Molecular Human Reproduction, Vol. 6, No. 4, 352-360,
April 2000
© 2000 European Society of Human Reproduction and Embryology
Pregnancy |
Pregnancy is associated with altered response to neuropeptide Y in uterine artery
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
Pregnancy is associated with a significant increase in uterine blood flow which contributes to optimal fetal development. Although neuropeptide Y (NPY) is considered to be an important regulator of uterine blood flow, it is not known whether: (i) products from the vascular endothelium modulate NPY action in the uterine artery; (ii) pregnancy changes the responsiveness of the uterine artery to NPY, or (iii) NPY interacts with noradrenaline and acetylcholine on the uterine artery, with pregnancy regulating this possible interaction. In the present study, NPY induced a concentration-dependent contraction of guinea pig uterine arterial rings both intact and denuded of endothelium. Pregnancy significantly decreased the potency of NPY to contract uterine artery with and without endothelium. In all preparations, addition of NG-monomethyl-l-arginine acetate (l-NMMA), indomethacin and diethylcarbamazine did not modify the effect of NPY. In the presence of NPY concentration–response curves for acetylcholine and noradrenaline were significantly shifted to the right and left respectively. This effect of NPY was independent of endothelial condition or pregnancy status. The receptor reserve (KA/EC50) for acetylcholine was decreased and for noradrenaline was increased in the presence of NPY, although no changes in the dissociation constants of the neurotransmitter–receptor complexes were observed. Thus, this study has shown that: (i) NPY induces contraction of guinea pig uterine arteries acting on receptors localized in smooth muscle; (ii) pregnancy alters the response of guinea pig uterine arteries to NPY in such a way as to promote vasorelaxation, and (iii) NPY modulates the effect of neurotransmitters on guinea pig uterine arteries, but pregnancy is not associated with the changes at the level of NPY–neurotransmitter interaction.
endothelium/neuropeptide Y/pregnancy/uterine artery
Introduction
Pregnancy is associated with characteristic changes in function and anatomy of the cardiovascular system and uterine blood flow (Rosenfeld, 1977
; Peeters et al., 1980; Easterling et al., 1991; Jovanovic and Jovanovic, 1997, 1998; Jovanovic et al., 1999). The mechanism of this vascular adaptation to pregnancy is yet to be fully understood (Sladek et al., 1997). A blunted vascular response to vasoconstrictors (Weiner et al., 1991; Nelson et al., 1995; Grbovic and Jovanovic, 1996, 1997; Jovanovic et al., 1998b) and an increased response to vasodilators (Weiner et al., 1989; Nelson et al., 1995, 1998; Gangula et al., 1999) have been suggested to underlie the pregnancy-associated increase in uterine blood flow. Furthermore, it has been postulated that pregnancy increases the production of endothelium-derived relaxing factors from the uterine artery which augments endothelium-dependent relaxation and/or reduce smooth muscle responsiveness to vasoconstrictors (Weiner et al., 1994; Buhimschi et al., 1995; Magness et al., 1996; 1997; Grbovic and Jovanovic, 1996; 1997; Janowiak et al., 1998; Nelson et al., 1998). However, 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 endothelium-dependent vasodilators (Matsumoto et al., 1992; Jovanovic et al., 1994a; 1995b; 1997a). Hence, it seems that vascular adaptation to pregnancy is associated with changes beyond the endothelial function (Magness et al., 1991; Jovanovic et al., 1998a).
Neuropetide Y (NPY) is typically localized in noradrenergic axons supplying arteries, including the uterine artery (Morris and Murphy, 1988; Kong et al., 1990; Jorgensen et al., 1991; Stjernquiest et al., 1991). Together with some other peptides (Jovanovic et al., 1995d, 1997b), NPY is one of the most important regulators of uterine blood flow (Morris and Murphy, 1988; Fried and Samuelson, 1991; Jorgensen, 1991; Stjernquiest et al., 1991). It has been proposed that during pregnancy, NPY takes over the role of main uterine vasoconstrictor due to both a dramatic decrease in the number of noradrenaline-containing nerve fibres and an increase in the number of NPY-containing nerve fibres supplying uterine artery (Mione et al., 1990). In addition, NPY may potentiate adrenergic contraction and counteracts cholinergic vasodilation in uterine arterial smooth muscle (Fallgren et al., 1989; Stjernquist et al., 1991; Edvinsson and Adamsson, 1992). Therefore, any changes in the responsiveness of the uterine artery to NPY would have a profound effect on uterine blood flow during pregnancy. Since effects of the neurotransmitters, acetylcholine and noradrenaline, are not altered by pregnancy (Jovanovic et al., 1994a, 1995a,b.,1997a), changes of NPY action may be, at least in part, responsible for pregnancy-associated increase in uterine blood flow essential for optimal fetal development.
Therefore, this study was undertaken in order to determine whether: (i) NPY action on the uterine artery is altered during pregnancy; and (ii) whether pregnancy regulates the interaction between NPY and neurotransmitters, acetylcholine and noradrenaline, on the uterine artery.
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 right and left uterine arteries were dissected free from surrounding fat and connective tissue, cut into 3 mm long circular segments and 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. The endothelium was removed from some rings by gently rubbing the intimal surface with stainless steel wires. For ring preparations, one of the triangles was attached to a displacement unit and the other was connected to a force-displacement transducer (Hugo Sachs K30). 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 vessels 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; Jovanovic et al., 1994a), and equilibrated 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; CaEDTA 0.026; glucose 11.1. The solution was continuously bubbled with 95% O2 and 5% CO2 resulting in a pH 7.4, and temperature was kept at +37°C. The following drugs were used: acetylcholine chloride, indomethacin, diethylcarbamazine, prostaglandin (PG) F2
, noradrenaline bitartrate (Sigma, St Louis, MO, USA); NG-monomethyl-L-arginine acetate (L-NMMA; Wellcome, Buckingham, UK), neuropeptide Y (NPY; Peninsula Laboratories, San Carlos, CA, USA); dibenamine hydrochloride (Smith Kline & French, Irvine, UK); papaverine hydrochloride (Merck, Rashway, NJ, USA). All agents were dissolved in distilled water and diluted to the desired concentration with buffer. Exceptions were indomethacin and dibenamine, which were dissolved in equimolar Na2CO3 solution or 99% ethanol respectively. All drugs were added directly to the bath in 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, the rings were precontracted with EC80 PGF2 80% of the response to K+-rich Krebs—Ringer bicarbonate solution, (see Grbovic and Jovanovic, 1996, 1997) and thereafter challenged with acetylcholine (10 µmol/l). Relaxation >80% or <20% of maximal relaxation evoked by acetylcholine was indicative of structurally intact or denuded endothelium, respectively (Jovanovic et al., 1994a,b, 1997a).
To investigate the direct effect of NPY on uterine artery, concentration–response curves for NPY were made by adding increasing concentrations of this compound once 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 with all types of preparations (n = 4 for each) demonstrated that the first and second concentration–response curves for NPY were not significantly different. Therefore, the following protocol was used: (i) the concentration–response curve for NPY, followed by three washes, addition of the antagonist and an equilibration time of 15 min (L-NMMA), 20 min (4-aminopyridine), 30 min (diethylcarbamazine) or 40 min (indomethacin) (Jovanovic et al., 1994b, 1995b, 1997a); and (ii) concentration–response curve for NPY.
To investigate the interaction between NPY and acetylcholine on the uterine artery, concentration—response curves for acetylcholine were made by adding increasing concentrations of this neurotransmitter on rings precontracted with EC80 PGF2 (Jovanovic et al., 1994c, 1995b, 1997a), in the absence and presence of NPY. The following protocol was applied: (i) contraction in response to PGF2 and concentration—response curve for acetylcholine, followed by three washes, addition of NPY and a 30 min equilibration period; (ii) contraction in response to PGF2 and concentration—response curve with acetylcholine.
In a separate series of experiments, the dissociation constant (KA) for acetylcholine in the presence of NPY was determined using the irreversible antagonist, dibenamine (Jovanovic et al., 1994a,c). After determination of the concentration–response curve for acetylcholine in the presence of NPY, rings were exposed to dibenamine (5 µmol/l) for 30 min and then rinsed for the next 60 min. After this period, reproducible concentration—response curves to acetylcholine were obtained which were depressed and shifted to the right with the respect to the control. 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,b, 1997a).
To investigate the interaction between NPY and noradrenaline on uterine artery, concentration–response curves for noradrenaline were made by adding increasing concentrations of noradrenaline on vascular rings (Jovanovic et al., 1995a) in the absence and presence of NPY. The following protocol was used: (i) concentration–response curve for noradrenaline, addition of NPY and a 30 min equilibration period; (ii) concentration–response curve for noradrenaline. The dissociation constant (KA) for noradrenaline in the presence of NPY was also determined using dibenamine (Jovanovic et al., 1995a). After determination of the concentration–response curve for noradrenaline in the presence of NPY, rings were exposed to dibenamine (50 nmol/l) for 30 min and then rinsed for the next 60 min. After this period, reproducible concentration–response curves to acetylcholine were obtained which were depressed and shifted to the right with the respect to the control.
Calculations and statistical analysis
Contraction induced by each concentration of NPY or noradrenaline was expressed as a percentage of the maximum with K+-rich Krebs–Ringer bicarbonate solution, while relaxation induced by each concentration of acetylcholine were expressed as a percentage of the maximum relaxation to papaverine. Concentrations of NPY, noradrenaline and acetylcholine eliciting 50% of its own maximum response (EC50) was determined graphically for each curve by linear interpolation, and presented as pEC50 (pEC50 = –log EC50).
Acetylcholine and noradrenaline dissociation constants (KA), in the presence of NPY, were calculated according to a previously described method (Furchgott and Bursztyn, 1967), using dibenamine as an irreversible antagonist (Jovanovic et al., 1994a,c, 1995a): equi-effective concentrations of acetylcholine or noradrenaline prior [A] or after treatment [A'] with dibenamine 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 acetylcholine or noradrenaline (KA) dissociation constants: KA = (Slope-1)/intercept. KA is presented as pKA (–log KA).
Estimates of the receptor reserve were made from KA/EC50 (Kenakin, 1987). The fraction of receptors occupied (RA/RT) was calculated from the equation [RA]/[RT] = [A]/(KA + [A]) (Furchgott and Bursztyn, 1967).
The results are expressed as means ± SEM; n = number of animals. The statistical significance of differences between two means was determined using 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 NPY
NPY (1–1000 nmol/l) induced a concentration-dependent contraction of non-pregnant guinea pig uterine artery both intact and denuded of endothelium (with endothelium: pEC50 = 7.32 ± 0.07, maximal response = 71.0 ± 3.7%; without endothelium: pEC50 = 7.20 ± 0.08, maximal response = 69.1 ± 4.2%; n = 14–16, P > 0.05, Figure 1). Pregnancy induced a significant shift of concentration–response curves for NPY guinea pig uterine artery to the right, irrespective of whether endothelium was intact or removed (with endothelium: pEC50 = 6.87 ± 0.05, maximal response = 59.0 ± 4.2%; without endothelium: pEC50 = 6.83 ± 0.07, maximal response = 58.1 ± 4.3%; 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 NPY-induced contractions, it was possible that endothelium released a mixture of contracting and relaxant substances in equi-effective amounts. Therefore, in order to further address the possible involvement of vascular endothelium in NPY action, the effects of L-NMMA (10 µmol/l), an inhibitor of nitric oxide (NO) synthesis, indomethacin (10 µmol/l), a cyclo-oxygenase inhibitor, and diethylcarbamazine (100 µmol/l), a lipoxygenase inhibitor, were tested. Addition of these compounds did not modify the effect of NPY in uterine arteries from both non-pregnant and pregnant animals, regardless of the condition of endothelium (n = 4 for each, Figure 2
).
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Effect of NPY on acetylcholine-induced relaxation
NPY (100 nmol/l) induced a significant rightward shift of concentration–response curves for acetylcholine in non-pregnant and pregnant guinea pig uterine arteries (non-pregnant: pEC50 values for acetylcholine were 7.65 ± 0.04 in the absence and 6.95 ± 0.03 in the presence of NPY, n = 5 for each, P < 0.01; pregnant: pEC50 values for acetylcholine were 7.57 ± 0.03 in the absence and 6.80 ± 0.05 in the presence of NPY, n = 5 for each, P < 0.01; Figure 3
). Thus NPY antagonized acetylcholine-induced relaxation, regardless of pregnancy status.
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Acetylcholine–receptor complex in the presence of NPY
Changes in acetylcholine potency in the presence of NPY (100 nmol/l) might be due to changes of receptor affinity (defined with the KA value) to acetylcholine and/or changes in receptor coupling efficiency. Therefore, to explore these possibilities, KA values for acetylcholine were determined in the absence (Jovanovic et al., 1994a
) and presence of NPY using irreversible antagonist dibenamine. Examples of these experiments are shown in Figure 4. NPY did not significantly change KA values for acetylcholine–receptor interaction in non-pregnant and pregnant guinea pig uterine arteries with endothelium (Table I). In contrast, all other parameters that define efficiency of the receptor coupling were significantly diminished in the presence of NPY (Table I). In the presence of NPY, the curve that describes the relationship between receptor occupancy and the response to acetylcholine changed from its hyperbolic in the absence to almost linear shape in the presence of NPY (Figure 5). Therefore, in the presence of NPY, acetylcholine needed to occupy a higher percentage of receptors to induce the same effect, regardless of pregnancy status.
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Effect of NPY on noradrenaline-induced contraction
NPY (100 nmol/l) induced a significant leftward shift of concentration–response curves for noradrenaline in non-pregnant and pregnant guinea pig uterine arteries with and without endothelium (Figure 6
; Table II). Thus, NPY potentiated noradrenaline-induced contractions, regardless of pregnancy status and endothelial condition.
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Noradrenaline–receptor complex in the presence of NPY
The increase in noradrenaline potency in the presence of NPY (100 nmol/l) may have been due to the increase in receptor affinity to noradrenaline and/or increase in receptor coupling efficiency. Therefore, to explore these possibilities KA values were determined for noradrenaline in the absence (Jovanovic et al., 1995a
) and presence of NPY using the irreversible antagonist, dibenamine. The examples of these experiments are shown on Figure 7. NPY did not significantly change KA values for noradrenaline–receptor interaction in non-pregnant and pregnant guinea pig uterine arteries with and without endothelium (Table III). In contrast, all other parameters that define efficiency of the receptor coupling were significantly increased in the presence of NPY (Table III). In the presence of NPY, curves that describe relationship between receptor occupancy and the response to noradrenaline changed from almost linear in the absence of NPY to hyperbolic shape in the presence of NPY (Figure 8). Therefore, in the presence of NPY, noradrenaline needed to occupy a lower percentage of receptors to induce the same effect regardless of pregnancy status and endothelial condition.
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Discussion
In the present study, it is reported that pregnancy is associated with changes in the interaction between NPY and uterine artery. This alteration was independent of production of vasoactive factors from the vascular endothelium.
It has been postulated that increased sensitivity to vasodilators and decreased sensitivity to vasoconstrictors of the uterine artery during pregnancy mediate the increased blood flow to the uterus (Peeters et al., 1980). More recent studies suggested that pregnancy is associated with increased expression of NO synthase and cyclo-oxygenase, enzymes responsible for the production of potent endogenous vasodilators, NO and prostacyclin (Weiner et al., 1994; Grbovic and Jovanovic, 1996). It has been proposed that an increase in production of endothelium-derived relaxing factors augments vasodilation and reduces vasoconstriction (Weiner et al., 1994; Grbovic and Jovanovic, 1996; Nelson et al., 1998). However, in disagreement with such a concept, it has been shown that responsiveness of the uterine artery to some regulators of uterine blood flow, including neurotransmitters acetylcholine and noradrenaline, is not altered by pregnancy (Jovanovic et al., 1994a, 1995a, b,c, 1998a), suggesting that pregnancy-associated vascular adaptation is more complex then exclusive changes at the level of endothelial function.
NPY is known as a neuronal factor that plays an important role in the regulation of uterine blood flow (Morris and Murphy, 1988; Jorgensen et al., 1989; Mione et al., 1990; Stjernquist et al., 1991). It has been recognized that NPY contracts uterine vascular smooth muscle and modulates effects of noradrenaline and acetylcholine on this blood vessel. In the present study, NPY induced contraction of the uterine artery, which is in agreement with previous reports (Morris and Murphy, 1988). Arterial segments taken from pregnant animals were less sensitive to NPY suggesting that, as opposed to noradrenaline, acetylcholine or vasopressine (Jovanovic et al., 1994a, 1995a, c), pregnancy does decrease the potency of NPY in the uterine artery. This, in turn, would contribute to the pregnancy-associated increase in uterine blood flow. Since the removal of endothelium did not modulate the interaction between NPY and uterine artery, it seems that products derived from the vascular endothelium do not participate in NPY action on the uterine artery. Such a notion would be in agreement with the view that basal secretion of endothelium-derived relaxing factors plays little role in regulation of uterine artery blood flow as well as in adjustments of uterine artery to pregnancy (Jovanovic et al., 1995d, 1997b; Grbovic et al., 1996). However, it was still possible that apparent lack of involvement of endothelium-derived relaxing factors in NPY-induced contraction was due to balanced production of relaxing and contracting factors in response to NPY. Indeed, simultaneous release of endothelium-derived relaxing and contracting factors in response to vasoactive compounds has been previously described in different blood vessels, including uterine artery (Nigro et al., 1990; Weiner et al., 1992). When activated by vasoactive agents, vascular endothelium possess the ability to release relaxing factors (reviewed by Vane et al., 1990), including NO (Palmer et al., 1987) and vasodilator cyclooxygenase or lipoxygenase products (Uotila et al., 1987; Karlsson et al., 1998). The finding that, in the present study, an inhibitor of NO synthase or inhibitors of cyclo-oxygenase and lipoxygenase (Methews and Murphy, 1982; Toda et al., 1984; Rees et al., 1989) did not alter NPY-induced contraction, support the conclusion that products from vascular endothelium do not modulate NPY action on the guinea pig uterine artery.
It is generally accepted that the most significant role of NPY in regulation of uterine arterial tone is through the modulation of interaction between NPY and neurotransmitters, acetylcholine and noradrenaline (Morris and Murphy, 1988; Jorgensen et al., 1991; Stjernquiest et al., 1991). In the present study, NPY decreased the potency of acetylcholine on uterine artery with endothelium and increased potency of noradrenaline on arteries both intact and denuded of endothelium. This effect of NPY was observed in both non-pregnant and pregnant guinea pig uterine arteries, suggesting that NPY plays an important role in the regulation of uterine blood flow regardless of the pregnancy status. Decrease or increase in agonist potency may reflect changes of the agonist affinity to its receptor and/or in efficiency of receptor coupling that underlies receptor activation (Kenakin, 1987). In the present study, irreversible antagonism with dibenamine revealed that NPY does not change affinity of cholinergic receptors and adrenoceptors to acetylcholine and noradrenaline respectively. However, receptor reserve, a parameter that reflects efficiency of receptor coupling (Kenakin, 1987), was significantly decreased for acetylcholine and increased for noradrenaline in the presence of NPY, suggesting that NPY interferes with receptor coupling of these two neurotransmitters. It has been previously suggested that NPY may interact with other vasoctive agents by decreasing production of relaxing factors from vascular endothelium (Grundemar and Hogestatt, 1992), increase in vascular smooth muscle Ca2+ (Cressier et al., 1995), reduction of cAMP production and membrane depolarization (Prieto et al., 1997), or by an as yet unidentified mechanism (Roberts et al., 1999). At present, the mechanism underlying interaction of NPY with uterine arteries remains to be determined. Regardless of the mechanism, NPY possesses the ability to regulate interactions between uterine artery and neurotransmitters, as opposed to another vasoactive peptide, vasoactive intestinal polypeptide, co-localized in neurons supplying the uterine artery (Jovanovic et al., 2000).
In conclusion, this study has shown that: (i) NPY induces contraction of guinea pig uterine artery acting on receptors localized in smooth muscle; (ii) pregnancy alters the response of guinea pig uterine artery to NPY in such a way as to promote vasorelaxation, and (iii) NPY modulate the effect of neurotransmitters on guinea pig uterine artery and pregnancy is not associated with the changes at the level of NPY–neurotransmitter interaction. Thus, it seems that NPY is an important regulator of uterine blood flow and that pregnancy is associated with changes in NPY action that may contribute to the uterine arterial vasodilation during pregnancy.
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 
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Submitted on August 12, 1999; accepted on December 22, 1999.
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