Received for publication July 15, 2005.
Revised September 14, 2005.
Accepted for publication September 14, 2005.

Dosing-Time-Dependent Effect of Temocapril on the Mortality of Stroke-Prone Spontaneously Hypertensive Rats

Abstract

This study was undertaken to evaluate a dosing-time-dependent effect of temocapril, an angiotensin-converting enzyme (ACE) inhibitor, on the mortality of stroke-prone spontaneously hypertensive rats (SHRSP). Temocapril (1 mg/kg/day) prolonged the survival rate of these animals, with a maximum effect after dosing at the early resting period and a minimum effect after dosing at the early active period. The pharmacokinetics of temocaprilat, an active metabolite of temocapril, did not differ significantly between the two dosing times. However, the inhibition of ACE activity in serum and organs (brain and aorta) and the reduction of blood pressure were significantly greater after dosing at the early resting period than at the early active period. These data suggest that the effect of temocapril on the mortality of SHRSP depends on the time of dosing, with a maximum effect seen after dosing at the early resting period. Dosing-time-dependent differences in the pharmacodynamics of temocapril might be involved in explaining this phenomenon.

Key words: ACE inhibitor, SHR, chronotherapy, hypertension, mortality, temocapril