ACUTE ANTIHYPERTENSIVE EFFECTS OF THE NEW-GENERATION CALCIUM-ANTAGONIST 3-PYRIDINE CARBOXYLIC-ACID L]-1,4-DIHYDRO-2,6-DIMETHYL-4-(2-NITROPHENYL)OCTYL ESTER ON CONSCIOUS SPONTANEOUSLY HYPERTENSIVE RATS AND RENAL HYPERTENSIVE RATS

The acute antihypertensive effects of 3-pyridine carboxylic acid 5-[(c yclo-propylamino) bonyl]-1,4-dihy-dro-2,6-dimethyl-4-(2-nitrophenyl) o ctyl ester (NP252, CAS 132031-81-3) administered orally to conscious s pontaneously hypertensive rats (SHRs) and renal hypertensive rats (RHR s) were evaluated using the impedance plethysmographical technique as a modified tail cuff method, and compared with those of nifedipine (NF ). In the fitness test of this indirect method, the average value of b lood pressure (BP) measured in 7 conscious SHRs was 201 +/- 6.9 mmHg. This value showed good correlation with that (201 +/- 8.8 mmHg) of sys tolic BP measured by the direct method in the same animals. In the com parative study of antihypertensive activities of the compounds on both models of hypertension using this method, NP-252 and NF dose-dependen tly lowered BP having a different peak time and restoration after dosi ng Therefore, the antihypertensive activities were compared using a 20 % effective dose (ED20) for producing hypotension and the ED20 values of NP-252 and NF were 2.55 and 2.00 mg/kg in SHRs, and 1.25 and 0.67 m g/kg in RHRs, respectively. Moreover, the duration of actions of the c ompounds were evaluated by the simulated duration time (SDT) which was calculated from the peak time of BP-fall and the pharmacological half life time for the maximum BP-fall and the SDT values of NP-252 and NF were 1.85-4.70 and 0.90-0.75 h in SHRs, and 3.30-12.80 and 0.576. 90 h in RHRs, respectively. Also, the BP-falls by the compounds were acco mpanied by an increase in heart rate. The tachycardia by NP-252 was le ss potent than or equipotent io that of NF at the doses which indicate d similar hypotensive activity, whereas the maximum increase rate of N P-252 for causing tachycardia was not significantly different from tha t of NF. The present studies suggest that the modified tail cuff metho d is useful for the evaluation of acute or chronic antihypertensive ef fect of a vasodilator in a small animal, and that the antihypertensive action of NP-252 on both models of experimental hypertension is almos t equipotent to that of NF but slower in onset and much longer in dura tion.