nitroarginine and Pre-Eclampsia

Agonist-induced tone oscillations (rhythmic contractions and relaxations) occur in vascular beds to allow acute regulation of volume flow and thus the delivery of oxygen and nutrients to the tissue. Mechanisms responsible for the control of human placental vasomotor tone and blood flow are poorly characterized. This study aimed to characterise thromboxane-induced tone oscillations in human placental and myometrial arteries. Chorionic plate and myometrial arteries obtained from biopsies at term were mounted for isometric tension measurement. Tone oscillations were observed in chorionic arteries only when exposed to sub-maximal (<1 microM) concentrations of U46619. Slow (mean+/-SEM) frequency (2.6+/-0.5 per hour), large amplitude (39+/-7% of peak contraction) tone oscillations were elicited by 0.03 microM U46619 (n=18). In the presence of the nitric oxide synthase (NOS) inhibitor l-NNA (100 microM) the amplitude was significantly reduced (40+/-13% to 18+/-8%, P<0.05, n=6), frequency was unaltered and the bradykinin-dependent vasodilator response was reduced (68+/-13% to 40+/-19%, P<0.05, n=6). Myometrial arteries exposed to 1 microM U46619 developed tone oscillations within 10 min, which increased in amplitude over 30min occurring at relatively constant frequency. The mean amplitude of oscillations at 30 min (31+/-7%, n=16) was similar to that in chorionic arteries but the occurrence more frequent (42.8+/-9.7 per hour, P<0.001). Inhibition of NOS did not alter tone oscillations in myometrial arteries. Tone oscillations in chorionic arteries from pre-eclamptic and growth restricted (FGR) pregnancies were reduced in amplitude whereas those in myometrial arteries had increased frequency. Inhibition of NOS further reduced oscillation amplitude in chorionic arteries from FGR pregnancies. The alterations may contribute to the vasculopathology of these conditions, or, may represent compensatory mechanisms to maintain a matching of materno-placental blood flow.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adolescent; Adult; Arteries; Birth Weight; Blood Pressure; Bradykinin; Chorion; Female; Fetal Growth Retardation; Humans; Muscle Tonus; Muscle, Smooth, Vascular; Myography; Myometrium; Nitric Oxide; Nitroarginine; Placenta; Pre-Eclampsia; Pregnancy; Regional Blood Flow; Vasoconstriction; Vasodilation

We investigated how hypertension during pregnancy affected passive structural (wall:lumen, wall stress) and active (myogenic activity) responses of the cerebral circulation. Female nonpregnant (NP; n=8) Sprague Dawley rats were compared with late-pregnant (LP; day 19 to 20, n=6) rats. Some animals were treated with the NO synthase inhibitor nitro-L-arginine in their drinking water to raise blood pressure. LP rats (n=6) were treated for the last 7 days of pregnancy (last trimester) to mimic preeclampsia and compared with NP rats treated for the same duration (n=8). Active and passive responses were determined on isolated and pressurized third-order posterior cerebral arteries. Nitro-L-arginine treatment significantly raised blood pressure in both groups of animals that was associated with increased wall thickness and wall:lumen ratio in the NP hypertensive animals versus controls (P<0.05). In contrast, this response to pressure was absent in LP animals, which had similar wall measurements. In addition, arteries from NP hypertensive animals had increased myogenic tone and pressure of forced dilatation compared with NP control animals (P<0.01). Again, this response was lacking in the LP hypertensive animals that had similar tone and pressure of forced dilatation as normotensive controls. The increased tone and wall thickness decreased wall stress in the NP hypertensive animals, a response that did not occur in LP hypertensive animals. Because medial hypertrophy is considered a protective response to elevated blood pressure, these results suggest that hypertension in pregnancy may predispose the cerebral circulation to autoregulatory breakthrough and blood-brain-barrier disruption when blood pressure is elevated, as during eclampsia.

Topics: Animals; Blood Pressure; Blood-Brain Barrier; Cerebral Arteries; Eclampsia; Enzyme Inhibitors; Female; Gestational Age; Homeostasis; Hypertension; Microscopy, Video; Nitric Oxide Synthase; Nitroarginine; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Rats; Rats, Sprague-Dawley

We sought to compare flow-mediated dilatation and myogenic and norepinephrine-induced tone in myometrial resistance arteries from women with preeclampsia and healthy pregnant women and to evaluate the role that nitric oxide may play in these responses.. Arteries (approximately 200 microm, at 50 mm Hg) were dissected from myometrial biopsy specimens from women undergoing emergency cesarean delivery because of preeclampsia (n = 6) and from healthy control subjects undergoing planned cesarean delivery (n = 9). Responses to intraluminal flow, pressure, and a constrictor agonist (norepinephrine, 10(-6) mol/L) were studied in the absence and presence of the nitric oxide synthase inhibitor N omeganitro-L -arginine (10(-4) mol/L). Myogenic and norepinephrine-induced tone were calculated after the determination of artery diameter in the absence of extracellular calcium and in the presence of papaverine (10(-4) mol/L).. An increase in intraluminal flow led to dilatation of isolated myometrial arteries from healthy gravid women, whereas flow-mediated dilatation was absent in arteries from gravid patients with preeclampsia (increase in diameter at maximum flow rate of 204 microL/min, 28% +/- 5% in healthy gravid patients vs -15% +/- 6% in gravid women with preeclampsia; analysis of variance, P <.05). Addition of N omega-nitro-L -arginine had no significant effect on flow-mediated responses in arteries from women with preeclampsia, whereas flow-mediated dilatation was abolished after addition of N omega-nitro-L -arginine in arteries from healthy gravid women (increase in diameter at a maximum flow rate of 204 microL/min, 28% +/- 5% control vs -9% +/- 5% N omega-nitro-L -arginine; analysis of variance, P <.05). Arteries from women with preeclampsia developed pressure-induced myogenic and norepinephrine-induced tone, similar to that obtained in arteries from healthy gravid women. In arteries from gravid women with preeclampsia, inhibition of nitric oxide synthase enhanced myogenic-induced tone (25% +/- 4% control vs 35% +/- 5% N omega-nitro-L -arginine; P <.05) and norepinephrine-induced tone (36% +/- 4% control vs 46% +/- 6% N omega-nitro-L -arginine; P <.05), as in arteries from healthy gravid women.. Nitric oxide may participate in modulation of pressure- and norepinephrine-induced tone even in preeclampsia, but the shear stress-mediated release of nitric oxide is absent. Failure of shear stress-mediated dilation in myometrial arteries from gravid women with preeclampsia might contribute to the impaired uteroplacental blood flow in this disease.

Topics: Adult; Arteries; Blood Flow Velocity; Cesarean Section; Enzyme Inhibitors; Female; Humans; In Vitro Techniques; Muscle, Smooth, Vascular; Myometrium; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Norepinephrine; Pre-Eclampsia; Pregnancy; Pressure; Rheology; Uterus; Vasodilation

We investigated the characteristic changes in histamine-induced, endothelium-derived nitric oxide (NO)-mediated relaxation in human omental resistance arteries seen in pre-eclampsia. Isometric contraction was provoked by a stable analogue of thromboxane A(2) in endothelium-intact strips from both pre-eclamptic and normotensive pregnant women. Histamine (0.3 nM-10 microM) produced a concentration-dependent relaxation of this contraction in both groups. The magnitude of the relaxation induced by histamine (1 microM) was significantly smaller in pre-eclampsia both in the presence and absence of famotidine (H(2)-receptor blocker). In the presence of famotidine, L-N(G)-nitroarginine significantly attenuated the histamine-induced relaxation in strips from normotensive pregnant women but not in those from pre-eclamptic women. The relaxation induced by human atrial natriuretic peptide (0. 1 nM-1 microM) was also significantly smaller in the pre-eclamptic group. It is concluded that the histamine-induced, endothelium-derived NO-mediated relaxation (mediated via H(1)-receptors) is down-regulated in resistance arteries in pre-eclampsia and we suggest that this is due, at least in part, to an attenuation of the action of cyclic GMP in smooth muscle cells.

Topics: Adult; Arteries; Atrial Natriuretic Factor; Cyclic GMP; Down-Regulation; Endothelium, Vascular; Famotidine; Female; Histamine; Humans; Isometric Contraction; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitroarginine; Pre-Eclampsia; Pregnancy; Pyrilamine; Receptors, Histamine H1; Receptors, Histamine H2; Vascular Resistance; Vasodilation

1. The purpose of the present study was to examine the effect of nitric oxide (NO) inhibition on mean arterial pressure (MAP), endothelin (ET) and the renin-aldosterone system in pregnancy in the non-human primate (baboon). 2. Twenty pregnant baboons (Papio hamadryas) were examined prospectively after the administration of an oral NO inhibitor in different phases of pregnancy. Haemodynamic responses to NO inhibition, evidence of pre-eclampsia and the renin-aldosterone system were examined under anaesthesia. 3. Oral NL-nitro-L-arginine (NOLA; 5 or 10 mg/kg) was given for 1 week in early (6-8 weeks gestation), middle (14-16 weeks gestation) and late (22-24 weeks gestation) pregnancy and while non-pregnant. Mean arterial pressure, heart rate, haematology, biochemistry, ET, plasma renin activity (PRA) and aldosterone were measured. Foetal effects of NOLA were also examined by ultrasound and neonatal measurements. 4. Nitric oxide inhibition led to an increase in MAP in non-pregnant animals (9 mmHg) and in middle and later pregnancy (6 and 7 mmHg, respectively). Mean arterial pressure in early pregnancy was not affected. A reduction in PRA occurred after NO inhibition in all stages of pregnancy. Significant proteinuria occurred only in late pregnancy. 5. Nitric oxide is involved in the maintenance of lower blood pressure in late pregnancy and inhibition leads to an increase in blood pressure and proteinuria in the baboon. Nitric oxide insufficiency may contribute to the clinical manifestations of human pre-eclampsia. Nitric oxide was not involved in the normal vasodilation of early primate pregnancy.

Topics: Aldosterone; Animals; Body Weight; Endothelins; Enzyme Inhibitors; Female; Hemodynamics; Male; Nitric Oxide; Nitroarginine; Papio; Pre-Eclampsia; Pregnancy; Renin

The vascular pathophysiology of preeclampsia, a hypertensive disorder unique to human pregnancy, has been postulated to be due to endothelial dysfunction, primarily manifest as deficient nitric oxide (NO) synthesis. We evaluated contraction (KCl and arginine vasopressin [AVP]) and dilation (acetylcholine and bradykinin) in small resistance-size omental arteries obtained during surgery from women with preeclampsia, postulating that these vessels would exhibit augmented contraction and diminished endothelium-dependent relaxation, most likely due to decreased NO synthesis. For comparison, vessels were also obtained from normotensive gravidas, pregnant women with chronic hypertension, or with chronic hypertension and superimposed preeclampsia, as well as from premenopausal nonpregnant controls. Vessels of approximately 200 micron in internal diameter were studied in vitro using a Mulvany-Halpern myograph. Maximal contraction due to either KCl or AVP was significantly augmented in vessels from women with preeclampsia; these vessels all exhibited endothelium- and cyclooxygenase-dependent phasic oscillations while vessels from all other groups exhibited only tonic contractions. Acetylcholine and bradykinin both led to dose- and endothelium-dependent relaxation which was unaffected by inhibitors of NO synthesis. Responses to bradykinin were similar in vessels from normal pregnant and preeclamptic women while those to acetylcholine were absent in vessels from women with preeclampsia. These data suggest specific defects in resistance-artery endothelium from women with preeclampsia.

Topics: Acetylcholine; Adult; Arginine Vasopressin; Arteries; Bradykinin; Endothelium, Vascular; Female; Humans; Nitric Oxide; Nitroarginine; Omentum; Pre-Eclampsia; Pregnancy; Vasodilation

During gestation endothelium induces decreases in vascular responses to vasopressor agents but endothelium disease is followed by hypertension and enhanced vascular reactivity during preeclampsia. In a rat model of preeclampsia induced by NO synthase inhibition we study here isolated aortic contractions. From day 13 of gestation 2 groups of Wistar female rats were fed control (C) or nitro-arginine enriched diets (0.063%, i.e. 30 mg/kg/d) (treated) (T). On gestational day 20 systolic blood pressure (SBP, mmHg) is measured by tail cuff method and isolated thoracic ring aorta contractions are studied after depolarisation (KCl 60 mM) or norepinephrine (cumulative concentrations 10-9 M-10-5 M). After chronic NOS inhibition, hypertension develops: SBP is 154 +/- 2.17 in T and 116 +/- 3.75 in C, p < 0.01 and significant proteinuria (mg/d) appears: T, 63.4 +/- 21.6 versus C 3.08 +/- 0.48, p < 0.01. NO synthase inhibition in treated rats impairs the depressed contractile response obtained in the presence of endothelium in control rats but addition of L-arginine suppresses the effect of nitroarginine. Taking in account our results and those described in literature it appears that L-arginine treatment could ameliorate some pathologic pregnancies.

Topics: Animals; Aorta, Thoracic; Constriction, Pathologic; Disease Models, Animal; Drug Evaluation, Preclinical; Endothelium, Vascular; Female; In Vitro Techniques; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Norepinephrine; Pre-Eclampsia; Pregnancy; Rats; Rats, Wistar; Vasoconstrictor Agents

Isolated human placental cotyledons from normal (NG) and preeclamptic gestants (PG) were perfused in vitro, and the effect of N omega-nitro-L-arginine (L-NA, 100 microM), methylene blue (MB, 50 microM), and indomethacin (INDO, 10 microM), on resting perfusion pressure and on the 5-hydroxytryptamine (5-HT)-induced vasoconstriction was established. In the HG, L-NA and MB increased resting perfusion pressure (p < 0.001) and INDO had no significant effect on resting pressure. In the PG, these agents did not significantly modify resting perfusion pressure. In the PG, 5-HT (10 microM-1 microM) caused greater maximal increases in perfusion pressure than in NG. In the NG, L-NA greatly enhanced the 5-HT-induced pressure, however INDO attenuated this effect. In the PG, L-NA did not modify significantly the 5-HT-induced response, but INDO reduced this response. These results suggest that basal release of nitric-oxide but not of vasodilator prostanoids may contribute to the low resting vascular tone in the NG and attenuates the strong vasoconstrictor effect induced by 5-HT. Impairment of action of nitric oxide could contribute to the enhanced pressor response to 5-HT observed in the PG.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antidotes; Arginine; Dose-Response Relationship, Drug; Female; Humans; In Vitro Techniques; Indomethacin; Methylene Blue; Neurotransmitter Agents; Nitric Oxide; Nitroarginine; Placenta; Pre-Eclampsia; Pregnancy; Prostaglandins; Serotonin; Vasoconstriction; Vasoconstrictor Agents

1. It has been suggested that a deficiency of nitric oxide (NO) may explain many of the pathophysiological features of pre-eclampsia (PE) and intra-uterine (foetal) growth retardation (IUGR). To elucidate further the role of NO in the pathophysiology of pregnancy we have determined the relative amount and activity of NO synthase (NOS) in first trimester and normal-term placental tissues, as well as in the placenta and umbilical cord in pregnancies complicated by PE and IUGR, using NG-nitro-L-[2,3,4,5(-3)H]-arginine ([3H]-L-NOARG) binding, quantitative in vitro autoradiography, [3H]-arginine to [3H]-citrulline conversion and Western blotting. 2. Specific, high affinity (KD = 38 nM) [3H]-L-NOARG binding was demonstrated in the villous trophoblast of normal-term placentae. Binding was calcium-independent, stereoselective and exhibited a rank order of inhibition by NOS inhibitors and substrate (L-NOARG > or = L-NMMA > or = 7-NI > L-NAME > L-Arg > or = L-NIO > ADMA). 3. [3H]-L-NOARG binding density and NOS activity were both significantly greater in placental tissues from first trimester and PE or IUGR complicated pregnancies compared to normal-term placentae. 4. Western blotting, using an endothelial NOS peptide antiserum, demonstrated a approximately 140 KDa protein band in placental extracts and indicated that the amount of immunoreactive material was significantly greater in first trimester compared to normal-term placentae. 5. Specific [3H]-L-NOARG binding was also localized to the endothelial lining of umbilical arteries and veins, binding density being greater in the artery than the vein. [3H]-L-NOARG binding to the umbilical artery endothelium was significantly lower in PE and IUGR complicated pregnancies compared to normal-term controls. 6. The role of trophoblast-derived NO in human placental pathophysiology remains to be established, but differences in the amount of placental [3H]-L-NOARG binding, NOS activity and immunoreactive material indicate that expression of NOS in the villous trophoblast falls during pregnancy. Conversely, the apparent reduction in NOS in the umbilical artery endothelium in PE and IUGR complicated pregnancies may be indicative of endothelial dysfunction.

Topics: Adult; Animals; Arginine; Binding, Competitive; Blotting, Western; Endothelium, Vascular; Female; Fetal Growth Retardation; Humans; Nitric Oxide Synthase; Nitroarginine; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, First; Rats; Umbilical Arteries

This study examined the activity of sodium nitroprusside (SNP) in the human fetal-placental circulation in vitro in pathological and experimental conditions in which vascular function may be impaired. SNP (13-3400 nM) caused a concentration-dependent reduction in fetal arterial perfusion pressure (FAP) in Krebs' perfused placental cotyledons, at basal tone and following pre-constriction with prostaglandin F2 alpha (PGF2 alpha). SNP-induced reduction in FAP in the PGF2 alpha pre-constricted fetal-placental circulation was enhanced approximately six-fold (5.85) in those placentae pre-treated with the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine (100 microM). Reductions in FAP in the preconstricted fetal-placental vasculature caused by SNP were not altered by prior infusion of ouabain (100 nM) into the fetal circulation or during low oxygen perfusion (O2 tension < 50 mmHg). No differences were observed in the responses obtained to SNP in placentae obtained from women with normotensive pregnancies or those associated with (i) pregnancy-induced hypertension, (ii) intra-uterine growth retardation, or (iii) an elevated umbilical-artery Doppler-ultrasound systolic/diastolic ratio, in either preconstricted placentae or those at basal tone. These findings are consistent with an up-regulation of guanylate cyclase/cGMP-mediated vasodilatation in the fetal-placental vasculature following complete blockade of endogenous NO production.

Topics: Adolescent; Adult; Arginine; Blood Pressure; Dinoprost; Enzyme Inhibitors; Female; Fetal Growth Retardation; Fetus; Humans; Hypertension; In Vitro Techniques; Nitric Oxide Synthase; Nitroarginine; Nitroprusside; Ouabain; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Vasoconstriction; Vasodilation