Antihypertensive Effect of Chronic KT3-671, a Structurally New Nonpeptide Angiotensin AT1-Receptor Antagonist, in Stroke-Prone Spontaneously Hypertensive Rats

Abstract

ABSTRACT-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 AT,-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.

Antiproteinuric Effect of KD3-671, an Angiotensin II Type 1 Receptor Antagonist, in Rats With Accelerated Passive Heymann Nephritis

“…This difference may result from the dose of enalapril used and/ or severity of glomerular alterations. Amano et al demonstrated that repeated administration of KD3-671 (10 mg/kg) to 15-week-old stroke-prone spontaneously hypertensive rats for 7 weeks did not affect renal function during the experimental period (12). In this study, KD3-671 (30 mg/ kg per day) had no effect on urea nitrogen, which was measured for evaluating renal function.…”

An update on non-peptide angiotensin receptor antagonists and related RAAS modulators

“…KT3-671 produces sustained decrease in blood pressure and attenuates ang IIinduced pressor response after oral administration to rats (Yanagisawa et al, 1993) and dogs (Takata et al, 1998). KT3-671 does not affect normal renal function and reduces hypertension-induced pathological changes in the kidney (Amano et al, 1995). KT3-671 has recently been demonstrated to produce vascular sympathoinhibitory activity (Takata et al, 2001).…”

The effects of KT3‐671, a new angiotensin II (AT 1) receptor blocker in mild to moderate hypertension

“…KT3-671 is a novel chemical entity, which has been shown to be a potent, orally active, specific AT 1 receptor antagonist. KT3-671 has undergone in vitro and in vivo pharmacological studies in which it demonstrated a selective affinity for AT 1 receptors in a variety of animal models where a dose dependent reduction in blood pressure (BP) was observed [1][2][3][4][5][6][7].…”