Effects of DuP 753 on renal function of normotensive and spontaneously hypertensive rats.
This study examined the effects of a new, orally-active, nonpeptide angiotensin II (AII) receptor antagonist, 2-n-butyl-4-chloro-5-hydroxymethyl-1-[2'-(1H-tetrazol-5-yl)biph eny l-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.(ABSTRACT TRUNCATED AT 250 WORDS)
Fenoy
F J
FJ
Department of Physiology, Medical College of Wisconsin, Milwaukee 53226.
Milicic
I
I
Smith
R D
RD
Wong
P C
PC
Timmermans
P B
PB
Roman
R
R
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects*; D019808:Losartan; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D011921:Rats, Inbred WKY; D012016:Reference Values; D012083:Renin / Q000097:blood; D013777:Tetrazoles / Q000494:pharmacology*
D000959:Antihypertensive Agents; D007093:Imidazoles; D013777:Tetrazoles; D012083:Renin; D019808:Losartan