Endothelium-dependent and -independent mechanisms of vasorelaxation by corticotropin-releasing factor in pregnant rat uterine artery

Venu Jain, Yurij P. Vedernikov, George Saade, Kristof Chwalisz, Robert E. Garfield

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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, N(w)-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.

Original languageEnglish (US)
Pages (from-to)407-413
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume288
Issue number2
StatePublished - Feb 1999

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Uterine Artery
Corticotropin-Releasing Hormone
Vasodilation
Endothelium
Vasodilator Agents
6-anilino-5,8-quinolinedione
Miconazole
Nitrendipine
Pregnancy
Cyclooxygenase Inhibitors
Thiopental
Glyburide
Guanylate Cyclase
Cyclic GMP
Epoprostenol
Ammonium Compounds
Nitric Oxide Synthase
Indomethacin
Vascular Resistance
Cyclic AMP

ASJC Scopus subject areas

  • Pharmacology

Cite this

Endothelium-dependent and -independent mechanisms of vasorelaxation by corticotropin-releasing factor in pregnant rat uterine artery. / Jain, Venu; Vedernikov, Yurij P.; Saade, George; Chwalisz, Kristof; Garfield, Robert E.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 288, No. 2, 02.1999, p. 407-413.

Research output: Contribution to journalArticle

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T1 - Endothelium-dependent and -independent mechanisms of vasorelaxation by corticotropin-releasing factor in pregnant rat uterine artery

AU - Jain, Venu

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AU - Saade, George

AU - Chwalisz, Kristof

AU - Garfield, Robert E.

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N2 - 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, N(w)-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.

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