.1% (p < 0.01). Intramedullary atrasentan decreased MAP (176 ± 4 to 167 ± 7 mmHg, p < 0.001); NO increased by 10% and MBF by 26% (p < 0.02–0.05). Evidently, in both hypertension models atrasentan always decreased MAP and increased tissue NO. Conclusions: To summarise, in both hypertension models blockade of ETA receptors decreased MAP, reflecting systemic vasodilation. The pressure decrease was followed by a decrease in RBF, probably the result of reduced renal perfusion pressure and imperfect autoregulation. Remarkably, MAP decrease was also seen with intramedullary ETA blockade but then without impairment of renal circulation. Of particular interest was a regular increase in tissue NO: we propose that the blockade of ETA unmasked the action of unbound ET-1 via ETB receptors, leading to NO release.