Urocortin-induced relaxation in the human internal mammary artery.
OBJECTIVE
Urocortin, a potent vasodilator, plays physiological or pathophysiological roles in the cardiovascular system. However, little is known about its action in human vascular tissues. The present study was designed to investigate the vascular effect of urocortin on human internal mammary artery (IMA) in vitro and the possible underlying mechanisms.


METHODS
Human IMA was obtained from patients undergoing coronary artery bypass grafting. The isolated IMA rings were mounted in organ baths and changes in isometric tension were measured by using Grass force-displacement transducer. Corticortropin-releasing factor-receptors (CRF-R) were also analyzed in the IMA by using RT-PCR analysis.


RESULTS
In 9,11-dideoxy-11alpha,9alpha-epoxy-methanoprostaglandin F(2alpha) (U46619)-precontracted endothelium-intact rings, urocortin induced concentration-dependent relaxations with pD(2) of 8.69+/-0.11 and this effect was markedly reduced in endothelium-denuded rings. Relaxations to urocortin in endothelium-intact rings were attenuated to the same extent after treatment with N(G)-nitro-l-arginine (l-NNA) and 1H-[1,2,4]oxadizolo[4,3-a]quinoxalin-1-one (ODQ). Urocortin-induced relaxations were also inhibited by treatment with putative K(+) channel blockers, such as tetraethylammonium (TEA(+)), charybdotoxin (CTX), and iberiotoxin (IBX). In endothelium-denuded rings, treatment with TEA(+), CTX, or IBX attenuated relaxation to urocortin as well as sodium nitroprusside (SNP). The bands for CRF-R1, CRF-R2alpha, and CRF-R2beta mRNAs were observed in both endothelium-intact and endothelium-denuded human IMA.


CONCLUSIONS
Urocortin produced both endothelium-dependent and -independent relaxation in human IMA rings. The endothelium-dependent component primarily involves the release of endothelial nitric oxide (NO) that in turn stimulates Ca(2+)-activated K(+) channels in vascular smooth muscle via cyclic GMP-dependent mechanisms. CRF-R1, CRF-R2alpha, and CRF-R2beta mRNAs are present in the human IMA.
Chen
Zhi-Wu
ZW
Cardiovascular Research, Starr Academic Center for Cardiac Surgery, Providence Heart and Vascular Institute and Department of Surgery, Oregon Health and Science University, Portland, USA.
Huang
Yu
Y
Yang
Qin
Q
Li
Xianwu
X
Wei
Wei
W
He
Guo-Wei
GW
D000368:Aged; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008323:Mammary Arteries / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology; D019335:Nitroarginine / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D018019:Receptors, Corticotropin-Releasing Hormone / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects; D046509:Tissue Culture Techniques / Q000379:methods; D054832:Urocortins; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
C116907:1H-(1,2,4)oxadiazolo(4,3-a)-quiloxalin-1-one; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D024681:Potassium Channels, Calcium-Activated; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; D014665:Vasodilator Agents; D019335:Nitroarginine; D003346:Corticotropin-Releasing Hormone; D019001:Nitric Oxide Synthase