Calcium modulation of endothelium-derived prostacyclin production in ovine pregnancy.
Refractoriness to angiotensin-II (ANG II)-induced vasoconstriction is greater in the uteroplacental vs. systemic vascular beds during pregnancy, possibly reflecting enhanced uterine artery prostacyclin production. We determined the role(s) of calcium and calcium channels in regulating basal and ANG II-induced vascular prostacyclin production in uterine and omental (systemic) arteries obtained from pregnant (P) and nonpregnant (NP) ewes. To evaluate the endothelial contribution to basal and stimulated prostacyclin production, arteries with and without endothelium also were incubated in the absence and presence of 50 nM ANG II, 5 microM A23187, or 5 microM arachidonate. Basal prostacyclin production by intact and denuded uterine and systemic arteries was P > NP (P < 0.05), plus in intact arteries, production fell approximately 33% in calcium-free Krebs-Henseleit and 5 microM EGTA. Although basal prostacyclin production by P and NP uterine and NP systemic arteries was unaffected by 5 microM verapamil, P systemic artery synthesis fell 41% (P < 0.05). P uterine artery prostacyclin production increased similarly with ANG II (61%) and A23187 (78%) in the presence of calcium (2 mM), whereas NP uterine arteries responded only to A23187 (71%). Verapamil inhibited ANG II-induced increases in prostacyclin synthesis by P uterine arteries. Neither calcium removal nor verapamil altered prostacyclin responses to arachidonate (5 microM). The endothelium accounted for approximately 68% of basal prostacyclin production by all arteries studied and for 100% of ANG II-induced increases by P uterine arteries (P < 0.01). A23187 and arachidonate increased both endothelial and smooth muscle prostacyclin production (P < 0.01). During ovine pregnancy, extracellular calcium entry via activation of potential-gated calcium channels are involved in modulating basal vascular prostacyclin production as well as ANG II-induced increases in uterine artery production. Furthermore, the endothelium is the primary source of basal vascular prostacyclin synthesis and the sole source of ANG II-stimulated increases by uterine arteries during pregnancy.
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas 75235-9063.
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Magness
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Rosenfeld
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001158:Arteries; D002118:Calcium / Q000494:pharmacology / Q000502:physiology*; D015220:Calcium Channels / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism*; D011464:Epoprostenol / Q000096:biosynthesis*; D005260:Female; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D012016:Reference Values; D012756:Sheep; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D014599:Uterus / Q000098:blood supply
D015220:Calcium Channels; D000804:Angiotensin II; D016718:Arachidonic Acid; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; D013254:Steroid 17-alpha-Hydroxylase; D002118:Calcium