Contraction Of Uterine Artery Research Articles

Peroxisome proliferator-activated receptor gamma blunts endothelin-1-mediated contraction of the uterine artery in a murine model of high-altitude pregnancy.

The environmental hypoxia of high altitude (HA) increases the incidence of intrauterine growth restriction (IUGR) approximately threefold. The peroxisome proliferator-activated receptor γ (PPAR-γ), a ligand-activated nuclear receptor that promotes vasorelaxation by increasing nitric oxide and downregulating endothelin-1 (ET-1) production, has been implicated in IUGR. Based on our prior work indicating that pharmacologic activation of the PPARγ pathway protects against hypoxia-associated IUGR, we used an experimental murine model to determine whether such effects may be attributed to vasodilatory effects in the uteroplacental circulation. Using wire myography, ex vivo vasoreactivity studies were conducted in uterine arteries (UtA) isolated from pregnant mice exposed to hypoxia or normoxia from gestational day 14.5 to 18.5. Exposure to troglitazone, a high-affinity PPARγ agonist-induced vasorelaxation in UtA preconstricted with phenylephrine, with HA-UtA showing increased sensitivity. Troglitazone blunted ET-1-induced contraction of UtA in hypoxic and normoxic dams equivalently. Immunohistological analysis revealed enhanced staining for ET-1 receptors in the placental labyrinthine zone in hypoxic compared to normoxic dams. Our results suggest that pharmacologic PPAR-γ activation, via its vasoactive properties, may protect the fetal growth under hypoxic conditions by improving uteroplacental perfusion and thereby justify further investigation into PPARγ as a therapeutic target for IUGR in pregnancies complicated by hypoxia.

Acute intravenous exposure to silver nanoparticles during pregnancy induces particle size and vehicle dependent changes in vascular tissue contractility in Sprague Dawley rats

The use of silver nanoparticles (AgNP) raises safety concerns during susceptible life stages such as pregnancy. We hypothesized that acute intravenous exposure to AgNP during late stages of pregnancy will increase vascular tissue contractility, potentially contributing to alterations in fetal growth. Sprague Dawley rats were exposed to a single dose of PVP or Citrate stabilized 20 or 110nm AgNP (700μg/kg). Differential vascular responses and EC50 values were observed in myographic studies in uterine, mesenteric arteries and thoracic aortic segments, 24h post-exposure. Reciprocal responses were observed in aortic and uterine vessels following PVP stabilized AgNP with an increased force of contraction in uterine artery and increased relaxation responses in aorta. Citrate stabilized AgNP exposure increased contractile force in both uterine and aortic vessels. Intravenous AgNP exposure during pregnancy displayed particle size and vehicle dependent moderate changes in vascular tissue contractility, potentially influencing fetal blood supply.

Gestational hypoxia up-regulates protein kinase C and inhibits calcium-activated potassium channels in ovine uterine arteries.

Objective: The present study tested the hypothesis that gestational hypoxia up-regulates protein kinase C (PKC) and inhibits calcium-activated potassium channels (KCa)-mediated relaxations of uterine arteries in pregnancy. Study design: Uterine arteries were isolated from nonpregnant (NPUA) and pregnant (PUA) (~140 day gestation) sheep maintained at either sea level or high altitude (3,820 m for 110 days, PaO2: 60 mmHg). Contractions of uterine arteries were determined. Key findings: In normoxic PUA, selective inhibition of large-conductance KCa (BK) channels significantly enhanced PKC activator phorbol 12, 13-dibutyrate (PDBu)-induced contractions. This effect was abrogated by chronic hypoxia in gestation. Unlike BK channels, inhibition of small-conductance KCa (SK) channels had no significant effect on PDBu-mediated contractions. In normoxic PUA, activation of both BK with NS1619 or SK with NS309 produced concentration-dependent relaxations, which were not altered by the addition of PDBu. However, in uterine arteries treated with chronic hypoxia (10.5% O2 for 48 h), both NS1619- and NS309-induced relaxations were significantly attenuated by PDBu. In NPUAs, inhibition of BK channels significantly enhanced PDBu-induced contractions in both normoxic and hypoxic animals. Conclusion: The results suggest that in the normoxic condition BK inhibits PKC activity and uterine vascular contractility, which is selectively attenuated by chronic hypoxia during gestation. In addition, hypoxia induces PKC-mediated inhibition of BK and SK activities and relaxations of uterine arteries in pregnancy.

PKC Regulates α1-Adrenoceptor-Mediated Contractions and Baseline Ca2+ Sensitivity in the Uterine Arteries of Nonpregnant and Pregnant Sheep Acclimatized to High Altitude Hypoxia

Chronic hypoxia has a profound effect on uterine artery adaptation to pregnancy. The present studies tested the hypothesis that pregnant kinase C (PKC) differentially regulates alpha(1)-adrenoceptor-mediated contractions and Ca(2+) sensitivity in the uterine arteries of nonpregnant and pregnant sheep acclimatized to high altitude hypoxia. Uterine arteries were isolated from nonpregnant (NPUA) and near-term pregnant (PUA) ewes maintained at high altitude (3801 m, Pao(2) approximately 60 torr) for 110 days. Phorbol 12,13-dibutyrate (PDBu) decreased phenylephrine-induced contractions in PUA but not in NPUA, which was partly inhibited by the PKC inhibitor GF109203X. Additionally, GF109203X shifted the concentration-response curve of phenylephrine-induced contractions to the right in PUA. In beta-escin-permeabilized arteries, Ca(2+)-induced increases in 20-kDa myosin light chain phosphorylation (MLC(20)-P) were similar in NPUA and PUA. However, Ca(2+) produced a concentration-dependent increase in the ratio of tension to MLC(20)-P in PUA, as compared with NPUA. PKC inhibition decreased Ca(2+)-induced contractions in both NPUA and PUA. PDBu induced contractions of PUA in the absence of changes in MLC(20)-P, which was not affected by PD098059. There was a significant increase in the basal activity of PKCvarepsilon in PUA, but not in NPUA, in hypoxic sheep, as compared with normoxic animals. The results demonstrate that the inhibitory effect of PKC on alpha(1)-adrenoceptor-mediated contractions of uterine arteries is preserved in pregnant sheep at high altitude. However, the PKC-mediated thin-filament regulatory pathway is upregulated, resulting in increased baseline Ca(2+) sensitivity in the uterine artery during pregnancy at high altitude.

Regulation of α1-adrenoceptor-mediated contractions of uterine arteries by PKC: effect of pregnancy

Protein kinase C (PKC) plays an important role in the regulation of uterine artery contractility and its adaptation to pregnancy. The present study tested the hypothesis that PKC differentially regulates alpha(1)-adrenoceptor-mediated contractions of uterine arteries isolated from nonpregnant (NPUA) and near-term pregnant (PUA) sheep. Phenylephrine-induced contractions of NPUA and PUA sheep were determined in the absence or presence of the PKC activator phorbol 12,13-dibutyrate (PDBu). In NPUA sheep, PDBu produced a concentration-dependent potentiation of phenylephrine-induced contractions and shifted the dose-response curve to the left. In contrast, in PUA sheep, PDBu significantly inhibited phenylephrine-induced contractions and decreased their maximum response. Simultaneous measurement of contractions and intracellular free Ca(2+) concentrations ([Ca(2+)](i)) in the same tissues revealed that PDBu inhibited phenylephrine-induced [Ca(2+)](i) and contractions in PUA sheep. In NPUA sheep, PDBu increased phenylephrine-induced contractions without changing [Ca(2+)](i). Western blot analysis showed six PKC isozymes, alpha, beta(I), beta(II), delta, epsilon, and zeta, in uterine arteries, among which beta(I), beta(II), and zeta isozymes were significantly increased in PUA sheep. In contrast, PKC-alpha was decreased in PUA sheep. In addition, analysis of subcellular distribution revealed a significant decrease in the particulate-to-cytosolic ratio of PKC-epsilon in PUA compared with that in NPUA sheep. The results suggest that pregnancy induces a reversal of PKC regulatory role on alpha(1)-adrenoceptor-mediated contractions from a potentiation in NPUA sheep to an inhibition in PUA sheep. The differential expression of PKC isozymes and their subcellular distribution in uterine arteries appears to play an important role in the regulation of Ca(2+) mobilization and Ca(2+) sensitivity in alpha(1)-adrenoceptor-mediated contractions and their adaptation to pregnancy.

Regulation of a1‐adrenoceptor‐mediated contractions of the uterine artery by PKC in pregnant sheep

Little is known about the adaptation of contractile mechanisms of uterine arterial smooth muscle to pregnancy. We hypothesize that PKC plays an important role in the regulation of α1-adrenoceptor-mediated contractions of the uterine artery and their adaptation to pregnancy. Uterine arteries were isolated from pregnant ewes (~140 days gestation). α1-adrenoceptor-mediated contractions were measured with increasing concentrations of phenylephrine (PE) in half-log increments in the absence or presence of the PKC activator phorbol 12, 13-dibutyrate (PDBu) and/or PKC inhibitor GF-109203X (GF). PE produced dose-dependent contractions of uterine arteries. PDBu (0.3 and 1 μM) significantly decreased pD2 value and maximum contraction (Emax) induced by PE. GF itself (0.1, 0.3, 1 μM) markedly decreased pD2 value and Emax induced by PE in a dose dependent pattern. However, treatment with PDBu and 1 μM GF significantly increased pD2 and Emax as compared with PDBu treatment alone without GF. These results suggest that activation of PKC plays an inhibitory role in the regulation of α1-adrenoceptor-mediated contraction of the uterine arteries during late pregnancy, which is likely to be important in the adaptation of α1-adrenoceptor-mediated contractions to pregnancy. (Supported in part by NIH grants HL57787 and HD 31226)

Regulation of baseline Ca2+sensitivity in permeabilized uterine arteries: effect of pregnancy

The adaptation of contractile mechanisms of the uterine artery to pregnancy is not fully understood. The present study examined the effect of pregnancy on the uterine artery baseline Ca2+ sensitivity. In beta-escin-permeabilized arterial preparations, Ca2+ -induced concentration-dependent contractions were significantly decreased in uterine arteries from pregnant animals compared with those of nonpregnant animals. Time-course studies showed that Ca2+ increased phosphorylation of 20-kDa myosin light chain (MLC20), which preceded the tension development in vessels from both pregnant and nonpregnant animals. When compared with vessels from nonpregnant animals, there was a significant increase in the protein level of MLC20 and an accordance increase in the level of Ca2+ -induced phosphorylated MLC20 (MLC20-P) in uterine arteries during pregnancy. Simultaneous measurements of MCL20-P levels and contractions stimulated with Ca2+ in the same tissues demonstrated a significant attenuation in the tension-to-MLC20-P ratio in uterine arteries during pregnancy. Activation of PKC with phorbol 12,13-dibutyrate (PDBu) potentiated Ca2+ -induced contractions in uterine arteries from nonpregnant but not pregnant animals. Accordingly, inhibition of PKC attenuated Ca2+ -induced contractions in uterine arteries from nonpregnant but not pregnant animals. PDBu produced contractions in the presence or absence of Ca2+ in the beta-escin-permeabilized arteries, which were significantly decreased in uterine arteries from pregnant compared with nonpregnant animals. The results suggest that pregnancy upregulates the thick-filament regulatory pathway by increasing MLC20 phosphorylation but downregulates the thin-filament regulatory pathway by decreasing the contractile sensitivity of MLC20-P, resulting in attenuated baseline Ca2+ sensitivity in the uterine artery. In addition, PKC plays an important role in the regulation of basal Ca2+ sensitivity, which is downregulated during pregnancy.

Adaptation of uterine artery thick- and thin-filament regulatory pathways to pregnancy.

Little is known about the adaptation of uterine artery smooth muscle contractile mechanisms to pregnancy. The present study tested the hypothesis that pregnancy differentially regulates thick- and thin-filament regulatory pathways in uterine arteries. Isometric tension, intracellular free Ca(2+) concentration, and phosphorylation of 20-kDa myosin light chain (MLC(20)) were measured simultaneously in uterine arteries isolated from nonpregnant and near-term (140 days gestation) pregnant sheep. Phenylephrine-mediated intracellular free Ca(2+) concentration, MLC(20) phosphorylation, and contraction tension were significantly increased in uterine arteries of pregnant compared with nonpregnant animals. In contrast, phenylephrine-mediated Ca(2+) sensitivity of MLC(20) phosphorylation was decreased in the uterine arteries of pregnant sheep. Simultaneous measurement of phenylephrine-stimulated tension and MLC(20) phosphorylation in the same tissue indicated a decrease in MLC(20) phosphorylation-independent contractions in the uterine arteries of pregnant sheep. In addition, activation of PKC produced significantly lower sustained contractions in uterine arteries of pregnant compared with nonpregnant animals in the absence of changes in MLC(20) phosphorylation levels in either vessels. In uterine arteries of nonpregnant sheep, the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase inhibitor PD-098059 significantly increased phenylephrine-mediated, MLC(20) phosphorylation-independent contractions. The results suggest that in uterine arteries, pregnancy upregulates alpha(1)-adrenoceptor-mediated Ca(2+) mobilization and MLC(20) phosphorylation. In contrast, pregnancy downregulates the Ca(2+) sensitivity of myofilaments, which is mediated by both thick- and thin-filament pathways.

Cortisol-mediated regulation of uterine artery contractility: effect of chronic hypoxia

We previously demonstrated that cortisol regulated alpha(1)-adrenoceptor-mediated contractions differentially in nonpregnant and pregnant uterine arteries. Given that chronic hypoxia during pregnancy has profound effects on maternal uterine artery reactivity, the present study investigated the effects of chronic hypoxia on cortisol-mediated regulation of uterine artery contractions. Pregnant (day 30) and nonpregnant ewes were divided between normoxic control and chronically hypoxic [maintained at high altitude (3,820 m), arterial Po(2): 60 mmHg for 110 days] groups. Uterine arteries were isolated and contractions measured. In hypoxic animals, cortisol (10 ng/ml for 24 h) increased norepinephrine-induced contractions in pregnant, but not in nonpregnant, uterine arteries. The 11beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone did not change cortisol effects in nonpregnant uterine arteries, but abolished it in pregnant uterine arteries by increasing norepinephrine pD(2) (-log EC(50)) in control tissues. The dissociation constant of norepinephrine-alpha(1)-adrenoceptors was not changed by cortisol in nonpregnant, but decreased in pregnant uterine arteries. There were no differences in the density of glucocorticoid receptors between normoxic and hypoxic tissues. Cortisol inhibited the norepinephrine-induced increase in Ca(2+) concentrations in nonpregnant arteries, but potentiated it in pregnant arteries. In addition, cortisol attenuated phorbol 12,13-dibutyrate-induced contractions in normoxic nonpregnant and pregnant uterine arteries, but had no effect on the contractions in hypoxic arteries. The results suggest that cortisol differentially regulates alpha(1)-adrenoceptor- and PKC-mediated contractions in uterine arteries. Chronic hypoxia suppresses uterine artery sensitivity to cortisol, which may play an important role in the adaptation of uterine vascular tone and blood flow in response to chronic stress of hypoxia during pregnancy.

Comparison of the Responses to Thrombin in Monkey Renal and Uterine Arteries

Thrombin is known to regulate vascular tone. We analyzed and compared mechanisms of thrombin action in primate renal and uterine arteries. Isolated Japanese monkey renal and uterine arteries were suspended in Ringer-Locke solution for tension recordings. Renal arteries responded to thrombin with relaxation, which was inhibited by N(G)-nitro-L-arginine or indomethacin and reversed to contractions by the combination. The relaxations were also reversed to contractions by endothelial denudation. Conversely, thrombin caused uterine arterial contractions that were unaffected by endothelial denudation. Relaxations in both renal arteries and contractions in uterine arteries were suppressed by hirudin (a specific thrombin inhibitor). Relaxant responses to A23187 (Ca(2+) ionophore), nitroprusside sodium (nitric oxide donor), and beraprost sodium (prostacyclin analogue) did not differ between renal and uterine arteries. Thrombin-induced relaxation of renal arteries appears to be mediated by nitric oxide and vasodilator prostaglandins liberated from the endothelium, whereas uterine arterial contraction is caused by an endothelium-independent mechanism.

ERK MAP kinases regulate smooth muscle contraction in ovine uterine artery: effect of pregnancy

The present study investigated the potential role of extracellular signal-regulated kinase (ERK) in uterine artery contraction and tested the hypothesis that pregnancy upregulated ERK-mediated function in the uterine artery. Isometric tension in response to phenylephrine (PE), serotonin (5-HT), phorbol 12,13-dibutyrate (PDBu), and KCl was measured in the ring preparation of uterine arteries obtained from nonpregnant and near-term (140 days gestation) pregnant sheep. Inhibiting ERK activation with PD-98059 did not change the KCl-evoked contraction but significantly inhibited the contraction to 5-HT in both nonpregnant and pregnant uterine arteries. PD-98059 did not affect PE-induced contraction in the uterine arteries of nonpregnant sheep but significantly decreased it in the uterine arteries of pregnant sheep. In accordance, PE stimulated activation of ERK in uterine arteries of pregnant sheep, which was blocked by PD-98059. PD-98059-mediated inhibition of the PE-induced contraction was associated with a decrease in both intracellular Ca(2+) concentration and Ca(2+) sensitivity of contractile proteins in the uterine arteries of pregnant sheep. PDBu-mediated contraction was significantly less in pregnant than in nonpregnant uterine arteries. PD-98059 had no effect on PDBu-induced contraction in nonpregnant but significantly increased it in pregnant uterine arteries. In addition, PD-98059 significantly enhanced PDBu-stimulated protein kinase C activity. The results indicate that ERK plays an important role in the regulation of uterine artery contractility, and its effect is agonist dependent. More importantly, pregnancy selectively enhances the role of ERK in alpha(1)-adrenoceptor-mediated contractions and its effect in suppressing protein kinase C-mediated contraction in the uterine artery.

Noradrenaline-mediated contractions of ovine uterine artery: role of inositol 1,4,5-trisphosphate

To elucidate the role of inositol 1,4,5-triphosphate (Ins(1,4,5)P 3) as a second messenger through which noradrenaline regulates contractions of the uterine artery, we present here studies designed to characterize simultaneously the noradrenaline-mediated contractions and Ins(1,4,5)P 3 formation in isolated uterine arteries from near-term pregnant sheep. Noradrenaline stimulated a rapid increase of Ins(1,4,5)P 3 formation with the peak at 30 second. Simultaneous measurement of noradrenaline-induced contractile responses and Ins(1,4,5)P 3 formation revealed a significant linear correlation between these two events. In accordance with the contractile results, the noradrenaline-mediated inositol phosphate accumulation was blocked by prazosin (0.1 μM), but not by yohimbine (0.1 μM). Pre-treatment of tissues with pertussis toxin (200 ng/ml, 3 h) failed to block noradrenaline-induced inositol phosphate accumulation. We conclude that, in the uterine artery of late pregnancy, the α 1-adrenoceptor-elicited contraction, at least the initial phasic component, is predominantly mediated by the formation of Ins(1,4,5)P 3, leading to release of Ca 2+ from intracellular stores.

Relaxation by calcitonin gene-related peptide may involve activation of K + channels in the human uterine artery

The vasodilatory role of calcitonin gene-related peptide in activating K + channels was examined in isolated, suffused human uterine arteries. Calcitonin gene-related peptide produced a concentration-dependent relaxation of norepinephrine (1 μM)-induced contractions. Calcitonin gene-related peptide was antagonized by glybenclamide (1–100 μM), an inhibitor of ATP-sensitive K + channels, but not by tetraethylammonium (1 mM), an inhibitor of calcium 2+-activated K + channels. Glybenclamide (10 μM) produced a 6.7 fold and an 11-fold shift to the right of calcitonin gene-related peptide (0.1 to 100 nM) in uterine arteries from pregnant patients (n = 3) and nonpregnant patients (n = 6), respectively. Calcitonin gene-related peptide (10 nM) less effectively (P < 0.05) relaxed contractions produced by KCl (50 mM) (29.4 ± 1.6%) than by norepinephrine and glybenclamide (10 μM) did not reverse this relaxation (22.2 ± 6.8%, n = 4 nonpregnant patients). Pinacidil (1 μM), an ATP-sensitive K + channel opener, relaxed norepinephrine-induced contractions of uterine arteries. Glybenclamide (10 μM) also antagonized pinacidil. These results suggest that calcitonin gene-related peptide relaxes norepinephrine-contracted human uterine arteries, at least in part, by activation of a K + channel, perhaps of the ATP-sensitive type.

Evidence for declining extracellular calcium uptake and protein kinase C activity in uterine arterial smooth muscle during gestation in gilts.

Uterine arterial blood flow and uterine arterial diameter are known to increase dramatically and progressively throughout gestation. Previous data from our laboratory have demonstrated that the KCl-induced membrane depolarization of uterine arterial smooth muscle specifically induces Ca2+ uptake through the potentially sensitive channels (PSC). Evidence from other laboratories suggests that calcium uptake through the PSC mediates long-term changes in uterine arterial diameter and flow (tone), possibly through activation of protein kinase C (PKC). In study 1 we evaluated uterine arteries removed from gilts on Days 20, 50, 80, and 110 of gestation for their ability to take up extracellular Ca2+ and to contract in response to a depolarizing dose of KCl. The ability of KCl to induce contraction of uterine arteries as well as its ability to stimulate extracellular 45Ca2+ uptake by these same arteries declines (p less than 0.01) progressively from Day 20 through Day 110 of gestation. Estrogen concentrations in systemic blood were negatively correlated with the contractile response (r = -0.57; p less than 0.01) and extracellular 45Ca2+ uptake (r = -0.93; p less than 0.0001) of uterine arteries during gestation. In study 2 we evaluated changes in uterine arterial PKC and protein kinase M (PKM) throughout the estrous cycle and gestation. It was determined that cytosolic PKC declined with the advancement of gestation whereas PKM progressively increased (r = -0.63; p less than 0.01). These data suggest a decreasing ability of the uterine artery to take up extracellular Ca2+ through the PSC as gestation advances, in association with decreasing cytosolic PKC.

Effect of pregnancy on endothelium and smooth muscle: their role in reduced adrenergic sensitivity

During pregnancy, vascular reactivity of the uterine artery is characterized by decreased contraction to norepinephrine and increased relaxation to acetylcholine. We investigated whether 1) relaxation to A23187 is increased during pregnancy and 2) endothelium-derived relaxing factor (EDRF) and/or prostaglandins are responsible for the decreased uterine artery sensitivity to norepinephrine during pregnancy. Isolated rings of uterine and carotid arteries were obtained from pregnant and nonpregnant guinea pigs. Relaxation to sodium nitroprusside in uterine but not carotid artery was reduced during pregnancy. Relaxation of both uterine and carotid arteries to the calcium ionophore A23187 was unaffected by pregnancy. During pregnancy, contractions to norepinephrine were reduced in the uterine artery compared with arteries from nonpregnant animals. Indomethacin slightly enhanced the contractions of uterine artery to norepinephrine during pregnancy. However, indomethacin-treated uterine arteries from pregnant animals were still less responsive to norepinephrine than control uterine arteries from nonpregnant animals. Methylene blue enhanced the efficacy of norepinephrine in uterine arteries of nonpregnant animals as well as carotid arteries of pregnant and nonpregnant animals but not in uterine arteries of pregnant animals. In contrast, N-monomethyl-L-arginine, a specific inhibitor of EDRF synthesis, not only enhanced uterine and carotid artery responses to norepinephrine in both pregnant and nonpregnant animals but fully reversed the blunted potency of norepinephrine on uterine arteries of pregnant to that of nonpregnant animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Magnesium sulfate-induced relaxation of uterine arteries from pregnant and nonpregnant patients

The effects of magnesium sulfate at different concentrations were investigated in isolated rings of uterine arteries from pregnant and nonpregnant patients. Addition of magnesium sulfate (0.5 to 9.6 mmol/L) to the suffusion medium containing the normal concentration of 1.2 mmol/L magnesium sulfate produced concentration-dependent relaxation of norepinephrine (1 mumol/L)-induced or potassium chloride (35 mmol/L)-induced contractions. Magnesium sulfate was about three times more potent in causing inhibition of potassium chloride-induced contractions in uterine arteries from pregnant patients than in those from nonpregnant patients. The concentrations that inhibited 50% of the contraction induced by potassium chloride were 0.6 +/- 0.2 mmol/L (n = 4) in the arteries from pregnant patients and 1.6 +/- 0.2 mmol/L (n = 4) in the arteries from nonpregnant patients. At high concentrations (4.8 and 9.6 mmol/L), magnesium sulfate also was more potent in inhibiting norepinephrine-induced contractions in arteries from pregnant women than in arteries from nonpregnant women. The magnesium sulfate-induced relaxation was almost completely inhibited by calcium chloride (2 mmol/L) added to the suffusion medium containing the normal concentration of 2.5 mmol/L calcium chloride but was not affected by indomethacin (5 mumol/L), methylene blue (10 mumol/L), or removal of the endothelium. The results show that magnesium sulfate, at therapeutic blood concentrations, acts as a potent dilator of human uterine arteries, especially those from pregnant patients. The results are consistent with the view that magnesium sulfate may facilitate uteroplacental perfusion.

Calcium influx and protein kinase C activation involved in uterine vasoconstriction in guinea pigs

The mechanical responses of circular segments of uterine arteries to different combinations of vasoactive agents and putative inhibitors of calcium fluxes were examined using a sensitive in vitro method. Exposure to high potassium (127 mM) or to noradrenaline (NA; 0.1 mM) resulted in a rapid, initial increase in tension of the vascular preparation to reach a sustained level of contraction (approximatively 12 mN) which lasted for at least 15 min. The protein kinase C activator, 4-β-phorbol-12,13-esther-dibutyrate (10 μM), induced a slowly developing but sustained contractile response with maximum (PDBu max) of only 4 mN. Addition of the calcium ionophore, A23187, to PDBu-contracted vessels did not increase tension, while the maximum tension evoked by A23187 per se (3 μM) was 5 mN. Ionomycin had only a small contractile effect on the uterine atery. The contraction evoked by depolarization (potassium) or α 1-adrenoceptor stimulation (NA) was decreased in nominally calcium-free medium containing EDTA (0–100 μM) or EGTA, while uterine arteries loaded intracellularly with the calcium chelator, quin-2, responded to the vasoconstrictors almost as well as the control preparations. Blockade of calcium influx with Cd 2+ (> .01 mM), nifedipine (> 3 μM), verapamil (> 1 μM) and TMB-8 (> 10 μM) reduced the tension evoked by potassium somewhat more than it reduced the contractions induced by NA, while the opposite was seen in the presence of Ni 2+ (> 0.1 mM). Inhibition of calmodulin-dependent enzymes by W7 (> 10 μM) reduced the maximum on evoked by potassium and NA to a similar extent. These data suggest that the strong contractions of uterine arteries primarily depend on calcium mobilized from the extracellular medium through different types of calcium channels, and that activation of a protein kinase C contributes, by approximatively 30% to the contraction.

The action of vasopressors on isolated uterine arteries

Isolated uterine arteries from nonpregnant human uteri and pregnant sheep uteri responded in a similar manner to 7 vasopressor drugs. Epinephrine and norepinephrine were equal in vasoconstrictor activity and about 10 times more active than phenylephrine and metaraminol which were also equally active. Ephedrine, mephentermine, and dopamine produced contractions of uterine arteries but only at high concentrations. Neither halothane (0.45 to 0.50 per cent), nitrous oxide (70 per cent), nor lidocaine (3 μg per milliliter) altered contractions to epinephrine or norepinephrine.