title: 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.
authors.affiliation: Department of Clinical Pharmacology, Jichi Medical School, Tochigi 329-0498, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Nozawa
authors.forename: Koh-ichi
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Masami
authors.initials: M
authors.lastname: Ohmori
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ando
authors.forename: Akio
authors.initials: A
authors.lastname: Fujimura
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects; D006973:Hypertension / Q000235:genetics / Q000401:mortality*; D009929:Organ Size / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D012982:Sodium, Dietary / Q000494:pharmacology; D020521:Stroke / Q000235:genetics / Q000401:mortality*; D013534:Survival; D013841:Thiazepines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D012982:Sodium, Dietary; D013841:Thiazepines; C055603:temocapril hydrochloride; D007703:Peptidyl-Dipeptidase A