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      Effect of Methyldopa on Renal Function in Rats with L-NAME-Induced Hypertension in Pregnancy

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          Background: Pregnancy-induced hypertension is characterized by an increased sympathetic activity and probably by a decreased synthesis/activity of nitric oxide. The aim of the present study is to evaluate whether the beneficial action of the sympathetic antagonist methyldopa (a first-choice hypotensive agent in the treatment of PIH) may be associated to changes in nitric-oxide synthesis. Methods: Forty pregnant Wistar rats received L-NAME (NO synthase inhibitor, 9–10 mg/kg/day) from mid-pregnancy (day 11) through to term. Some rats were treated with daltroban (TxA receptor antagonist, 60 mg/kg/day), diltiazem (calcium channel blocker, 30 mg/kg/day), methyldopa (central adrenergic antagonist, 400 mg/kg/day) or L-arginine (260 mg/kg/day) from mid-pregnancy. The effect of the different treatments on systolic blood pressure (SBP), creatinine clearance (CCR), urine protein excretion (UP) and urinary nitrate excretion (UNO<sub>3</sub>, representing urine NO metabolite) were evaluated and the results compared with those found in normal pregnancy. Normal pregnant rats receiving similar treatment were used as controls. Results: In normal pregnant (P) rats, SBP values decreased from 94 ± 2 to 83 ± 3 mm Hg at the end of pregnancy (p < 0.01) and CCR augmented significantly. Drug treatment had no significant effect. In NAME-treated rats, at the same period, the SBP augmented from 92 ± 1 to 129 ± 1.8 mm Hg (p < 0.01). At the end of pregnancy, NAME rats had significantly lower CCR values and higher UP excretion when compared with P rats. UNO<sub>3</sub> increased significantly in P and in P rats treated with methyldopa. As expected, in NAME rats UNO<sub>3</sub> excretion was significantly reduced. Treatment with methyldopa normalized SBP, improved CCR and proteinuria and was associated with an increase in UNO<sub>3</sub>. Similar results were obtained with L-arginine treatment. Diltiazem lowered SBP significantly but had no effect on renal function or UNO<sub>3</sub> and daltroban had no effect. Conclusion: The increased UNO<sub>3</sub> found in NAME rats treated with methyldopa suggests that the vasoconstriction secondary to chronic NO inhibition may be partially related to an increased sympathetic activity. The efficient action of the sympathetic antagonist methyldopa may be due not only to its antihypertensive effects but also by its stimulating effect on NO synthesis leading also to an improvement of renal function.

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          Preeclampsia -- a state of sympathetic overactivity.

          Preeclampsia is characterized by a marked increase in peripheral vascular resistance leading to an increase in blood pressure, but the triggering mechanisms are unclear. To determine whether augmented sympathetic vasoconstrictor activity may be an important mechanism in mediating the increase in vasomotor tone, we measured postganglionic sympathetic-nerve activity in the blood vessels of skeletal muscle by means of intraneural microelectrodes in nine women with preeclampsia, eight normotensive pregnant women, six normotensive nonpregnant women, and seven nonpregnant women with hypertension, both at rest and during noninvasive cardiovascular-reflex testing (with the Valsalva maneuver and the cold pressor test). The mean (+/-SE) rate of sympathetic-nerve activity in the normotensive pregnant women (10+/-1 bursts per minute) was not significantly different from that in normotensive nonpregnant women (12+/-2 bursts per minute) or hypertensive nonpregnant women (15+/-3 bursts per minute). In contrast, the rate of sympathetic-nerve activity in the patients with preeclampsia (33+/-3 bursts per minute) was more than three times as high as that in the normotensive pregnant women (P<0.05) and more than twice as high as in the group of nonpregnant women with hypertension (P<0.05). Hemodynamic and sympathetic-nerve responses to both reflex tests did not differ significantly among the four groups. Six patients with preeclampsia were studied again after delivery; mean sympathetic-nerve activity at that time had decreased significantly from the value during pregnancy (from 36+/-4 to 13+/-2 bursts per minute, P<0.01), as had mean arterial pressure (from 118+/-3 to 96+/-1 mm Hg, P<0.01). Preeclampsia is a state of sympathetic overactivity, which reverts to normal after delivery. Our data indicate that the increases in peripheral vascular resistance and blood pressure that characterize this disorder are mediated, at least in part, by a substantial increase in sympathetic vasoconstrictor activity.
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            A spectrophotometric assay for nitrate using NADPH oxidation by Aspergillus nitrate reductase.

            An assay based on the oxidation of NADPH during the enzymatic conversion of nitrate to nitrate by Aspergillus nitrate reductase [EC] was developed for specific quantification of nitrate. This spectrophotometric method was used to measure nitrate present in human urine, human serum, and tissue culture medium. Used as a kinetic assay, the method exhibited (1) linearity over a range of 1.25 to 40 microM nitrate, (2) an upper sensitivity of 20 microM, (3) a lower sensitivity of 1.25 microM nitrate, and (4) intraday and interday variability ranging from 0.6 to 6.1%. To judge the acceptability of this method as a kinetic assay, we determined the Km for Aspergillus nitrate reductase to be 199 microM. The Km was based on analyzing three separate lots of commercially purified enzyme. Mean nitrate content of eight urine specimens analyzed by this assay (1111 microM) was not significantly different from that determined by a chemiluminescence method (1144 microM). Analysis of serum using the two methods showed mean nitrate concentrations of 23 and 36 microM, respectively. Based on serial dilutions of serum, the lower nitrate content of serum observed with nitrate reductase assay could not be explained by the presence of inhibitors. Rat pulmonary alveolar macrophages were induced to produce nitric oxide which oxidizes to nitrite and nitrate. Nitrite and nitrate present in tissue culture medium of unactivated and activated macrophages were in proportion to total nitrogen oxides (NO(x)) determined by the chemiluminescence method. We conclude that the Aspergillus nitrate reductase assay is an accurate spectrophotometric method for determining nitrate content of human urine and tissue culture supernatants.
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              Cold-induced stress stimulates the sympathetic nervous system, causing hypertension and proteinuria in rats.

               L She,  N Kanayama,  K Maehara (1997)
              To determine whether cold-stress stimulation of the soles of the paws would produce a preeclampsia-like syndrome in rats. Pregnant or nonpregnant rats were kept in 0 degree C floor and 23 degrees C room temperature cages (the cold-stressed group) or in 23 degrees C floor and 23 degrees C room temperature cages (the control group) for 2 weeks. Their blood pressure, proteinuria, and plasma catecholamines were measured, and histologic studies were performed on all groups. There were no significant differences in systolic blood pressure between the two groups during the first week of the experimental period; however, during the last week of gestation the blood pressure of the cold-stressed group did not fall and was significantly higher than that of the control group. A significant increase in urinary protein excretion was observed in the cold-stimulated pregnant rats, in contrast to the control rats. The concentrations of norepinephrine and epinephrine in the cold-stressed pregnant rats were markedly higher than those in the control rats. A decrease in trophoblast invasion, congestion, and fibrinoid deposits of the labyrinth were observed in the cold-stressed rats. A marked increase in subendothelial fibrinoid deposits in the glomerular capillary was found only in the cold-stressed pregnant rats. The blood pressure, biochemical parameters, and histologic findings in the nonpregnant rats were almost the same as those in the pregnant rats. Chronic local cold stimulation of the soles of the paws induces preeclampsia-like phenomena in pregnant and nonpregnant rats, and this model suggests that the cause of preeclampsia is involved in chronic stimulation of the sympathetic nerve.

                Author and article information

                S. Karger AG
                25 July 2001
                : 88
                : 4
                : 354-359
                Department of Nephrology, Meir Hospital, Sapir Medical Center, Kfar-Saba, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
                46020 Nephron 2001;88:354–359
                © 2001 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 3, References: 33, Pages: 6
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                Original Paper

                Cardiovascular Medicine, Nephrology

                Nitric oxide, Pregnancy, Hypertension, Glomerular filtration rate


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