Endothelium-independent relaxation to raloxifene in porcine coronary artery.
Although the vascular action of raloxifene has been studied in several vascular beds, the underlying mechanisms are still incompletely understood. The role of endothelium in raloxifene-induced vascular responses was controversial. The present study was designed to examine endothelium-independent effects of raloxifene in isolated porcine left circumflex coronary arteries. Arterial rings were suspended in organ baths and changes in isometric tension were measured. The large-conductance Ca2+-activated K+(BK(Ca)) currents were recorded using a whole-cell patch-clamp technique. Treatment with raloxifene (1-10 micromol/l) reduced the contractions to 9,11-dideoxy-11alpha,9alpha-epoxy-methanoprostaglandin F2alpha (U46619), serotonin (5-HT), endothelin-1 in normal Krebs solution and to CaCl2 in a Ca2+-free, high K+-containing solution. In endothelin-1-contracted rings, raloxifene (0.3 to 50 micromol/l) caused relaxations which were comparable in rings with and without endothelium. The raloxifene-induced relaxation was reduced by putative K+ channel blockers, iberiotoxin and tetraethyl ammonium chloride (TEA+) in rings with and without endothelium, or by elevated extracellular K+ ions (30 mmol/l K+ and 60 mmol/l K+). 13-methyl-7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-7,8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta[a] phenanthrene-3,17-diol (ICI 182,780) did not affect raloxifene-induced relaxation. Raloxifene enhanced the outward BK(Ca) currents, which were sensitive to inhibition by iberiotoxin. In summary, the present study shows that raloxifene acutely relaxes porcine coronary arteries via an endothelium-independent mechanism without involving the ICI 182,780-sensitive estrogen receptors. Raloxifene mainly acts on the vascular smooth muscle cells to induce vasorelaxation by the inhibition of Ca2+ channels and the activation of BK(Ca) channels. The former mechanism appears to play a more significant role.
Leung
Hok Sum
HS
Li Ka Shing Institute of Health Sciences and Department of Physiology, Chinese University of Hong Kong, Hong Kong, China.
Seto
Sai Wang
SW
Kwan
Yiu Wa
YW
Leung
Fung Ping
FP
Au
Alice Lai Shan
AL
Yung
Lai Ming
LM
Yao
Xiaoqiang
X
Huang
Yu
Y
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology; D002122:Calcium Chloride / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D000077267:Fulvestrant; D066298:In Vitro Techniques; D010455:Peptides / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000502:physiology; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D012701:Serotonin / Q000494:pharmacology; D013552:Swine; D019789:Tetraethylammonium / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D019332:Endothelin-1; D004965:Estrogen Antagonists; D010455:Peptides; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D014662:Vasoconstrictor Agents; D000077267:Fulvestrant; D012701:Serotonin; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D019789:Tetraethylammonium; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C064719:iberiotoxin; D002122:Calcium Chloride