Predominant role for nitric oxide in the relaxation induced by vasoactive intestinal polypeptide in human uterine artery

Abstract

It has been previously shown that vasoactive intestinal polypeptide (VIP) induces endothelium-dependent relaxation of the human uterine artery. However, the nature of the mediator of the VIP-induced endothelium-dependent relaxation of the human uterine artery has not yet been determined. Therefore these experiments were undertaken to examine the effects of VIP on human uterine arteries and to establish the role of various endothelial factors on the relaxation induced by VIP. The experiments were performed on isolated human uterine arterial rings. VIP (0.3-100 nM) induced a concentration-dependent relaxation of human uterine arteries with intact endothelium (pEC50 = 8.06+/-0.14, n = 28). After the removal of the endothelium this relaxation was abolished (n = 6). Indomethacin (10 microM), a cyclooxygenase inhibitor, and diethylcarbamazine (100 microM), a lipoxygenase blocker, had no effects on VIP-induced relaxation. In contrast, methylene blue (10 microM), a blocker of guanylate cyclase, NG-monomethyl-L-arginine (10 microM), an inhibitor of nitric oxide (NO) synthase, and 4-aminopyridine (1 mM), a non-selective blocker of K+ channels, antagonized the effect of VIP with suppression of maximal VIP-induced relaxation. Non-competitive antagonism with methylene blue revealed that the pKa value for VIP-receptor complex was 8.10+/-0.10 (n = 6) and the receptor reserve expressed as KA/EC50 was 0.89+/-0.11, where pKa = log10KA, and KA is the dissociation constant of VIP-receptor complex. Therefore, on the basis of the results presented, we can conclude that VIP induces endothelium-dependent relaxation in human uterine arteries, acting as a partial agonist on this blood vessel. It appears that endothelium-dependent relaxation induced by VIP in human uterine artery can be entirely explained by the release of NO from endothelial cells.

Maternal Vascular Physiology in Preeclampsia

“…9 Reactivity to agonist-induced vasodilation in the main uterine artery relies primarily on NO, although PGI 2 contribution has been reported. [103][104][105] In rat uterine arteries, EDH contribution has also been reported. 105,106 As in systemic arteries, pregnancy mediates the contribution of NO, PGI 2 , and EDH to total vasodilation in uterine arteries as well.…”

Potential immunomodulatory role of VIP in the implantation sites of prediabetic nonobese diabetic mice

“…As a neuropeptide of the peripheral nervous system, it stimulates exocrine secretion and vasodilatation (Ekströ m et al 1983, Inoue et al 1985. Interestingly, VIP contributes to smooth muscle relaxation and vasodilatation favoring uterus quiescence (Clark et al 1981, Jovanovic et al 1998. As an immunopeptide, it promotes anti-inflammatory and Th2 cytokine responses in various models of inflammatory response and autoimmune disease (Gonzalez Rey & Delgado 2007, Leceta et al 2007.…”

Reduced nitric oxide synthase and cyclo-oxygenase activity in the uterus of non-obese diabetic mice

“…Actually, VIP, a neuro-and immunopeptide that promotes secretion in glandular epithelium (Ekström et al 1983, Inoue et al 1985, contributes to the smooth muscle relaxation and vasodilation in the uterus through nitric oxide production (Clark et al 1981, Jovanovic et al 1998 and, similar to progesterone, it promotes Th2 cytokine production (Delgado et al 2002). VIPacts through stimulation of constitutive NOS activity, prostaglandinmediated pathways and cAMP to inhibit uterine contractility (Ottesen et al 1982, Murthy et al 1993.…”