Labedipinedilol-C : A third-generation dihydropyridine-type calcium channel antagonist displaying K+ channel opening, NO-dependent and adrenergic antagonist activities

Intravenous and oral labedipinedilol-C showed a dose-dependent long-lasting hypotension and a decrease of heart rate in normotensive and conscious spontaneously hypertensive rats (SHR). In isolated Wistar rat and guinea pig tissues, labedipinedilol-C competitively antagonized (-)isoproterenol-induced cardiac stimulation, tracheal relaxation, and phenylephrine-, CaCl 2 -, and high-K + -induced aorta contractions in a concentration-dependent manner. The estimated pA 2 and pK C a - 1 values were 8.22 ′ 0.04 and 7.11 ′ 0.52, respectively. [ 3 H]CGP-12177 binding to ventricle and lung tissues as well as [ 3 H]prazosin and [ 3 H]nitrendipine binding to brain membranes were inhibited by labedipinedilol-C with K, values of 2.86, 9.03, 0.39, and 0.05 μM, respectively. The vasorelaxant effects of labedipinedilol-C on phenylephrine (10 μM)-induced contractions were attenuated by removing endothelium, by pretreatment with soluble guanylyl cyclase (sGC) inhibitors ODQ (10 μM) and methylene blue (10 μM), a NOS inhibitor L-NAME (100 μM), a K' channel blocker TEA (10 mM), a K A T P channel blocker glibenclamide (I μM), and Ca 2 + -dependent K' channel blockers apamin (1 μM) and charybdo-toxin (0.1 μM). In human umbilical vein endothelial cells (HUVECs), labedipinedilol-C increased NO release, which was significantly inhibited by L-NAME. The Western blot analysis on HUVECs indicated that labedipinedilol-C increased the expression of eNOS. These results indicate that hypotension effects of labedipinedilol-C result from α-adrenoceptor and Ca 2 + entry-blocking activities and release of NO or NO-related substance from vascular endothelium. The endothelium-independent relaxation of vascular smooth muscle is probably linked to K + channel opening and α-adrenoceptor-blocking activities.