Abstract
Corticotropin-releasing factor (CRF), a potent vasorelaxant, is increased tremendously during human pregnancy. Placenta is the main source for this increase. CRF is thought to be important in modulating vascular resistance and uteroplacental blood flow during pregnancy. Here we investigated pathways mediating a vasorelaxant effect of CRF in the uterine artery. Two-millimeter segments of uterine artery (o.d. 300–400 μm) from day 18 pregnant rats were mounted in a small vessel myograph and precontracted with norepinephrine, and relaxation responses to CRF were studied. CRF relaxed the uterine artery in a concentration-dependent manner. Relaxation of uterine artery by CRF was abolished completely by α-helical CRF 9-41 (CRF antagonist, 1 μmol) and partially by removal of endothelium, Nω-nitro-l-arginine methyl ester (nitric oxide synthase inhibitor, 0.1 mmol), 6-anilino-5,8-quinolinedione (guanylate cyclase inhibitor, 10 μmol), or thiopental/miconazole (cytochrome P-450 inhibitors, 0.3 mmol/30 μmol), but remained unaffected by indomethacin (cyclo-oxygenase inhibitor, 10 μmol). Relaxation was also inhibited when depolarizing solution (K+, 120 mmol) was used for precontraction. In deendothelized preparations, relaxation was not inhibited by 9-tetrahydro-2-furanyl-9H-purin-6-amine (adenylate cyclase inhibitor, 0.2 mmol), glibenclamide (adenosine triphosphate-dependent K+ channel blocker, 10 μmol), tetrabutyl ammonium (nonspecific K+ channel blocker, 1 mmol), nitrendipine (voltage-gated Ca++ channel blocker, 1 μmol), or when vessels were precontracted with depolarizing solution. CRF causes vasorelaxation by receptor-operated, endothelium-dependent and -independent pathways. The endothelium-dependent relaxation is mediated by nitric oxide-cyclic guanosine monophosphate pathway and endothelium-derived hyperpolarizing factor but not prostacyclin. However, cyclic adenosine monophosphate, K+ channels, or Ca++ channels are not involved in endothelium-independent vasorelaxation by CRF.
Footnotes
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Send reprint requests to: R.E. Garfield, Ph.D., Division of Reproductive Sciences, Department of Obstetrics and Gynecology, The University of Texas Medical Branch, 301 University Boulevard, Rt. J-62, Galveston, TX 77555-1062. E-mail:rgarfiel{at}utmb.edu
- Abbreviations:
- AQD
- 6-anilino-5,8-quinolinedione
- CRF
- corticotropin-releasing factor
- CRF-A
- α-helical CRF 9-41
- EDHF
- endothelium-derived hyperpolarizing factor
- l-NAME
- Nω-nitro-l-arginine methyl ester
- NE
- norepinephrine
- NO
- nitric oxide
- TBA
- tetrabutyl ammonium
- TFPA
- 9-tetrahydro-2-furanyl-9H-purin-6-amine
- Received March 6, 1998.
- Accepted August 6, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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