Antihypertensive effect of chronic KT3-671, a structurally new nonpeptide angiotensin AT1-receptor antagonist, in stroke-prone spontaneously hypertensive rats.
KT3-671 (2-propyl-8-oxo-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4-yl)methyl]-4,5,6, 7-tetrahydrocycloheptimidazole), a structurally new nonpeptide angiotensin AT1-receptor antagonist, was administered orally and repeatedly to 15-week-old stroke-prone spontaneously hypertensive rats for 7 weeks; and its effects on blood pressure, heart rate, renal function, plasma renin concentration (PRC), plasma aldosterone concentration (PAC) and hypertension-related tissue damage in the brain, heart, kidney and mesenteric artery were investigated. KT3-671 at a dose of 3 or 10 mg/kg, p.o. per day prevented development of hypertension and produced a significant and consistent reduction of blood pressure in a dose-dependent manner. Enalapril at a dose of 10 mg/kg per day produced cardiovascular effects similar to those of KT3-671 at 10 mg/kg. Despite marked reduction in blood pressure, neither KT3-671 nor enalapril affected the heart rate. KT3-671 at 10 mg/kg produced a transient and significant reduction of urinary sodium excretion in the second week, but did not affect renal function at any other time during the experimental period. Both KT3-671 at 10 mg/kg and enalapril at 10 mg/kg produced a significant increase in PRC and showed a tendency to decrease PAC. Repeated administration of KT3-671 reduced the severity of the pathological changes in the kidney. These results suggest that KT3-671 is a potentially useful antihypertensive drug.
Amano
H
H
Department of Pharmacology, Kyoritsu College of Pharmacy, Tokyo, Japan.
Fujimoto
K
K
Suzuki
T
T
Fujii
T
T
Mochizuki
S
S
Tomiyama
A
A
Kawashima
K
K
D000450:Aldosterone / Q000097:blood; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001835:Body Weight / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D012083:Renin / Q000097:blood; D013777:Tetrazoles / Q000494:pharmacology*; D013997:Time Factors; D014554:Urination / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; C093160:KT3 671; D013777:Tetrazoles; D000450:Aldosterone; D012083:Renin