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-, CaCl₂-, and high-K⁺-induced aorta contractions in a concentration-dependent manner. The estimated pA₂ and pK_Ca^-1 values were 8.22 ± 0.04 and 7.11 ± 0.52, respectively. [ ³H]CGP-12177 binding to ventricle and lung tissues as well as [ ³H]prazosin and [³H]nitrendipine binding to brain membranes were inhibited by labedipinedilol-C with K_i 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_ATP channel blocker glibenclamide (1 μM), and Ca ²⁺-dependent K⁺ channel blockers apamin (1 μM), and charybdotoxin (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.