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 pKCa values were 8.22+/-0.04 and 7.11+/-0.52, respectively. [H]CGP-12177 binding to ventricle and lung tissues as well as [H]prazosin and [H]nitrendipine binding to brain membranes were inhibited by labedipinedilol-C with Ki values of 2.86, 9.03, 0.39, and 0.05 muM, respectively. The vasorelaxant effects of labedipinedilol-C on phenylephrine (10 microM)-induced contractions were attenuated by removing endothelium, by pretreatment with soluble guanylyl cyclase (sGC) inhibitors ODQ (10 microM) and methylene blue (10 microM), a NOS inhibitor L-NAME (100 microM), a K channel blocker TEA (10 mM), a KATP channel blocker glibenclamide (1 microM), and Ca-dependent K channel blockers apamin (1 microM) and charybdotoxin (0.1 microM). 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 alpha-adrenoceptor and Ca 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 alpha-adrenoceptor-blocking activities.
Yeh
Jwu-Lai
JL
Department and Graduate Institute of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Liou
Shu-Fen
SF
Liang
Jhy-Chong
JC
Lee
Chih-Hsiung
CH
Chiu
Chaw-Chi
CC
Lin
Young-Tso
YT
Chen
Ing-Jun
IJ
D018674:Adrenergic Antagonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D004095:Dihydropyridines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D015221:Potassium Channels / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D014132:Trachea / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
C505397:(N-(4-(2-hydroxy-3-(1-(2-chlorophenyl)piperazinyl)propoxy)-3-methoxy)benzyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine; D018674:Adrenergic Antagonists; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D010879:Piperazines; D015221:Potassium Channels; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D014662:Vasoconstrictor Agents; D009569:Nitric Oxide