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.Angiotensin-converting enzyme (ACE) inhibitors are widely used in the treatment of hypertension and related diseases. These agents have been shown to improve the morbidity and mortality of patients with hypertension (Kostis, 1995;Hansson et al., 1999) and are recommended as a firstline drug for the treatment of hypertension (European Society of Hypertension-European Society of Cardiology Guidelines Committee, 2003).There is increasing evidence that the effectiveness and/or toxicity of many agents are affected by their time of dosing (Cui et al., 2004;Filipski et al., 2004;Matsunaga et al., 2004;Tsuruoka et al., 2004). A chronopharmacological approach seems to be desirable for developing a more effective and safe dosage regimen. There are precedents for this approach in clinical practice (Tsuruoka et al., 2003;Debon et al., 2004;Shimonov et al., 2005).Previous animal (Oosting et al., 1999) and human (Palatini et al., 1992;Witte et al., 1993;Sunaga et al., 1995) studies have shown dosing time-dependent differences in the blood pressure-lowering effects of ACE inhibitors. In addition, the preventive effect of an ACE inhibitor for cardiac hypertrophy in hypertensive animals was reported to depend on its dosing time (Sugimoto et al., 2001). However, it remained to be determined whether the morbidity and mortality of patients with hypertension are affected by the dosing time of ACE inhibitors. The present study aimed to address this issue using stroke-prone spontaneously hypertensive rats (SHRSP), an animal model of human stroke (Okamoto et al., 1974;Yamori et al., 1976). Temocapril is a nonsulfhydryl ACE inhibitor, and its active metabolite (temocaprilat) is eliminated by the renal and biliary routes (Suzuki et al., 1993). Renal function decreases with age; however, our recent observation that the plasma accumulation of temocaprilat is low during repeated treatments in the elderly indicates that temocapril is a safe antihypertensive drug for these patients (Arakawa et al., 2005). Te...

Administration-Time-Dependent Effects of Spirapril on Ambulatory Blood Pressure in Uncomplicated Essential Hypertension

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Chronotherapy With the Angiotensin-Converting Enzyme Inhibitor Ramipril in Essential Hypertension

“…26 A recent study with another ACE inhibitor, temocapril, evaluated its time-dependent effect on the mortality of stroke-prone spontaneous hypertensive rats. 27 Temocapril prolonged the survival rate of the animals, with a maximum effect after dosing at the early resting period and a minimal effect after dosing at the early active period. These results are relevant inasmuch as, similar to the results found here for ramipril, evening dosing with temocapril significantly reduces nocturnal BP to a greater extent than diurnal BP and, thus, increases the awake:asleep BP ratio toward a more dipper profile.…”

Dosing-time dependent effect of dexamethasone on bone density in rats

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