Pharmacological and toxicological properties of ryodipine.

2,6-Dimethyl-3,5-dimethoxycarbonyl-4-(o-difluoromethoxy-p hen yl)-1,4-dihydropyridine (ryodipine, PP-1466) causes lasting decrease in systolic and diastolic arterial pressure at intravenous and oral administration to anesthetized animals. In conscious rats with DOCA-salt (des-oxycortone) and spontaneous hypertension, as well as in rats with hypertension provoked by method of cellophane perinephritis, PP-1466 (1 and 10 mg/kg, orally) decreases systolic pressure considerably. Therapeutic doses of PP-1466 do not essentially affect rhythm and frequency of cardiac contractions. High doses of the drug increase the heart rate. PP-1466 increases coronary blood flow. PP-1466 antagonizes considerably the pressor effect of angiotensin. In this respect PP-1466 is superior to SKF-24260 (2,6-dimethyl-3,5-diethoxycarbonyl-4-(o-difluoromethylphenyl)-1, 4-dihydropyridine). PP-1466 reduces hypotensive reaction and tachycardia induced by isoprenaline administration, inhibits decrease in arterial pressure caused by electric stimulation of the vagus nerve and administration of acetylcholine. Hypotension caused by PP-1466 and its negative inotropic effect can be antagonized with calcium chloride. In mice and rats PP-1466 at doses exceeding 10 mg/kg exerts a certain dose dependent depressant effect on the CNS. More protracted depressant effect on the CNS is exerted by nifedipine which was studied parallelly. In rabbits oral PP-1466 decreases in EEG basic rhythm amplitude both in cortical and subcortical structures. High doses of the drug lead to dysrhythmia in bioelectric activity. Acute, subacute and chronic toxicity studies in mice, rats and dogs show that PP-1466 possesses low acute toxicity and is well tolerated at protracted repeated administration of therapeutic and several times higher doses.