Effects of DuP 753 on Renal Function of Normotensive and Spontaneously Hypertensive Rats

This study examined the effects of a new, orallyactive, nonpeptide angiotensin II (AII) receptor antagonist, 2-n-butyl-4-chloro-5-hydroxymethyl-l-[2’-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl] imidazole, DuP 753, on renal function of anesthetized, volume-expanded Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR), and in a group of euvolemic Munich-Wistar (MW) rats. Plasma renin activities were similar and averaged 4.4 ± 0.7 and 4.3 ± 1.4 ng AI/mL · h, respectively, in the SHR and WKY rats. In WKY rats (n = 15), DuP 753 (2 or 10 mg/kg, intravenously) had no effect on urine flow, sodium excretion, renal blood flow (RBF), or glomerular filtration rate (GFR). Fractional excretion of lithium (FELi) rose from 32 ± 5 to 40 ± 4% of the filtered load and arterial pressure decreased slightly from 129 ± 2 to 122 ± 2 mm Hg. In SHR (n = 9), urine flow fell 24%, and FELi and RBF increased by 27% and 30%, respectively, after 2 mg/kg DuP 753, but sodium excretion, GFR, and arterial pressure were not significantly altered. A higher dose of DuP 753 (10 mg/kg; n = 8) reduced arterial pressure, urine flow, and sodium excretion in the SHR. RBF increased 34%, while GFR and FELi were not significantly altered. Similar effects were seen in SHR (n = 11), given an equivalent antihypertensive dose of Captopril (20 mg/kg). In euvolemic MW rats in which plasma renin activity was elevated to 18.8 ± 3.3 ng AI/mL · h, DuP 753 (2 mg/kg, n = 7) increased RBF, urine flow, and sodium excretion, while mean arterial pressure and GFR were unaltered. These results indicate that blockade of AII receptors with DuP 753 has little effect on arterial pressure or renal function in volume-expanded WKY rats with normal PRA. In volume-expanded SHR, high doses of DuP 753 (10 mg/kg) and Captopril (20 mg/kg) lower arterial pressure and renal vascular resistance with only small changes in sodium and water excretion. Am J Hypertens 1991;4:321S-326S