CARDIOVASCULAR SELECTIVITY OF 1,4-DIHYDROPYRIDINE DERIVATIVES, EFONIDIPINE (NZ-105), NICARDIPINE AND STRUCTURE RELATED-COMPOUNDS IN ISOLATED GUINEA-PIG TISSUES

1. The cardiovascular selectivities of 1,4-dihydropyridine derivatives , efonidipine (NZ-105), nicardipine, 3NZ5NIC (the drug with NZ-105-typ e side-chain at C3 position and nicardipine-type at C5) and 3NIC5NZ (t he drug with nicardipine-type side chain at C3 and NZ-105-type at C5) were studied in vitro. 2. All four compounds caused relaxation of guin ea-pig aortae precontracted with a high K+. The pEC(50) values were 7. 5, 8.3, 8.1 and 5.6, for NZ-105, nicardipine, 3NICSNZ and 3NZSNIC, res pectively. The relaxation produced by NZ-105 was slower in onset than those produced by the other compounds. The rate constant K(hr(-1)) of the relaxations were 0.59, 1.31, 1.02 and 1.24, for NZ-105, nicardipin e, 3NIC5NZ and 3NZ5NIC, respectively. 3. In the electrically paced gui nea-pig papillary muscles, NZ-105, 3NIC5NZ and 3NZSNIC, even at concen trations as high as 10(-6) M, slightly decreased the contractile force (by 44.9 +/- 7.1%, 58.6 +/- 5.4% and 52.2 +/- 3.9%, respectively), wh ereas 10(-6) M nicardipine decreased the force by 84.9 +/- 3.3%. The n egative inotropic effect of NZ-105 and 3NICSNZ, but not that of 3NZSNI C or nicardipine, was over IO times weaker than their vasorelaxant eff ect. 4. In the guinea-pig right atria, NZ-105 and nicardipine at 10(-8 ) M decreased the spontaneous contraction rate by 67.9 +/- 15.0% and 3 9.7 +/- 15.4%, respectively. 3NIC5NZ at 3 x 10(-9) M and 3NZSNIC at 3 x 10(-8) M had little effect on the rate, whereas 10(-8) M 3NICSNZ and 10(-7) M 3NZ5NIC arrested the beating within 3 hr after administratio n. The ratio of the negative chronotropic effect to the inotropic effe ct for NZ-105 and 3NIC5NZ were over 100, but those for 3NZSNIC and nic ardipine were only about or below 10. 5. These findings indicate that phosphonate at the C5 position of the 1,4-dihydropyridine structure of NZ-105 might be important to cause relatively strong vasorelaxation a nd negative chronotropic action, and slow vasorelaxation.