Chronopharmacology of angiotensin II-receptor blockers in stroke-prone spontaneously hypertensive rats

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. © the japanese pharmacological society.