Cardiovascular selectivity of 1,4-dihydropyridine derivatives, efonidipine (NZ-105), nicardipine and structure related compounds in isolated guinea-pig tissues

1. 1. The cardiovascular selectivities of 1,4-dihydropyridine derivatives, efonidipine (NZ-105), nicardipine, 3NZ5NIC (the drug with NZ-105-type side-chain at C3 position and nicardipine-type at C5) and 3NIC5NZ (the drug with nicardipine-type side chain at C3 and NZ-105-type at C5) were studied in vitro. 2. 2. All four compounds caused relaxation of guinea-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, 3NIC5NZ and 3NZ5NIC, respectively. 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, nicardipine, 3NIC5NZ and 3NZ5NIC, respectively. 3. 3. In the electrically paced guinea-pig papillary muscles, NZ-105, 3NIC5NZ and 3NZ5NIC, even at concentrations 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), whereas 10 −6M nicardipine decreased the force by 84.9 ± 3.3%. The negative inotropic effect of NZ-105 and 3NIC5NZ, but not that of 3NZ5NIC or nicardipine, was over 10 times weaker than their vasorelaxant effect. 4. 4. In the guinea-pig right atria, NZ-105 and nicardipine at 10 −8M decreased the spontaneous contraction rate by 67.9 ± 15.0% and 39.7 ±15.4%, respectively. 3NIC5NZ at 3 × 10 −9 M and 3NZ5NIC at 3 × 10 −8 M had little effect on the rate, whereas 10 −8 M 3NIC5NZ and 10 −7 M 3NZ5NIC arrested the beating within 3 hr after administration. The ratio of the negative chronotropic effect to the inotropic effect for NZ-105 and 3NIC5NZ were over 100, but those for 3NZ5NIC and nicardipine were only about or below 10. 5. 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 and negative chronotropic action, and slow vasorelaxation.