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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 pKCa−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 Ki 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 KATP channel blocker glibenclamide (1 μM), and Ca2+-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 Ca2+ 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.