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

Abstract

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.

• Authors: Jwu-Lai Yeh, Shu-Fen Liou, Jhy-Chong Liang, Chih-Hsiung Lee, Chaw-Chi Chiu, Young-Tso Lin, Ing-Jun Chen
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 46 Issue 2 Pg. 130-40 (Aug 2005) ISSN: 0160-2446 [Print] United States
• PMID: 16044023 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• (N-(4-(2-hydroxy-3-(1-(2-chlorophenyl)piperazinyl)propoxy)-3-methoxy)benzyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine
• Adrenergic Antagonists
• Calcium Channel Blockers
• Dihydropyridines
• Piperazines
• Potassium Channels
• Receptors, Adrenergic, alpha
• Receptors, Adrenergic, beta
• Vasoconstrictor Agents
• Nitric Oxide

Topics

• Adrenergic Antagonists (administration & dosage, pharmacology, therapeutic use)
• Animals
• Aorta (drug effects)
• Binding, Competitive
• Blood Pressure (drug effects)
• Calcium Channel Blockers (administration & dosage, pharmacology, therapeutic use)
• Cell Line
• Dihydropyridines (administration & dosage, pharmacology, therapeutic use)
• Guinea Pigs
• Heart Rate (drug effects)
• Humans
• Hypertension (drug therapy, metabolism, physiopathology)
• In Vitro Techniques
• Ion Channel Gating (drug effects)
• Nitric Oxide (metabolism)
• Piperazines (administration & dosage, pharmacology, therapeutic use)
• Potassium Channels (metabolism)
• Radioligand Assay
• Rats
• Rats, Inbred SHR
• Rats, Wistar
• Receptors, Adrenergic, alpha (metabolism)
• Receptors, Adrenergic, beta (metabolism)
• Trachea (drug effects)
• Vasoconstrictor Agents (pharmacology)
• Vasodilation (drug effects)