Takata Y, Tajima S, Mochizuki S, Suzaka H, Tomiyama A, Kato H
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa, Japan.
J Cardiovasc Pharmacol. 1998 Nov;32(5):834-44. doi: 10.1097/00005344-199811000-00021.
The antihypertensive activity and pharmacokinetics of KD3-671 (previously named KT3-671), a nonpeptide AT1-receptor antagonist, were investigated in renal hypertensive dogs with normal or high plasma renin activity (PRA). A single administration of KD3-671 at 3 and 10 mg/kg, p.o., to the hypertensive dogs with high PRA dose-dependently reduced mean blood pressure (MBP), which was not correlated with plasma KD3-671 concentration. Significant increases in PRA and plasma angiotensin (Ang) II occurred 2 h after KD3-671 dosing. Enalapril at 3 mg/kg, p.o., also reduced MBP. Neither KD3-671 nor enalapril affected heart rate. When given orally once a day for 29 days to the hypertensive dogs with normal PRA, KD3-671 at 3 and 10 mg/kg/day dose-dependently reduced MBP, which was smaller than that in the dogs with high PRA. This was the case for enalapril. The hypotension induced by the first dose of KD3-671 or enalapril was consistently observed after doses 8, 15, 22, and 29. After cessation of repeated dosing, no rebound phenomenon in MBP was observed. Pharmacokinetic parameters of KD3-671 were not influenced by repeated dosing. KD3-671 markedly increased both PRA and plasma Ang II concentration at 2 h after dosing. These results suggest that KD3-671 may be useful for the treatment of hypertension.
研究了非肽类血管紧张素Ⅱ1型受体（AT1）拮抗剂KD3-671（曾用名KT3-671）在血浆肾素活性（PRA）正常或较高的肾性高血压犬中的降压活性和药代动力学。以3和10mg/kg的剂量口服给予PRA较高的高血压犬单次剂量的KD3-671，可剂量依赖性降低平均血压（MBP），且与血浆KD3-671浓度无关。给予KD3-671 2小时后，PRA和血浆血管紧张素（Ang）Ⅱ显著升高。口服3mg/kg依那普利也可降低MBP。KD3-671和依那普利均不影响心率。以3和10mg/kg/天的剂量对PRA正常的高血压犬每天口服一次，连续给药29天，KD3-671可剂量依赖性降低MBP，且降低幅度小于PRA较高的犬。依那普利也是如此。在第8、15、22和29次给药后，均持续观察到首次剂量的KD3-671或依那普利引起的低血压。重复给药停止后，未观察到MBP的反跳现象。重复给药不影响KD3-671的药代动力学参数。给药2小时后，KD3-671可显著升高PRA和血浆AngⅡ浓度。这些结果表明，KD3-671可能对高血压治疗有用。
