Augmented EDHF signaling in rat uteroplacental vasculature during late pregnancy.
A successful pregnancy outcome relies on extensive maternal cardiovascular adaptation, including enhanced uteroplacental vasodilator mechanisms. The objective of the present study was to determine the contribution of the endothelium-derived hyperpolarizing factor (EDHF) signaling in pregnancy-enhanced uterine vasodilation, to define the role of Ca(2+)-activated K(+) channels in mediating EDHF effects, and to explore the impact of endothelial Ca(2+) signaling in pregnancy-specific upregulation of EDHF. Fura 2-based measurements of smooth muscle cell (SMC) and endothelial cell cytosolic Ca(2+) concentration ([Ca(2+)](i)) were performed simultaneously with measurements of the diameter of uterine radial arteries from nonpregnant (NP) and late pregnant (LP) rats. Changes in SMC membrane potential of pressurized arteries from LP rats were assessed using glass microelectrodes. After blockade of nitric oxide and prostacyclin production, a cumulative application of ACh induced rapid and effective dilatation of uterine vessels from both NP and LP rats. This vasodilation was associated with SMC hyperpolarization and SMC [Ca(2+)](i) reduction and was abolished by a high-K(+) solution, demonstrating that N(G)-nitro-L-arginine (L-NNA)- and indomethacin-resistant responses are attributable to EDHF. Pregnancy significantly potentiates EDHF-mediated vasodilation in part due to enhanced endothelial Ca(2+) signaling. L-NNA- and indomethacin-resistant responses were insensitive to iberiotoxin but abolished by a combined treatment with apamin and charybdotoxin, supporting the key role of small- and intermediate-conductance K(+) channels in mediating EDHF signaling in the maternal uterine resistance vasculature.
Gokina
N I
NI
Dept. of Obstetrics, Gynecology, and Reproductive Sciences, College of Medicine, The Univ. of Vermont, Burlington, VT 05405, USA. Natalia.Gokina@uvm.edu
Kuzina
O Y
OY
Vance
A M
AM
D000818:Animals; D001030:Apamin / Q000494:pharmacology; D001685:Biological Factors / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology; D018999:Charybdotoxin / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D023421:Models, Animal; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D021041:Placental Circulation / Q000187:drug effects / Q000502:physiology*; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D001685:Biological Factors; D016861:Cyclooxygenase Inhibitors; D024681:Potassium Channels, Calcium-Activated; C067410:endothelium-dependent hyperpolarization factor; D018999:Charybdotoxin; D001030:Apamin; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin
Am J Physiol Heart Circ Physiol. 2005 Jun;288(6):H2869-77
15665052
Circulation. 2005 Feb 15;111(6):796-803
15699263
Br J Pharmacol. 2005 Jul;145(6):775-84
15895105
Hypertension. 2007 Mar;49(3):590-6
17200437
Microcirculation. 2005 Mar;12(2):169-82
15824039
Biol Reprod. 2003 Mar;68(3):1072-7
12604662
J Physiol. 1998 Apr 1;508 ( Pt 1):199-209
9490839
J Cardiovasc Pharmacol. 1999 May;33(5):779-84
10226866
Med Biol. 1974 Aug;52(4):219-28
4371556
Am J Physiol Regul Integr Comp Physiol. 2003 Feb;284(2):R245-58
12529278
Physiol Rev. 2001 Oct;81(4):1415-59
11581493
Kidney Int. 2007 Jul;72(2):145-50
17457372
Proc Natl Acad Sci U S A. 1994 May 24;91(11):5212-6
7515189
Nature. 1998 Nov 19;396(6708):269-72
9834033
Circ Res. 2000 Feb 18;86(3):341-6
10679487
Am J Obstet Gynecol. 2002 Nov;187(5):1416-23
12439541
Microcirculation. 2004 Apr-May;11(3):279-93
15280082
Br J Pharmacol. 1998 Oct;125(3):455-60
9806327
Physiology (Bethesda). 2006 Feb;21:69-78
16443824
Am J Physiol. 1997 Feb;272(2 Pt 2):R441-63
9124465
Microcirculation. 2004 Jan-Feb;11(1):9-38
15280095
Clin Sci (Lond). 2002 Jul;103(1):67-73
12095405
Clin Sci (Lond). 2009 Jul 16;117(4):139-55
19601928
Am J Physiol Heart Circ Physiol. 2002 May;282(5):H1760-7
11959641
J Cardiovasc Pharmacol. 1996 Nov;28(5):703-11
8945685
Am J Physiol Heart Circ Physiol. 2008 Mar;294(3):H1381-7
18192215
Cell Calcium. 2005 Apr;37(4):311-20
15755492
Am J Physiol Heart Circ Physiol. 2008 Jan;294(1):H272-84
17982020
Br J Pharmacol. 2002 Jan;135(1):48-54
11786479
Am J Physiol Endocrinol Metab. 2009 Mar;296(3):E503-12
19126786
Cell Calcium. 1990 Feb-Mar;11(2-3):75-83
2354505
Eur J Obstet Gynecol Reprod Biol. 2003 Sep 22;110 Suppl 1:S19-27
12965087
J Biol Chem. 1985 Mar 25;260(6):3440-50
3838314
Curr Pharm Biotechnol. 2007 Feb;8(1):11-25
17311549
Life Sci. 2002 Dec 20;72(4-5):511-20
12467891
Clin Exp Pharmacol Physiol. 2004 Sep;31(9):641-9
15479173
Am J Obstet Gynecol. 2003 Nov;189(5):1489-93
14634590
Am J Physiol Heart Circ Physiol. 2006 May;290(5):H2124-35
16327017
J Neurosci Methods. 2000 Apr 15;97(2):145-55
10788669
Microvasc Res. 2002 Jan;63(1):115-28
11749078
Anesthesiology. 2005 Jun;102(6):1261-77
15915041
Trends Pharmacol Sci. 2002 Aug;23(8):374-80
12377579
Am J Obstet Gynecol. 1997 Apr;176(4):856-64
9125611
Microcirculation. 2005 Jan-Feb;12(1):113-27
15804979
Physiology (Bethesda). 2009 Feb;24:58-71
19196652
J Physiol. 2002 Feb 15;539(Pt 1):77-91
11850503
Clin Exp Pharmacol Physiol. 2009 Jan;36(1):67-76
19018806
Circ Res. 2007 Feb 2;100(2):246-54
17218602
Am J Physiol Heart Circ Physiol. 2006 Jul;291(1):H216-22
16473954
Nature. 1990 Jul 5;346(6279):69-71
2366864
Hum Reprod. 1998 May;13(5):1361-7
9647573
Br J Pharmacol. 2009 Jun;157(4):509-26
19302590
Reprod Sci. 2007 Jan;14(1):43-50
17636215
Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9627-32
18621682