Molecular Human Reproduction, Vol. 6, No. 4, 361-368,
April 2000
© 2000 European Society of Human Reproduction and Embryology
Pregnancy |
Pregnancy does not alter the response of uterine arteries to vasoactive intestinal polypeptide
1 Tayside Institute of Child Health, University of Dundee, Ninewells Hospital & Medical School, Dundee, DD1 9SY, Scotland, UK and 2 Department of Clinical Pharmacology, Pharmacology and Toxicology, Medical School, Belgrade, Yugoslavia
Abstract
In order to provide sufficient nutrients for fetal development, pregnancy is associated with a significant increase in uterine blood flow. Although vasoactive intestinal polypeptide (VIP) is considered to be an important regulator of uterine blood flow it is not known whether endothelium-derived relaxing factors contribute to VIP action in the uterine artery, whether pregnancy alters the effect of VIP in the uterine artery and/or whether VIP interacts with noradrenaline and acetylcholine on the uterine artery and whether pregnancy regulates this possible interaction. In the present study, VIP induced a concentration-dependent relaxation of guinea pig uterine arterial rings, both intact and denuded of endothelium. Pregnancy did not alter the relaxation of uterine artery in response to VIP. In all preparations, addition of NG-monomethyl-L-arginine (L-NMMA), indomethacin and diethylcarbamazine did not modify the effect of VIP in uterine arteries. The VIP–receptor complex dissociation constant did not differ significantly between studied vessels, and in all experimental groups the relationship between receptor occupancy and the response was linear, with the receptor reserve (KA/EC50) close to unity. VIP did not modulate acetylcholine-induced relaxation or noradrenaline-induced contraction in both non-pregnant and pregnant guinea pig uterine arteries. This study has shown that: (i) VIP induces relaxation of guinea pig uterine artery acting as a partial agonist on receptors localized in smooth muscle; (ii) pregnancy does not alter the response of guinea pig uterine arteries to VIP and does not change the receptor affinity for VIP, the efficiency of the receptor coupling or the VIP receptor density; and (iii) VIP does not modulate effects of neurotransmitters on guinea pig uterine arteries and pregnancy is not associated with the changes of VIP–neurotransmitter interaction.
endothelium/pregnancy/uterine artery/vasoactive intestinal polypeptide
Introduction
The cardiovascular system is subjected to major functional and anatomical changes during pregnancy (Rosenfeld, 1977
; Easterling et al., 1991; Jovanovic and Jovanovic, 1997, 1998; Jovanovic et al., 1999) and uterine blood flow is dramatically increased during pregnancy to provide sufficient nutrients for fetal development (Peeters et al., 1980). It has been postulated that both the blunted vascular response to vasoconstrictors (Weiner et al., 1991; Grbovic and Jovanovic, 1996; 1997; Jovanovic et al., 1998b), and the increased response to vasodilators (Weiner et al., 1989), may be responsible for the increase in uterine blood flow. It has been proposed that the pregnancy-associated increase in the synthesis of nitric oxide (NO), a potent endogenous vasodilator (Palmer et al., 1987), may augment vasorelaxation and reduce vasoconstriction (Weiner et al., 1994). However, this concept has been challenged and several studies have demonstrated that the sensitivity of the uterine artery is not decreased to all vasoconstrictors (Jovanovic et al., 1995a,c) or increased to all vasodilators (Jovanovic et al., 1994a,b, 1997a). Such findings reaffirm the search for the identity of the neurohumoral factors which play an important role in cardiovascular adaptation to pregnancy.
Vasoactive intestinal polypeptide (VIP) is localized in vasodilator non-noradrenergic neurons supplying the uterine artery (Morris et al., 1985; Morris, 1993). Together with some other peptides (Jovanovic et al., 1995d; 1997b), VIP is considered to be an important regulator of uterine blood flow (Clark et al., 1981; Morris and Murphy, 1989; Bodelsson and Stjernquist, 1992; Jovanovic et al., 1998b) and it is possible that the sensitivity of the uterine artery to VIP during pregnancy is augmented which, in turn, contributes to the increased uterine blood flow. In addition, as has been reported for other arteries (Jorgensen, 1991), it is also possible that VIP may modulate the response of the uterine artery to the neurotransmitters, noradrenaline and acetylcholine, in such a way as to promote uterine vascular relaxation. Such an effect of VIP may be regulated by pregnancy.
This study was, therefore, undertaken in order to determine: (i) whether VIP-induced relaxation of uterine arteries is altered during pregnancy and (ii) whether pregnancy regulates the interaction between VIP and acetylcholine and noradrenaline on the uterine artery. To address these questions, experiments were undertaken on non-pregnant and pregnant guinea pig uterine arteries both intact and denuded of endothelium.
Materials and methods
Adult female non-pregnant and pregnant (50–60 days gestation; term = 65–68 days gestation) guinea pigs (700–900 g) were used in this study. The uterine artery, which originates in the pelvis, anastomoses with the uterine branch of the ovarian artery, forming a loop called the arcade artery. Along the arcade, several secondary arteries arise that supply the uterine tissue. The right and left uterine arteries respectively, were carefully dissected free from surrounding fat and connective tissue and cut into 3 mm long circular segments. All vessel segments were immediately placed in Krebs–Ringer bicarbonate solution (see below). The endothelium was removed from some rings by gently rubbing the intimal surface with stainless steel wires. Ring preparations were mounted between two stainless-steel triangles in an organ bath containing 10 ml Krebs–Ringer bicarbonate solution (37°C, pH 7.4), aerated with 95% O2 and 5% CO2. One of the triangles was attached to a displacement unit allowing a fine adjustment of tension and the other was connected to a force-displacement transducer (Hugo Sachs K30, Freiburg, Germany). Isometric tension was recorded on a Hugo Sachs model MC 6621 recorder.
The preparations were allowed to equilibrate for ~1 h in Krebs–Ringer bicarbonate solution. During this period the organ baths were washed with fresh (37°C) buffer solution every 15 min. After 60 min, each ring was gradually stretched to the optimal point of the resting tension (non-pregnant: 4.5 mN; pregnant: 6.2 mN) as has been previously determined (Jovanovic et al., 1994a). Once at their optimal length, the segments were allowed to equilibrate for 30 min before experimentation.
Reagents
The Krebs–Ringer bicarbonate solution had the following composition (in mmol/l): NaCl 118.3; KCl 4.7; CaCl2 2.5; MgSO4 1.2; KH2PO4 1.2; NaHCO3 25.0; Ca–EDTA 0.026; glucose 11.1. The solution was continuously bubbled with 95% O2 and 5% CO2 resulting in a pH 7.4, and the temperature was kept at +37°C. The following drugs were used: acetylcholine chloride, indomethacin, diethylcarbamazine, 4-aminopyridine, L-phenylephrine, noradrenaline bitartrate (Sigma, St Louis, MO, USA); NG-monomethyl-L-arginine (L-NMMA) acetate (Wellcome, Buckingham, UK), vasoactive intestinal polypeptide (VIP; Peninsula Laboratories, San Carlos, CA, USA) papaverine hydrochloride (Merck, Rashway, NJ, USA). All agents were dissolved in distilled water and diluted to the desired concentration with buffer. The only exception was indomethacin, which was dissolved in equimolar Na2CO3 solution. All drugs were added directly to the bath in a volume of 150 µl and the concentrations given are the calculated final concentration in the bath solution.
Experimental procedure
At the beginning of each experiment the vessel segment was exposed twice to a K+-rich Krebs–Ringer bicarbonate solution (126 mmol/l KCl, achieved by exchanging the 118.3 mmol/l NaCl with KCl). Only if the second contractile response to K+ was equivalent in magnitude to the first (variation <10%), was the preparation used for further experimentation. Subsequently, in order to confirm the presence or successful denudation of endothelium, the rings were precontracted with phenylephrine (80% of the response to K+-rich Krebs–Ringer bicarbonate solution, 0.2–0.6 µmol/l) and thereafter challenged with acetylcholine (10 µmol/l). On the basis of prior studies (Jovanovic et al., 1994a, 1995b, 1997a), relaxation of >80% or <20% of maximal relaxation evoked by acetylcholine (maximal relaxation represented complete return to the resting tension from the contraction in response to phenylephrine) was indicative of structurally-intact or denuded endothelium respectively, regardless of pregnancy status.
Effect of VIP on the uterine artery
Concentration–response curves for VIP were made by adding increasing concentrations of this peptide to rings precontracted with EC80 phenylephrine, when the previous concentration had produced its equilibrium response or after 5 min if no response was obtained. Experiments followed a multiple curve design since separate experiments in all types of preparations (n = 4 for each) demonstrated that first and second concentration–response curves for VIP were not significantly different. Therefore, the following protocol was used: (i) contraction in response to phenylephrine and concentration–response curve with VIP, followed by three washes, addition of the antagonist and an equilibration period of 15 min (L-NMMA), 20 min (4-aminopyridine), 30 min (diethylcarbamazine) or 40 min (indomethacin) followed by a further equilibration period of 15 min (Jovanovic et al., 1994b, 1995b, 1997a); and (ii) contraction in response to phenylephrine and concentration–response curve with VIP.
Interaction between VIP and acetylcholine
Concentration–response curves for acetylcholine were made by adding increasing concentrations of this neurotransmitter on rings precontracted with EC80 phenylephrine (Jovanovic et al., 1994c, 1995b, 1997a) in the absence and presence of VIP. The following protocol was used: (i) contraction in response to phenylephrine and concentration–response curve with acetylcholine, followed by three washes, addition of VIP and a 30 min equilibration period; and (ii) contraction in response to phenylephrine and concentration–response curve with acetylcholine.
Interaction between VIP and noradrenaline
Concentration–response curves for noradrenaline were made by adding increasing concentrations of this neurotransmitter on vascular rings (Jovanovic et al., 1995a) in the absence and presence of VIP. The following protocol was used: (i) concentration–response curve for noradrenaline, addition of VIP and a 30 min equilibration period; and (ii) concentration–response curve for noradrenaline.
At the end of each experiment with precontracted rings, papaverine (300 µmol/l) was added to the organ bath to determine the maximal relaxation of preparations (Jovanovic et al., 1994a, 1995b, 1997a).
Calculations and statistical analysis
The relaxation induced by each concentration of VIP or acetylcholine was expressed as a percentage of the maximum relaxation to papaverine, while the contraction induced by each concentration of noradrenaline was expressed as a percentage of the maximum with K+-rich Krebs–Ringer bicarbonate solution. Concentrations of VIP, acetylcholine and noradrenaline eliciting 50% of its own maximum response (EC50) were determined graphically for each curve by linear interpolation, and presented as pEC50 (pEC50 = –log EC50).
The VIP dissociation constant (KA) was calculated according to a previously described method (Kenakin, 1987), using 4-aminopyridine as a non-competitive antagonist (Jovanovic et al., 1998b); equi-effective concentrations of VIP in the absence [A] and presence of 4-aminopyridine [A'] were obtained. A plot of 1/[A] against 1/[A'] was constructed. The slope of the regression line and the y-intercept were used to calculate VIP (KA) dissociation constant: KA = (Slope-1)/intercept. KA is presented as pKA (–log KA). Estimates of the receptor reserve were made from KA/EC50 (Kenakin, 1987). The results are expressed as mean ± SEM; n refers to the number of animals. Statistical significance of differences between two means was determined with Student's t-test for paired or unpaired observations where appropriate. One-way analysis of variance (ANOVA) was used when more than two groups were analysed. P < 0.05 was considered to be statistically significant.
Results
Effect of VIP
VIP (0.3–500 nmol/l) induced a concentration-dependent relaxation of guinea pig uterine arteries both intact and denuded of endothelium (with endothelium: pEC50 = 8.13 ± 0.07, maximal response = 96.1 ± 1.7%; without endothelium: pEC50 = 7.85 ± 0.08, maximal response = 93.1.1 ± 3.7%; n = 14–16, P > 0.05, Figure 1). Pregnancy status did not alter the relaxation of uterine artery in response to VIP (with endothelium: pEC50 = 8.08 ± 0.05, maximal response = 95.0 ± 2.1%; without endothelium: pEC50 = 8.11 ± 0.03, maximal response = 91.1 ± 4.2%; n = 14–16, P > 0.05, Figure 1).
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Effects of L-NMMA, indomethacin and diethylcarbamazine
Although removal of endothelium did not affect VIP-induced vasorelaxation, it is possible that endothelium releases a mixture of contraction and relaxant substances in equi-effective amounts. Therefore, in order to further address the possible involvement of vascular endothelium in VIP action, the effects of an inhibitor of NO synthesis (L-NMMA; 10 µmol/l), a cyclo-oxygenase inhibitor (indomethacin; 10 µmol/l), and a lipoxygenase inhibitor (diethylcarbamazine; 10 µmol/l), were tested. Addition of these compounds did not modify the effect of VIP in uterine arteries from either pregnant or non-pregnant animals, regardless of the condition of endothelium (n = 4 for each, Figure 2
).
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Dissociation constant VIP–receptor complex
It was previously determined that VIP receptors found in vascular smooth muscle are coupled to potassium channels sensitive to 4-aminopyridine (Kawasaki et al., 1997
). In order to determine the dissociation constant of the VIP–receptor complex, the non-competitive inhibition of VIP-induced relaxation was used, as shown by depression of the maximum response (see Methods). An example of these experiments is presented in Figure 3. The mean pKA values did not differ significantly, regardless of pregnancy status or endothelial conditions (pEC50 for non-pregnant: 8.05 ± 0.11 versus 7.63 ± 0.12 for vessels with and without endothelium respectively; pEC50 values for pregnant: 7.97 ± 0.14 versus 7.86 ± 0.13 for vessels with and without endothelium respectively, n = 6 for each group, P > 0.05). The relationship between receptor occupancy and the response was linear (Figure 4; Table I). The receptor reserve expressed as KA/EC50 was close to unity (Table I).
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Effect of VIP on acetylcholine-induced relaxation
VIP (10 nmol/l) did not modulate endothelium-dependent relaxation of uterine arteries in response to acetylcholine, irrespective of pregnancy status (Figure 5
).
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Effect of VIP on noradrenaline-induced contraction
VIP (10 nmol/l) did not alter noradrenaline-induced contractions of uterine artery regardless of the pregnancy status or endothelial condition (Figure 6
).
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Discussion
In the present study, it is reported that VIP induces endothelium-independent relaxation of guinea pig uterine artery and is unaltered by pregnancy. For some time, it has been known that VIP possess the ability to induce vasodilation (Barnes et al., 1986; Beny et al., 1986; Sata et al., 1986). We previously determined that VIP induces endothelium-dependent relaxation in the human uterine artery (Jovanovic et al., 1998b); this is in contrast to the current finding that endothelium does not modulate the effect of VIP on guinea pig uterine artery. However, such a difference is not surprising in the light of previous reports showing that the role of vascular endothelium in VIP-induced relaxation varies in different vascular tissues, depending upon the anatomical location and species (Sata et al., 1986; Greenberg et al., 1987; Hattori et al., 1992; Bakken et al., 1995). However, it is still possible that the apparent lack of involvement of endothelium-derived relaxing factors in VIP-induced vasodilation was due to balanced production of both relaxing and contracting factors from endothelium in response to VIP. Indeed, simultaneous release of endothelium-derived relaxing and contracting factors in response to vasoactive compounds has been described previously in different blood vessels, including the uterine artery (Nigro et al., 1990; Weiner et al., 1992). When activated by vasoactive agents, vascular endothelium possesses the ability to release relaxing factors (Vane et al., 1990), including NO (Palmer et al., 1987) and vasodilator cyclo-oxygenase or lipoxygenase products (Uotila et al., 1987; Karlsson et al., 1998). The finding that inhibitors of NO synthase or inhibitors of cyclo-oxygenase and lipoxygenase (Mathews and Murphy, 1982; Toda, 1984; Rees et al., 1989) did not alter VIP-induced relaxation, strongly supports the notion that products from vascular endothelium are not involved in VIP action on the guinea pig uterine artery. It seems that VIP acts on guinea pig uterine arterial smooth muscle to induce vasorelaxation, as has been demonstrated in some other blood vessels (Sata et al., 1986; Greenberg et al., 1987).
It has been postulated that increased sensitivity to vasodilators of the uterine artery during pregnancy mediates the increased blood flow to the uterus (Peeters et al., 1980). It has been proposed that endothelium-dependent relaxation of the uterine artery to acetylcholine is augmented during pregnancy thus leading to an increase in uterine blood flow (Weiner et al., 1989; Nelson et al., 1998). It has been interpreted that the pregnancy-associated increase in endothelial NO production is responsible for the increased responsiveness to acetylcholine in the uterine artery (Weiner et al., 1989; 1991; Nelson et al., 1998). However, in some studies, including this one (see Figure 5
), such a concept has been challenged (Matsumoto et al., 1992; Jovanovic et al., 1994a; 1995b; 1997a). It has also been proposed that functional changes in uterine arterial smooth muscle may mediate the pregnancy-induced increase in uterine blood flow (Magness et al., 1991; Jovanovic et al., 1998b). It has been demonstrated that these changes are associated with the alterations at the level of specific receptor coupling (Jovanovic et al., 1995c, 1998a). In the present study, non-competitive antagonism with 4-aminopyridine revealed that the KA value for the VIP–receptor complex was within the nanomolar range. This value is within the range reported for VIP–receptor complex on other tissues (Rodriguez-Henche et al., 1994), including the human uterine artery (Jovanovic et al., 1998b). Receptor reserve expressed as KA/EC50 reflects efficiency of receptor coupling (see Kenakin, 1987). Findings that the receptor reserve was close to unity in all preparations tested means that: (i) VIP acts on guinea pig uterine artery as partial agonist and that (ii) during pregnancy there are no changes in affinity of receptors to VIP, receptor density or receptor coupling efficiency. The partial agonistic nature of VIP has been reported on human uterine artery and the present findings are in agreement with this previous report (Jovanovic et al., 1998b). However, in guinea pig uterine artery, VIP induced relaxation that was in maximal magnitude near to maximal papaverine-induced relaxation, which is apparently in contrast to its partial agonist property. This could be explained by high affinity of VIP for receptors and, very probably, high receptor density, which allow the achievement of maximal relaxation, regardless of the VIP low intrinsic activity. Lack of alterations in VIP-induced relaxation and underlying receptors suggest that VIP per se, although an important regulator of uterine blood flow, is not responsible for the adaptation of uterine vasculature to pregnancy.
Interaction between neurotransmitters and neuropeptides in the uterine artery is an important factor in regulation of uterine blood flow (Fallgren et al., 1989; Stjernquist et al., 1991). Noradrenaline and acetylcholine are neurotransmitters that regulate uterine blood flow (Bell, 1968), through activation of endothelial muscarinic receptors or smooth muscle adrenoceptors respectively (Jovanovic et al., 1994a,c, 1995a). In the present study, VIP did not modulate the effects of neurotransmitters, acetylcholine and noradrenaline, on guinea pig uterine artery irrespective of pregnancy status or endothelial condition. These findings suggest that interaction between VIP and acetylcholine and noradrenaline on uterine artery is not significant, as it has been observed with some other blood vessels (Bakken et al., 1995), and that pregnancy is not associated with the changes at the level of this interaction.
Acknowledgments
This work was supported by grants from the American Heart Association, British Heart Foundation and University of Dundee.
Notes
3 To whom correspondence should be addressed 
References
Bakken, I.J., Vincent, M.B., Sjaavaag, I. and White, L.R. (1995) Vasodilation in porcine ophthalmic artery: peptide interaction with acetylcholine and endothelial dependence. Neuropeptides, 29, 69–75.[Web of Science][Medline]
Barnes, P.J., Cadieux, A., Carstairs, J.R. et al. (1986) Vasoactive intestinal peptide in bovine pulmonary artery: localisation, function and receptor autoradiography. Br. J. Pharmacol., 89, 157–162.[Web of Science][Medline]
Bell, C. (1968) Dual vasoconstrictor and vasodilator innervation of the uterine arterial supply in the guinea pig. Circ. Res., 23, 279–289.
Beny, J.L., Brunet, P.C. and Huggel, H. (1986) Effect of mechanical stimulation, substance P and vasoactive intestinal polypeptide on the electrical and mechanical activities of circular smooth muscles from pig coronary arteries contracted with acetylcholine: role of endothelium. Pharmacology, 33, 61–68.[Web of Science][Medline]
Bodelsson, G. and Stjernquist, M. (1992) Smooth muscle dilatation in the human uterine artery induced by substance P, vasoactive intestinal polypeptide, calcitonin gene-related peptide and atrial natriuretic peptide: relation to endothelium-derived relaxing substances. Hum. Reprod., 7, 1185–1188.
Clark, K.E., Mills, E.G., Stys, S.J. and Seeds, A.E. (1981) Effects of vasoactive polypeptides on the uterine vasculature. Am. J. Obstet. Gynecol., 139, 182–188.[Web of Science][Medline]
Easterling, T.R., Benedetti, T.J., Schmucker, B.C. et al. (1991) Maternal hemodynamics and aortic diameter in normal and hypertensive pregnancies. Obstet. Gynecol., 78, 1073–1077.[Web of Science][Medline]
Fallgren, B., Ekblad, E. and Edvinsson, L. (1989) Co-existence of neuropeptides and differential inhibition of vasidilator responses by neuropeptide Y in guinea pig uterine arteries. Neurosci. Lett., 100, 71–76.[Web of Science][Medline]
Grbovic, L. and Jovanovic, A. (1996) Effect of the vascular endothelium on contractions induced by prostaglandin F2
in isolated pregnant guinea pig uterine artery. Hum. Reprod., 11, 2041–2047.
Grbovic, L. and Jovanovic, A. (1997) Indomethacin reduces prostaglandin F2-induced contraction of guinea pig uterine artery with both intact and denuded endothelium. Prostaglandins, 53,371–379.[Web of Science][Medline]
Greenberg, B., Rhoden, K. and Barnes, P.J. (1987) Relaxant effects of vasoactive intestinal peptide and peptide histidine isoleucine in human and bovine pulmonary arteries. Blood Vessels, 24, 45–50.[Web of Science][Medline]
Hattori, Y., Nagashima, M., Endo, Y. and Kanno, M. (1992) Glibenclamide does not block arterial relaxation caused by vasoactive intestinal polypeptide. Eur. J. Pharmacol., 213, 147–150.[Web of Science][Medline]
Jorgensen, J.C. (1991) Interaction between norepinephrine, NPY and VIP in the ovarian artery. Peptides, 12, 831–837.[Web of Science][Medline]
Jovanovic, S. and Jovanovic, A. (1997) Remodelling of guinea pig aorta during pregnancy: a selective alterations of endothelial cells. Hum. Reprod., 12, 2297–2302.
Jovanovic, S. and Jovanovic, A. (1998) Pregnancy is associated with hypotrophy of carotid artery endothelial and smooth muscle cells. Hum. Reprod., 13, 1074–1078.
Jovanovic, S., Blagojevic, Z., Mrvic, V. et al. (1999) Pregnancy is not associated with altered morphology of femoral artery. Hum. Reprod., 14, 1885–1889.
Jovanovic, A., Grbovic, L., Drekic, D. and Novakovic, S. (1994a) Muscarinic receptor function in the guinea pig uterine artery is not altered during pregnancy. Eur. J. Pharmacol., 258, 185–194.[Web of Science][Medline]
Jovanovic, A., Grbovic, L. and Tulic, I. (1994b) Predominant role for nitric oxide in the relaxation induced by acetylcholine in human uterine artery. Hum. Reprod., 9, 387–393.
Jovanovic, A., Grbovic, L. and Tulic, I. (1994c) Endothelium-dependent relaxation in human uterine artery in response to acetylcholine. Eur. J. Pharmacol., 256, 131–139.[Web of Science][Medline]
Jovanovic, A., Grbovic, L. and Jovanovic, S. (1995a) Effect of the vascular endothelium on noradrenaline-induced contractions in non-pregnant and pregnant guinea pig uterine arteries. Br. J. Pharmacol., 114,805–815.[Web of Science][Medline]
Jovanovic, A., Grbovic, L. and Jovanovic, S. (1995b) K+ channel blockers do not modify relaxation of guinea pig uterine artery evoked by acetylcholine. Eur. J. Pharmacol., 280, 95–100.[Web of Science][Medline]
Jovanovic, A., Grbovic, L., Jovanovic, S. and Zikic, I. (1995c) Effect of pregnancy on vasopressin-mediated responses in guinea pig uterine arteries with intact and denuded endothelium. Eur. J. Pharmacol., 280, 101–111.[Web of Science][Medline]
Jovanovic, A., Grbovic, L., Zikic, I. and Tulic, I. (1995d) Characterization of arginine vasopressin actions in human uterine artery: lack of role of the vascular endothelium. Br. J. Pharmacol., 115, 1295–1301.[Web of Science][Medline]
Jovanovic, A., Jovanovic, S. and Grbovic, L. (1997a) Endothelium-dependent relaxation in pregnant guinea pig uterine artery in response to acetylcholine. Hum. Reprod., 12, 1805–1809.
Jovanovic, A., Jovanovic, S., Tulic, I. and Grbovic, L. (1997b) Effect of oxytocin as a partial agonist at vasoconstrictor vasopressin receptors on the human isolated uterine artery. Br. J. Pharmacol., 121, 1468–1474.[Web of Science][Medline]
Jovanovic, A., Jovanovic, S. and Grbovic, L. (1998a) Characterization of oxytocin actions in guinea pig isolated uterine artery: the effect of pregnancy. Eur. J. Pharmacol., 343, 35–42.[Web of Science][Medline]
Jovanovic, A., Jovanovic, S., Tulic, I. and Grbovic, L. (1998b) Predominant role for nitric oxide in the relaxation induced by vasoactive intestinal polypeptide in human uterine artery. Mol. Hum. Reprod., 4, 71–76.
Kawasaki, J., Kobayashi, S., Miyagi, Y. et al. (1997) The mechanisms of the relaxation induced by vasoactive intestinal peptide in the porcine coronary artery. Br. J. Pharmacol., 121, 977–985.[Web of Science][Medline]
Karlsson, C., Bodelsson, G., Bodelsson, M. and Stjernquist M. (1998) Endothelium-derived prostanoids reduce 5-hydroxytryptamine-induced contraction in the human uterine artery. Hum. Reprod., 13, 1947–1951.
Kenakin, T.P. (1987) Pharmacologic Analysis of Drug–Receptor Interaction. Raven Press, New York, USA.
Magness, R.R., Rosenfeld, C.R. and Carr, B.R. (1991) Protein kinase C in uterine and systemic arteries during ovarian cycle and pregnancy. Am. J. Physiol., 260, E464–E470.
Mathews, W.R and Murphy, R.C. (1982) Inhibition of leukotriene biosynthesis in mastocytoma cells by diethylcarbamazine. Biochem. Pharmacol., 31, 2129–2132.[Web of Science][Medline]
Matsumoto, T., Kanamaru, K., Sugiyama, Y. and Murata, Y. (1992) Endothelium-derived relaxation of the pregnant and nonpregnant canine uterine artery. J. Reprod. Med., 37, 529–533.[Web of Science][Medline]
Morris, J.L. (1993) Co-transmission from autonomic vasodilator neurons supplying the guinea pig uterine artery. J. Auton. Nerv. Syst., 42, 11–21.[Web of Science][Medline]
Morris, J.L. and Murphy, R. (1989) Porcine VIP is more potent than guinea pig VIP in relaxing the guinea pig uterine artery. Peptides, 10, 887–889.[Web of Science][Medline]
Morris, J.L., Gibbins, I.L., Furness, J.B. et al. (1985) Co-localization of neuropeptide Y, vasoactive intestinal polypeptide and dynorphin in non-noradrenergic axons of the guinea pig uterine artery. Neurosci. Letts., 62, 31–37.[Web of Science][Medline]
Nelson, S.H., Steinsland, O.S., Suresh, M.S. and Lee, N.M. (1998) Pregnancy augments nitric oxide-dependent dilator response to acetylcholine in the human uterine artery. Hum. Reprod., 13, 1361–1367.
Nigro, D., Fortes, Z.B., Scivotetto, R. and Carvalho, M.H. (1990) Simultaneous release of endothelium-derived relaxing and contracting factors induced by noradrenaline in normotensive rats. Gen. Pharmacol., 21, 443–446.[Web of Science][Medline]
Palmer, R.M.J., Ferrige, A.G. and Moncada, S. (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature, 327, 524–526.[Medline]
Peeters, L.L.H., Grutters, G. and Martin, C.R. (1980) Distribution of cardiac output in the unstressed pregnant guinea pig. Am. J. Obstet. Gynecol., 138, 1177–1184.[Web of Science][Medline]
Rees, D.D., Palmer, R.M.J., Hodson, H.F. and Moncada, S. (1989) A specific inhibitor of nitric oxide formation from L-arginine attenuates endothelium-dependent relaxation. Br. J. Pharmacol., 96, 418–424.[Web of Science][Medline]
Rodriguez-Henche, N., Rodriguez-Pena, M.S., Guijarro, L.G. and Prieto, J.C. (1994) Characterization of vasoactive intestinal peptide receptors in human liver. Biochim. Biophys. Acta, 1221, 193–198.[Medline]
Rosenfeld, C.R. (1977) Distribution of cardiac output in ovine pregnancy. Am. J. Physiol., 232, H231-H235.
Sata, T., Misra, H.P., Kubota, E. and Said, S.I. (1986) Vasoactive intestinal polypeptide relaxes pulmonary artery by an endothelium-independent mechanism. Peptides, 7 (Suppl. 1), 225–227.
Stjernquist, M., Ekblad, E., Nordstedt, E. and Radzuweit, C. (1991) Neuropeptide Y (NPY) co-exist with tyrosine-hydroxylase and potentiates the adrenergic contractile response of vascular smooth muscle in the human uterine artery. Hum. Reprod., 6, 1034–1038.
Toda, N. (1984) Endothelium-dependent relaxation induced by angiotensin II and histamine in isolated arteries of dog. Br. J. Pharmacol., 81, 301–307.[Web of Science][Medline]
Uotila, P., Vargas, R., Wroblewska, B. et al. (1987) Relaxing effects of 15-lipoxygenase products of arachidonic acid in rat aorta. J. Pharmacol. Exp. Ther., 242, 945–949.
Vane, J.R., Anggard E.E. and Botting, R.M. (1990). Regulatory functions of the vascular endothelium. N. Engl J. Med., 323, 27–36.[Web of Science][Medline]
Weiner, C.P., Lizasoain, I., Baylis S.A. et al. (1994) Induction of calcium-dependent nitric oxide synthesis by sex hormones. Proc. Natl Acad. Sci. USA, 91, 5212–5216.
Weiner, C., Martinez, E., Zhu, L.K. et al. (1989) In vitro release of endothelium-derived relaxing factor by acetylcholine is increased during the guinea pig pregnancy. Am. J. Obstet. Gynecol., 161, 1599–1605.[Web of Science][Medline]
Weiner, C.P., Thompson, L.P., Liu, K.Z. and Herrig, J.E. (1992) Endothelium-derived relaxing factor and indomethcin-sensitive contracting factor alter arterial contractile responses to thromboxane during pregnancy. Am. J. Obstet. Gynecol., 166, 1171–1178.[Web of Science][Medline]
Weiner, C., Zhu, L.K., Thompson, L. et al. (1991) Effect of pregnancy on endothelium and smooth muscle: their role in reduced adrenergic sensitivity. Am. J. Physiol., 261, H1275–H1283.
Submitted on August 12, 1999; accepted on December 22, 1999.
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  S. Jovanovic, L. Grbovic, and A. Jovanovic Pregnancy is associated with altered response to neuropeptide Y in uterine artery Mol. Hum. Reprod., April 1, 2000; 6(4): 352 - 360. [Abstract] [Full Text] [PDF]
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