Pregnancy augments nitric oxide-dependent dilator response to acetylcholine in the human uterine artery

Abstract

The influence of pregnancy on the dilator effects of acetylcholine in the isolated human uterine artery was investigated. Acetylcholine (0.1 nM to 0.1 microM) produced concentration- and endothelium-dependent relaxation of norepinephrine (3 microM)-induced contraction. The relaxation was greater in arteries from pregnant patients (P arteries) than from non-pregnant patients (NP arteries). The maximal relaxation was 53.5+/-3.4% (n=21) in P arteries and 23.5+/-2.5% (n=35) in NP arteries. In both P and NP arteries the cholinergic relaxation was increased in the presence of superoxide dismutase and greatly reduced in the presence of the nitric oxide synthase inhibitors, NG-mono-methyl L-arginine (L-NMMA) and L-nitro-arginine-methylester (L-NAME). The effect of these nitric oxide synthase inhibitors was reversed by L-arginine. We conclude that pregnancy enhances acetylcholine-induced nitric oxide synthesis and release in the human uterine artery.

Increased Nitric Oxide Synthase Activity and Expression in the Human Uterine Artery During Pregnancy

“…These findings are in agreement with the results of our functional studies that show that in the human uterine artery, pregnancy causes an increase in the NO-dependent relaxation responses to acetylcholine or periarterial nerve stimulation. 6,7 Furthermore, the results are consistent with the findings that pregnancy increases Ca 2ϩ -dependent NOS activity and eNOS protein expression in the uterine artery of sheep 13 and in Ca 2ϩ -dependent NOS activity in the uterine artery of the guinea pig. 11 The following results indicate that eNOS accounts for most of the pregnancy-associated increase in NO production.…”

“…The studies were not conducted in the presence of a phosphodiesterase inhibitor such as 3-isobutyl-1-methylxanthine because of the interest in determining the levels of cGMP that existed during various experimental conditions in earlier studies on pregnancy-induced changes in constrictor functions of the uterine artery. 6,7 At the end of the incubation period, segments were quickly frozen in liquid nitrogen, immersed in ice-cold 1% trichloroacetic acid, homogenized, and centrifuged. The supernatant was frozen (Ϫ70°C) until assayed for cGMP with a radioimmunoassay kit (cGMP [ …”

“…We have previously reported that acetylcholine is more potent and efficacious in producing dilation of isolated uterine arteries from pregnant than from nonpregnant patients. 6,7 The acetylcholine-induced relaxation was blocked by NO synthase (NOS) inhibitors and thus is apparently mediated by NO. 6,7 Furthermore, pregnancy-induced increases in basal NO production have been found in the uterine vasculature of rats, 8,9 guinea pigs, 10,11 and sheep.…”

“…6,7 The acetylcholine-induced relaxation was blocked by NO synthase (NOS) inhibitors and thus is apparently mediated by NO. 6,7 Furthermore, pregnancy-induced increases in basal NO production have been found in the uterine vasculature of rats, 8,9 guinea pigs, 10,11 and sheep. 3,12,13 NO is produced by NOS, of which 3 isoforms have been identified: endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS).…”

Upregulation of endothelial cell Ca2+signaling contributes to pregnancy-enhanced vasodilation of rat uteroplacental arteries

“…Uterine vasodilation, induced both by chemical (ACh) or mechanical stimulation (shear stress), was significantly enhanced during gestation, suggesting that some common mechanism(s) might underlie the pregnancy-induced adaptive changes in endothelial cell function (1,9,10,30,36,38,49,54). Enhanced release of nitric oxide (NO) and prostacyclin in uterine arteries in response to agonist stimulation has been documented in both animal and human pregnancy and is associated with elevated endothelial NO synthase (eNOS) and cyclooxygenase activity and expression (2,3,29,37,49,53,54,56).…”