title: Chronopharmacology of angiotensin II-receptor blockers in stroke-prone spontaneously hypertensive rats.
abstract: Protective effect of valsartan (Val), an angiotensin II (AII)-receptor blocker (ARB), against organ damage is reported to depend on the dosing time in hypertensive patients. Dosing-time-dependent effect of Val on survival of stroke-prone spontaneously hypertensive rats (SHRSP) under a 12-h lighting cycle was examined. Val (4 mg/kg per day) and olmesartan medoxomil (OM) (1 mg/kg per day), another ARB with a slower dissociation from the AII receptor, were given once daily at 2, 8, 14, or 20 HALO (hours after lights on). Dosing-time-dependent differences in plasma drug concentrations and effect on blood pressure (BP) were also evaluated. Survival of SHRSP showed a dosing-time-dependent change during Val therapy, with a peak at 2 HALO and a trough at 14 HALO. OM equally prolonged survival in all groups. The BP-lowering effect persisted for more than 24 h after dosing of Val at 2 HALO and of OM at 2 and 14 HALO, but disappeared at 5.5-h after Val dosing at 14 HALO. Plasma concentrations of Val and OM were higher after dosing at 2 HALO than at 14 HALO. These results suggest that the chronopharmacological phenomenon of Val was partly due to the dosing-time-dependent difference in plasma concentration and subsequent duration of the antihypertensive effect. Slower dissociation of OM from AII receptors might have blunted a potential dosing-time-dependent event.
authors.affiliation: Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Yuwang
authors.initials: Y
authors.lastname: Liu
authors.forename: Kentarou
authors.initials: K
authors.lastname: Ushijima
authors.forename: Masami
authors.initials: M
authors.lastname: Ohmori
authors.forename: Makoto
authors.initials: M
authors.lastname: Takada
authors.forename: Masato
authors.initials: M
authors.lastname: Tateishi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ando
authors.forename: Akio
authors.initials: A
authors.lastname: Fujimura
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011945:Receptors, Angiotensin / Q000378:metabolism; D020521:Stroke / Q000150:complications* / Q000188:drug therapy; D013997:Time Factors
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D053583:Interleukin-1beta; D015850:Interleukin-6; D011945:Receptors, Angiotensin