A Novel 1,4 Dihydropyridine, BAY K 8644, with Contractile Effects on Vascular Smooth Muscle

Abstract

The effect of a new 1,4-dihydropyridine derivative, methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylase, BAY K 8644, was studied on isolated thoracic aorta obtained from male Wistar-Kyoto rats. In rat aorta BAY K 8644 had dual actions as the compound induced contractions in the concentration range 10-8-10-5 M and relaxation at higher concentrations. In low concentrations (10-8 M) BAY K 8644 increased the contractile response to both noradrenaline [norepinephrine] and K and shifted the concentration response curves to the left, while in high concentrations BAY K 8644 (10-4 M) had a relaxant effect on preparations precontracted by K. The contractile response to BAY K 8644 was resistant to wash out in drug free medium but was totally abolished in Ca-free medium. Re-addition of Ca restored the contractile response in a concentration dependent manner. BAY K 8644, 10-6 M, shifted the Ca-concentration response curve in high K solution to the left and increased the maximal response. Phentolamine or propranolol had no effect, neither on the contractile nor on the relaxant effect of BAY K 8644. The findings suggest that BAY K 8644 acts mainly by increasing the transmembrane influence of Ca in the vascular smooth muscle cells, and that this effect could be opposite to that of nifedipine. However, in high concentrations BAY K 8644 also seems to have a Ca-entry blocking effect.