Diurnal Variation in the Diuretic Effects of Nitrendipine in Saline Loaded Rats.

Abstract

We have previously reported that the responsiveness of blood pressure to nitrendipine, a dihydropyridine calcium antagonist, varies with its time of adminis tration. The present study was undertaken to examine whether the diuretic effects of the agent also show diurnal variation. There is increasing evidence demonstrating time-dependent changes in the effectiveness of cardiovascular agents (1). We already examined the chronopharmacological profiles of nitrendipine, a dihydropyridine calcium antagonist. This study demonstrated that the responsiveness of blood pressure to the agent varies with its administration time (2).Nitrendipine is frequently used in the treat ment of hypertension and the related car diovascular diseases. Unlike other vasodilators such as hydralazine, prazosin and minoxidil, calcium antagonists are not associated with water and sodium retention, but cause a mild diuresis and natriuresis following, at least, the first dosage (3, 4). This pharmacological prop erty of calcium antagonists may be involved in the mechanism responsible for their anti hypertensive action. Therefore, it is interesting to examine whether the diuretic effects of nit rendipine also show diurnal variations.In the present study, nitrendipine was given orally at 12 a.m. or 12 p.m. to rats. The diure tic effects following the agent at 12 a.m. were compared to those when it was given at 12 p.m.Male Wistar rats (Charles River Laboratory, Kanagawa, Japan) (10-11 weeks old, 300 350 g) were maintained for more than 2 weeks under conditions of light from 7 a.m. to 7 p.m. and dark from 7 p.m. to 7 a.m. with free access to food and water.Since a diuretic effect following a high dose of a calcium antagonist might be masked by a concomitant reduction in blood pressure (5), the first experiment was performed to deter mine the optimal dosage of nitrendipine for the subsequent study. Rats were randomly divided into two groups. The first group of rats (group I, n = 16) received nitrendipine at 12 a.m., while the second group of animals (group II, n = 16) received the agent at 12 p.m. Three percent body weight (b.w.) of 1% NaCI solution was given orally to each group of rats on day 1. Nitrendipine (Yoshitomi Pharmaceutical Industries, Ltd., Osaka, Japan) (0.5, 2.0 and 10.0 mg/kg in 3% b.w. of 1 % NaCl) was given orally to each group of