Pregnancy-associated increase in rat systemic arteries endothelial nitric oxide production diminishes vasoconstrictor but does not enhance vasodilator responses (original) (raw)
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Activated NO pathway in uterine arteries during pregnancy in an IUGR rat model
American Journal of Physiology-Heart and Circulatory Physiology
Insufficient development of the uteroplacental circulation may contribute to the development of intrauterine growth restriction (IUGR). We developed a rat model of IUGR by administering a low-Na+ diet. This diet reduces maternal blood volume expansion and uteroplacental perfusion. We hypothesized that an impaired endothelial function in radial arteries decreases vasorelaxation and lowers placental perfusion in this IUGR model. The objective was to assess radial uterine artery responses to vasoactive agents in the IUGR model versus controls. The vasoactive agents included phenylephrine and carbachol, use of a pressurized artery myograph, in the absence or presence of inhibitors of nitric oxide (NO) synthase [ N-nitro-l-arginine methyl ester (l-NAME)], cyclooxygenase (Ibuprofen), and endothelium-dependent hyperpolarization {apamin/1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole}, allowing better characterization of the mechanism implicated in endothelium-dependent relaxation. The resul...
Fundamental & Clinical Pharmacology, 1997
Pregnancy is associated with drastic hemcxlynamic adaptations. including a decrease in peripheral resistance. Vascular resistance is substantially influenced by endothelium-derived nitric oxide (NO). This study was designed to investigate whether pregnancy might influence endothelium-derived NO-mediated relaxations in human resistance arteries. Reactivity of isolated human subcutaneous arteries, dissected out of abdominal fat from women who underwent a laparotomy or cesarean section. was studied using a small vessel myograph. Addition of acetylcholine (I nM-I0 pM) or bradykinin (I nM-I0 pM) to precontrafted preparations elicited concentration-dependent relaxation responses that were dependent on the presence of the endothelium and were partially inhibited by the NO-synthase inhibitor nitro-L-arginine (0.1 mM). The relaxations to acetylcholine and bradykinin were similar in vessels isolated from pregnant and non-pregnant women. Nitro-L-arginine (0.1 mM) had no influence on basal tone and had a similar inhibitory influence on the endothelium-mediated relaxations in vessels from non-pregnant and pregnant women. These results indicate that the influence of endnthelium-derived NO in human subcutaneous resistance arteries is not altered at the end of pregnancy. pregnancy / human subcutaneous arteries / nitric oxide / acetykholine / bradykinin
The American journal of physiology, 1996
Uterine vasculature is less responsive than systemic vasculature to angiotensin II (ANG II)-induced vasoconstriction. We hypothesized that pregnancy augments basal and ANG II-stimulated endothelial prostacyclin (PGI2) and/or nitric oxide (NO) production, which locally increase vascular smooth muscle (VSM) adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP), respectively. Uterine (UA) and systemic arteries (SA) from pregnant (P) and nonpregnant (NP) sheep were incubated with isobutylmethylxanthine. Basal PGI2, cAMP, and cGMP production was 2.4-, 1.6-, and 5.9-fold greater (P < 0.01) in UA from P vs. NP sheep; endothelium removal lowered (P < 0.05) values 69, 44, and 88%. Basal SA PGI2 and cAMP, but not cGMP, also were elevated by pregnancy. Indomethacin (Indo; 100 microM) decreased PGI2 and cAMP, but not cGMP production; N omega-nitro-L-arginine methyl ester (L-NAME; 10 microM) and methylene blue (MB, 10 microM) only decre...
Enhanced Vascular Reactivity During Inhibition of Nitric Oxide Synthesis in Pregnant Rats
Hypertension, 1998
Pregnancy-induced hypertension has been suggested to be mediated by several mechanisms, including reduced nitric oxide (NO) synthesis. In this study, the effects of chronic treatment with the NO synthase inhibitor N G-nitro-L-arginine methyl ester (L-NAME) on blood pressure and the underlying changes in vascular reactivity were investigated in virgin and late-pregnancy Sprague-Dawley rats. The systolic blood pressure was 120Ϯ2, 124Ϯ5, 116Ϯ4, and 171Ϯ5 mm Hg in untreated virgin, virgin treated with L-NAME, untreated pregnant, and pregnant treated with L-NAME rats, respectively. The rats were killed, and the thoracic aorta was cut into strips for measurement of active stress in response to ␣ 1-adrenergic stimulation with phenylephrine and membrane depolarization by high KCl. In pregnant rats, the maximal active stress to phenylephrine (0.31Ϯ0.03ϫ104 N/m 2) and the high-KCl-induced active stress (0.55Ϯ0.09ϫ10 4 N/m 2) were smaller than those in virgin rats. By contrast, in the L-NAME-treated pregnant rats, the maximal phenylephrine-induced active stress (0.76Ϯ0.1ϫ10 4 N/m 2) was greater than that in virgin rats (0.52Ϯ0.1ϫ10 4 N/m 2), whereas the high-KCl-induced active stress (1.08Ϯ0.14ϫ10 4 N/m 2) was indistinguishable from that in virgin rats (1.03Ϯ0.14ϫ10 4 N/m 2). Treatment with L-NAME did not affect the phenylephrine-releasable Ca 2ϩ stores in pregnant rats and had minimal effect on active stress in virgin rats. Thus, reduction of NO synthesis during late pregnancy is associated with a significant increase in blood pressure and vascular responsiveness to ␣-adrenergic stimulation, which can possibly be explained in part by enhanced Ca 2ϩ entry from extracellular space. However, other mechanisms such as increased myofilament force sensitivity to Ca 2ϩ and/or activation of a completely Ca 2ϩ-independent mechanism cannot be excluded.
PLOS ONE, 2015
Background and Purpose We investigated whether pregnancy was associated with changed function in components of perivascular mesenteric innervation and the mechanism/s involved. Experimental Approach We used superior mesenteric arteries from female Sprague-Dawley rats divided into two groups: control rats (in oestrous phase) and pregnant rats (20 days of pregnancy). Modifications in the vasoconstrictor response to electrical field stimulation (EFS) were analysed in the presence/absence of phentolamine (alpha-adrenoceptor antagonist) or L-NAME (nitric oxide synthase-NOS-non-specific inhibitor). Vasomotor responses to noradrenaline (NA), and to NO donor DEA-NO were studied, NA and NO release measured and neuronal NOS (nNOS) expression/activation analysed. Key Results EFS induced a lower frequency-dependent contraction in pregnant than in control rats. Phentolamine decreased EFS-induced vasoconstriction in segments from both experimental groups, but to a greater extent in control rats. EFS-induced vasoconstriction was increased by L-NAME in arteries from both experimental groups. This increase was greater in segments from pregnant rats. Pregnancy decreased NA release while increasing NO release. nNOS expression was not modified but nNOS activation was increased by pregnancy. Pregnancy decreased NA-induced vasoconstriction response and did not modify DEA-NO-induced vasodilation response.
The vasoconstrictor effects of L-NAME, a nitric oxide synthase inhibitor, in pregnant rabbits
British Journal of Pharmacology, 1996
We have used anaesthetized, acutely instrumented non-pregnant (NP) and late pregnant (P) New Zealand white rabbits to examine the possible role of nitric oxide (NO) in the pregnancy-induced fall of vascular tone and arterial pressure. Systemic, renal and pulmonary vascular resistance, as well as plasma concentrations of cyclic GMP (PcGMP) were compared before and after the inhibition of NO synthesis by N0-nitro-L-arginine methyl ester (L-NAME). 2 P rabbits had lower baseline total peripheral resistance (TPR), mean arterial pressure (MAP) and higher PcGMP than NP controls (all P<0.05 or less). L-NAME (1, 10, 50 mg kg-', i.v.) resulted in dose-dependent elevation of TPR in both groups. However, the absolute, as well as percentage increases in TPR were greater (P<0.05) in NP than in P rabbits.. 3 Cardiac output (CO) was reduced more (P<0.01) by NO inhibition in NP than P rabbits. Therefore, despite the smaller increase in TPR, the elevation of MAP was greater (P<0.001) in P than NP rabbits. After L-NAME, NP rabbits developed more severe bradycardia and a greater increase of pulmonary vascular resistance which might have contributed to the more pronounced reduction of CO. 4 PcGMP increased in both groups following L-NAME, but more (P<0.01) in NP than P rabbits. 5 Infusion of acetylcholine (ACh, 0.02 tmol 1' kg-') reduced MAP and TPR more (both P<0.05) in NP than P rabbits and L-NAME reduced the ACh-induced depressor response only in NP rabbits. 6 These results suggest that the low vascular tone and arterial pressure in pregnant rabbits is not mediated by NO.
Sao Paulo Medical Journal, 1999
The exact mechanism involved in changes in blood pressure and peripheral vascular resistance during pregnancy is unknown. Objective: To evaluate the importance of endotheliumderivated relaxing factor (EDRF) and its main component, nitric oxide, in blood pressure and vascular reactivity in pregnant rats. Design: Clinical trial in experimentation animals. Setting: University laboratory of Pharmacology. Sample: Female Wistar rats with normal blood pressure, weight (152 to 227 grams) and age (90 to 116 days). Intervention: The rats were divided in to four groups: pregnant rats treated with L-NAME (13 rats); pregnant control rats (8 rats); virgin rats treated with L-NAME (10 rats); virgin control rats (12 rats). The vascular preparations and caudal blood pressure were obtained at the end of pregnancy, or after the administration of L-NAME in virgin rats. Main Measurements: The caudal blood pressure and the vascular response to acetylcholine in pre-contracted aortic rings, both with and without endothelium, and the effect of nitric oxide inhibition, N w -L-nitro-arginine methyl-ester (L-NAME), in pregnant and virgin rats. The L-NAME was administered in the drinking water over a 10-day period. Results: The blood pressure decreased in pregnancy. Aortic rings of pregnant rats were more sensitive to acetylcholine than those of virgin rats. After L-NAME treatment, the blood pressure increased and relaxation was blocked in both groups. The fetal-placental unit weight of the L-NAME group was lower than that of the control group. Conclusion: Acetylcholine-induced vasorelaxation sensitivity was greater in pregnant rats and that blood pressure increased after L-NAME administration while the acetylcholine-induced vasorelaxation response was blocked.
American Journal of Physiology-heart and Circulatory Physiology, 2001
Normal pregnancy and the follicular phase of the ovarian cycle are both estrogen-dominated physiological states that are characterized by elevations in uterine blood flow and endothelial nitric oxide synthase (eNOS) protein expression in the uterine artery (UA) endothelium. It is unknown if elevations in mRNA level account for the changes in protein or eNOS activity. We tested the hypothesis that pregnancy and the follicular phase are associated with increases in eNOS mRNA and the consequent elevated expression of eNOS protein results in increased circulating nitric oxide (NO) levels. UA were obtained from pregnant (PREG; n ϭ 8; 110-130 days gestation; term ϭ 145 Ϯ 3 days), nonpregnant luteal (LUT; n ϭ 6), nonpregnant follicular (FOL; n ϭ 6), and nonpregnant ovariectomized (OVEX; n ϭ 6) sheep. Circulating NO levels were analyzed as total NO 2-NO 3 (NO x). Western analysis performed on UA endothelial-isolated proteins demonstrated that eNOS protein levels were OVEX ϭ LUT Յ FOL Ͻ PREG (P Ͻ 0.05), whereas eNOS mRNA expression (RT-PCR) in UA endothelial cells obtained by limited collagenase digestion was OVEX Ͻ LUT Ͻ FOL Ͻ PREG (P Ͻ 0.05). Pregnancy dramatically elevated eNOS protein (4.1-to 6.9-fold) and mRNA (2.4-to 6.9-fold) over LUT controls (P Ͻ 0.01). Circulating NO x levels were not altered by ovariectomy or the ovarian cycle but were elevated from 4.4 Ϯ 1.1 M in LUT to 12 Ϯ 4, 22 Ϯ 3, and 41 Ϯ 3 M at 110, 120, and 130 days gestation (P Ͻ 0.01). Systemic NO x levels in singleton (12.5 Ϯ 1.6 M) were less (P Ͻ 0.01) than in multiple (twin 27.6 Ϯ 6.5 M; triplet ϭ 46 Ϯ 10 M) pregnancies. Therefore, the follicular phase and, to a much greater extent, pregnancy are associated with elevations in UA endothelium-derived eNOS expression, although significant increases in systemic NO x levels were only observed in the PREG group (multiple Ͼ singleton). Thus, although UA endothelial increases in eNOS protein and mRNA levels are associated with high estrogen states, increases in local UA NO production may require additional eNOS protein activation to play its important role in the maintenance of uterine blood flow in pregnancy.
Nitric oxide activity in the peripheral vasculature during normotensive and preeclamptic pregnancy
The American journal of physiology, 1999
We investigated the role of nitric oxide (NO) in the vascular resistance changes of normotensive and preeclamptic pregnancy. Forearm blood flow (FBF) responses to brachial artery infusion of N(G)-monomethyl-L-arginine (L-NMMA), an NO synthase inhibitor, and angiotensin II (ANG II), an NO-independent vasoconstrictor, were determined by plethysmography in 20 nonpregnant women, 20 normotensive primigravidae, and 15 primigravidae with untreated preeclampsia. In pregnant subjects, FBF was reduced to nonpregnancy levels by infusion of norepinephrine (NE), which was then coinfused with ANG II (2, 4, and 8 ng/min) and L-NMMA (200, 400, and 800 microgram/min) each for 5 min. In separate studies, responses to NE (20, 50, and 100 ng/min) were determined in 8 nonpregnant women, with FBF elevated to pregnancy levels by concomitant infusion of glyceryl trinitrate, and 10 pregnant women. Vasoconstrictor responses to L-NMMA were increased in pregnant compared with nonpregnant subjects [mean +/- SE ...
European Journal of Obstetrics & Gynecology and Reproductive Biology, 2001
Objectives: The purpose of the present study was to test the hypothesis that pregnancy is associated with an attenuation of the vasoconstrictor response not only in the uterine, but also in the systemic circulation. Decreased vascular reactivity should be characterized by an early onset to account for the rapid fall in peripheral resistance which was observed during the ®rst third of gestation. Study design: Dose-response curves for phenylephrine hydrochloride (PE), angiotensin II (ANG II), and endothelin 1 (ET 1) were recorded from isolated pressurized uterine and mesenteric arterioles. Vessels were obtained from virgin, early (day 7±9) pregnant (EP) and late (day 19±21) pregnant (LP) rats. Results: (1) In uterine resistance arteries, the response to PE and ANG II decreased early, but for ANG II the reduction did not persist. ET 1 sensitivity was unchanged in early, and diminished in late gestation; (2) in mesenteric vessels, sensitivity to ET 1 was enhanced in early pregnancy and did not differ from the non-pregnant level in late gestation. Sensitivity to PE and ANG II was unchanged in early, and reduced in late pregnancy. Conclusions: The vasoconstrictor response is not uniformly blunted during pregnancy. Changes in vascular reactivity are differentially regulated with respect to the agonist, to their time course, and. to the origin of the vessel. The relative increase of vasoconstrictor sensitivity in the splanchnic circulation during early pregnancy may prevent hypotensive dysregulation, while concentrations of endogenous vasodilators rise and the vascular ®lling state normalizes only gradually.