cardiovascular-agents and 1-4-dihydropyridine

Topics: Antioxidants; Antiviral Agents; Cardiovascular Agents; Cell Membrane Permeability; Dihydropyridines; Flavonoids; Pharmacology; Phenols; Polymers; Polyphenols; Psychotropic Drugs; Pyridines; Pyrimidines; Research; Vitamin E

To obtain new cardiovascular agents with mixed Ca2+-channel antagonistic and NO-donor properties, a series of "hybrid" 1,4-dihydropyridines (1,4-DHPs), bearing NO-donating furoxan moieties on the 3-positioned lateral ester chain were synthesized and pharmacologically characterized. Furazan analogues were also prepared and investigated for control purposes, because they are unable to release NO.. Synthesis of the models was achieved by a modified Hantzsch approach. All of the final furoxan 1,4-DHPs were assessed for their ability to produce nitrite in the presence of a large excess of cysteine by the Griess reaction. Vasodilating activity was evaluated on rat aorta and expressed as EC50 and EC50MB values, obtained in the absence and in the presence of methylene blue (MB) respectively, a well-known guanylate cyclase inhibitor. Affinities to 1,4-DHP receptor on Ca2+-channels, expressed as IC50 values, were determined through displacement experiments of [3H]-nitrendipine on rat cortex homogenates.. Some hybrid compounds (derivatives 15a, 15b, 16a, and 16b) displayed vasodilating activity depending predominantly on their Ca2+-channel blocker properties. By contrast, some others (derivatives 17a, 17b, and 21) behaved as well-balanced hybrids with mixed Ca2+-channel blocking and NO-dependent vasodilating activities.. This work demonstrates the possibility of obtaining well-balanced hybrids endowed with mixed NO-donor and Ca2+-channel blocker properties using appropriate 1,4-DHP and furoxan moieties. A procedure for the individual evaluation of the NO-dependent vasodilator component and that due to Ca2+-channel blocking is proposed.

Topics: Animals; Aorta; Calcium Channel Blockers; Cardiovascular Agents; Dihydropyridines; Dose-Response Relationship, Drug; Male; Nitric Oxide; Nitric Oxide Donors; Rats; Rats, Wistar; Vasodilation; Vasodilator Agents

2,6-Dimethyl-3,5-dimethoxycarbonyl-4-(o-difluoromethoxyphenyl)-1,4 -dihydropyridine (ryodipine, PP-1466), an effective Ca2+ channel blocker, diminishes contraction force and decreases duration of action potential in the frog heart ventricle strips. Dissociation constants K0.5 are 2 x 10(-7), 5 x 10(-7), and 10(-6) mol/l for PP-1466, nifedipine and nicardipine, respectively (at 0.25-0.3 Hz stimulation). One molecule of PP-1466 or nifedipine apparently interacts with two receptors on the channel (n = 0.5), nicardipine with one receptor (n = 1). The binding energy of PP-1466 and nifedipine increases at closed and diminishes at open channels which is in contrast to nicardipine, whose effect is irreversible. Thus, the site of nicardipine action differs from that of PP-1466 and nifedipine. PP-1466 (10(-8) mol/l--10(-6) mol/l) suppresses contraction force and diminishes frequency of spontaneous contractions of the rabbit atria, and also displays antagonism to the effect of Ca2+ upon rabbit auricle contractions. In the isolated rabbit aorta and portal vein PP-1466 is more antagonistic to contractions caused by Ca2+ than by epinephrine. Both competitive and non-competitive types of antagonism can be distinguished.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Anura; Calcium Channel Blockers; Cardiovascular Agents; Cattle; Dihydropyridines; Electric Stimulation; Electrophysiology; Heart; In Vitro Techniques; Mitochondria; Mitochondria, Liver; Mitochondrial Swelling; Muscle Contraction; Muscle, Smooth, Vascular; Myocardial Contraction; Nicardipine; Nifedipine; Pyridines; Rabbits; Rats