29 March 2004
Background: Angiotensin II type 1 (AT<sub>1</sub>) receptor antagonists provide end-organ protection and enhance resistance artery relaxation in uremia. The effect of AT<sub>1</sub> blockade on conduit artery function in renal failure is unknown. Methods: The influence of 8-week losartan therapy (20 mg/kg/day) on tone of isolated main branch mesenteric arterial rings was studied in 5/6 nephrectomized (NX) rats. Blood and urine chemistry were examined, and AT<sub>1</sub> receptors quantified using autoradiography. Results: NX rats showed decreased creatinine clearance without change in blood pressure. Losartan did not influence these variables, although [<sup>125</sup>I]-Sar1,Ile8-angiotensin II binding to renal AT<sub>1</sub> receptors was significantly prevented. Vasoconstriction to endothelin-1 was reduced by losartan in NX and Sham rats. Vasorelaxation to acetylcholine was attenuated in untreated but not in losartan-treated NX rats, and experiments with Ca<sup>2+</sup>-activated K<sup>+</sup> channel blockers suggested that impaired endothelium-mediated response after NX was due to deficient relaxation via K<sup>+</sup> channels. Endothelium-independent relaxation to levcromakalim, adenosine triphosphate-sensitive K<sup>+</sup> channel agonist, was impaired in untreated but not in losartan-treated NX rats. Conclusion: Losartan reduced conduit artery vasoconstriction to endothelin-1 and augmented vasorelaxation via K<sup>+</sup> channels in NX rats, although blood pressure and renal function were unchanged. Therefore, AT<sub>1</sub> blockade confers functional benefits to large arteries in renal failure.