Mechanism of the vasodilator effect of 12-O-methylcurine in rat aortic rings.
The vasodilator effects of 12-O-methylcurine (OMC), a bisbenzylisoquinoline alkaloid isolated from Chondrodendron platyphyllum (Menispermaceae), and its respective mechanism of action were investigated in rat aorta. In either endothelium-intact or endothelium-denuded aortic rings, OMC induced concentration-dependent relaxation in vessels pre-contracted with 0.1 microM phenylephrine (IC50 = 63.2+/-8.8 microM and 73.9+/-5.3 microM, respectively), 100 microM 5-hydroxytryptamine (IC50=49.6+/-13 microM and 49.9+/-10 microM, respectively) and 50 mM KCl (IC50= 19.9+/-6.8 microM and 21.1+/-4.5 microM, respectively). OMC also inhibited in a concentration-dependent and non-competitive manner the concentration-response curves induced by CaCl2 in high K+ (IC50 = 16.7+/-1.6 microM). In addition, OMC (100 microM) strongly inhibited phenylephrine-induced contractions dependent on calcium influx in the absence and presence of nifedipine (10 microM). In Ca2+-free medium, the transient contractions induced by phenylephrine (0.1 microM) were strongly inhibited by OMC (100 microM), whereas those induced by caffeine (20 mM) were not altered. H-89 (1 microM) and Rp-8-pCPT-cGMPs (3 microM), selective inhibitors of protein kinase A and G, respectively, did not change the relaxant effect of OMC in aortic rings pre-contracted with phenylephrine. Finally, OMC induced a concentration-dependent relaxation (IC50 = 62.8+/-12.5 microM) of the sustained contractions induced by the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate in normal, but not in Ca2+-free, solution. The above results suggest that OMC induces a vasodilator effect in rataortic rings by a mechanism independent of the presence of functional endothelium and dependent on the influx of calcium ions through voltage- and receptor-operated calcium channels. Furthermore, it can also be suggested that the inhibition of calcium influx activated by protein kinase C is involved in the vasodilator effect of OMC.
Guedes
Diego N
DN
Laboratório de Farmacologia Cardiovascular, Departmento de Farmacologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Barbosa-Filho
José M
JM
Lemos
Virginia S
VS
Côrtes
Steyner F
SF
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D029583:Menispermaceae; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000737:chemistry / Q000494:pharmacology*
C470992:12-O-methylcurine; D015220:Calcium Channels; D007546:Isoquinolines; D014665:Vasodilator Agents; D011494:Protein Kinases; D002118:Calcium