Calcium channel activation in vascular smooth muscle by BAY K 8644

BAY K 8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifuoromethylphenyl)pyridin e-5-carboxylate) and CGP 28 392 (ethyl-4(2-difluoromethoxyphenyl)-1,4,5,7-tetrahydro-2-methyl-5-oxofuro-[3 ,4-b]pyridine-3-carboxylate) are closely related in structure to nifedipine and other 1,4-dihydropyridine Ca²⁺ channel antagonists. However, both BAY K 8644 and CGP 28 392 serve as activators of Ca²⁺ channels. In the rat tail artery, responses to BAY K 8644 are dependent upon Ca(ext)²⁺ and prior stimulation by K⁺ or by the α-adrenoceptor agonists, phenylephrine and BHT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin dihydrochloride). Responses are blocked noncompetitively by the Ca²⁺ channel antagonists D-600 ((-)-D-600 > (+)-D-600) and diltiazem, but competitively by nifedipine (pA₂ = 8.27). This suggests that activator and inhibitor 1,4-dihydropyridines interact at the same site. BAY K 8644 potentiates K⁺ responses and Ca²⁺ responses in K⁺-depolarizing media. The leftward shift of the K⁺ dose-response curve produced by BAY K 8644 suggests that this ligand facilitates the voltage-dependent activation of the Ca²⁺ channel. The pA₂ value for nifedipine antagonism of BAY K 8644 responses is sufficiently lower than that for nifedipine antagonism of Ca²⁺ responses in K⁺ (25-80 nM) depolarizing media (9.4-9.6), suggesting that the state if the channel may differ according to the activating stimulus.