Magnesium sulfate effectively reduces blood pressure in an animal model of preeclampsia.

OBJECTIVE: We tested the ability of magnesium sulfate to reduce hypertension and neonatal growth retardation in an animal model of preeclampsia. STUDY DESIGN: On day 17 of pregnancy, osmotic minipumps were inserted subcutaneously to continuously deliver either vehicle (saline control group), or N-nitro-L-arginine methyl ester (L-NAME) (50 mg/kg/day), or L-NAME (50 mg/kg/day) in combination with magnesium sulfate (60 mg/kg/day). Prior to insertion, blood pressure and heart rate were monitored with a pneumatic tail cuff device. Blood pressure measurements were repeated on days 18, 20, and 21 of pregnancy. Blood was obtained on days 17 and 21, along with urine, to assess magnesium levels and degree of proteinuria. Pups were weighed and measured at 48 hours postpartum. RESULTS: Rats receiving L-NAME developed hypertension within 24 hours of implantation (108 +/- 3.9 vs. 123 +/- 3.4 mmHg, p < 0.05). Magnesium sulfate, given along with L-NAME did not prevent mean blood pressure from increasing, but reduced it by day 21 compared to L-NAME given alone (107 +/- 3.4 vs. 122 +/- 8.7 mmHg, respectively, p < 0.05). Magnesium sulfate reduced neonatal growth retardation by improving the weight of the pups compared to pups from maternal rats given L-NAME alone (6.1 +/- 0.1 vs. 5.2 +/- 0.3 grams, respectively, p < 0.05). CONCLUSION: Maternal magnesium sulfate reduces blood pressure and increases neonatal size compared to L-NAME without magnesium. These findings support a beneficial effect of magnesium in preeclampsia.

MgSO4 prevents left ventricular dysfunction in an animal model of preeclampsia.

OBJECTIVE: We hypothesized that cardiac function would be reduced in a pregnant rat model of preeclampsia induced by L-NAME, a NOS inhibitor, and be reversed with magnesium sulfate prophylaxis. STUDY DESIGN: Female Sprague-Dawley rats were bred in-house. On gestational day 17, rats were anesthetized and osmotic minipumps were implanted to continuously deliver saline, L-NAME, or L-NAME and MgSO4. On gestational day 21, hearts were isolated and perfused in the working mode using Krebs Henseleit buffer. RESULTS: Pregnant rats treated with L-NAME displayed significant hypertension compared to the saline-treated controls (P < 0.05). Moreover, cardiac output and cardiac work were significantly reduced in the L-NAME-treated rats compared to controls (P < 0.05). In the L-NAME-treated rats given MgSO4, cardiac function remained normal. CONCLUSION: Cardiac function is depressed in an animal model of preeclampsia induced by L-NAME infusion. MgSO4 prevented the reduction in cardiac function and is clearly beneficial in preserving normal heart function in preeclampsia.

Altered insulin-like growth factor-1 and nitric oxide sensitivities in hypertension contribute to vascular hyperplasia.

Vascular medial thickening, a hallmark of hypertension, is associated with vascular smooth muscle cell (VSMC) hypertrophy and hyperplasia. Although the precise mechanisms responsible are elusive, we have shown that strain induced regulation of autocrine insulin-like growth factor-1 (IGF-1) and nitric oxide (NO) reciprocally modulate VSMC proliferation. Therefore, we investigated potential IGF-1 and NO abnormalities in young (10-week-old) spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) and their respective VSMC ex vivo. The SHR had increased mean arterial pressure (173 +/- 2 v 128 +/- 3 mm Hg, n = 24, P <.05) but similar pulse pressures (31 +/- 2 v 30 +/- 3 mm Hg; P >.05) v WKY. The SHR exhibited increased aortic wall thickness in comparison with WKY (523 +/- 16 v 355 +/- 17 micro m; P <.05). No differences were seen in plasma combined NO(2) and NO(3) (NO(x)) (0.48 +/- 0.11 mmol/L for WKY v 0.58 +/- 0.18 mmol/L for SHR) or plasma IGF-1 (1007 +/- 28 ng/mL for WKY v 953 +/- 26 ng/mL for SHR). Aortic VSMC from SHR displayed enhanced proliferation in comparison with WKY (P <.05). Underlying this enhanced proliferation was altered SHR VSMC sensitivity to the antiproliferative NO donor 2,2"[Hydroxynitrosohydrazono] bis-ethanimine (DETA-NO) (ID(50): 270 +/- 20 mmol/L for SHR; 150 +/- 11 mmol/L for WKY; P <.05). Basal cyclic guanosine monophosphate (cGMP) secretion from SHR VSMC was 65-fold greater than that seen from WKY (P <.001). In response to DETA-NO, cGMP secretion from SHR VSMC increased modestly (1.5-fold; P <.01), whereas treatment of WKY VSMC resulted in a 26-fold (P <.001) increase in cGMP. The SHR VSMC did not respond to exogenous IGF-1, whereas WKY VSMC exhibited a dose dependent increase in proliferation with IGF-1 (10(-10) to 10(-7) mol/L). These data suggest that VSMC hyperplasia in early hypertension is not reflected by imbalances in plasma IGF-1 or NO. Rather, altered SHR VSMC sensitivity to NO is likely responsible in part for the observed hyperproliferation seen in early stages of hypertension.

Estrogen modulation of NMDA-induced seizures in ovariectomized and non-ovariectomized rats.

The objective of this study was to examine the neuroprotective effects of estrogen in response to N-methyl-D-aspartate (NMDA)-induced seizures in both male and female rats. Thirty-eight Long-Evans rats were divided into five groups: ovariectomized females, non-ovariectomized females, ovariectomized females with estrogen replacement (10 microg 17beta-estradiol in 100 microl sesame oil), males given exogenous estrogen and males receiving no estrogen. Using stereotaxic surgery, a cannula was placed in the lateral ventricle for convulsant agent administration (20 microg of NMDA), while an electrode was placed into the hippocampus for seizure recording. Seizure activity was monitored for 20 min. Onset to first seizure, first seizure duration, seizure frequency and total duration of seizures were determined. Rats were pretreated with either sesame oil (vehicle) or estrogen given subcutaneously for 4 days prior to seizure induction on the fourth day. Rats were euthanized 72 h later and the brains removed for histological processing. Electrode and cannula placement were verified microscopically and neuronal integrity was assessed via hematoxylin and eosin staining. Total seizure number was significantly higher in the ovariectomized females compared to the non-ovariectomized females and the ovariectomized females receiving estrogen (P<0.05). Moreover, hippocampal neuronal damage following seizure induction was significant in the ovariectomized rats compared to the non-ovariectomized rats (P<0.05). Pretreatment with estrogen did not affect any of the seizure parameters measured in the male rats. We conclude that estrogen appears to be neuroprotective against NMDA-induced seizures in female ovariectomized rats.

Identification of a functional Na+/Mg2+ exchanger in human trophoblast cells.

BACKGROUND: Ionized magnesium levels are elevated in fetal blood compared with maternal blood, suggesting that the placenta may possess an active transport mechanism for magnesium. In the present study, we sought to determine the existence of an active transport mechanism for magnesium in the placenta using cultured trophoblast cells. METHODS: Using choriocarcinoma cells as a model system, we attempted to demonstrate the presence of a functional Na+/Mg2+ exchanger. Human choriocarcinoma JEG-3 cells cultured on glass coverslips were loaded with MAG-Fura 2-AM (5 micromol/L x 30 min) to spectrofluorometrically assess kinetics of intracellular magnesium ([Mg2+]i). Cells were superfused with various concentrations of Na+, Mg2+, Ca2+ and imipramine, a blocker of erythrocyte Na/Mg exchange. [Mg2+]i calibration was determined via Triton X-100 and EDTA. RESULTS: Sequential lowering of extracellular Na+ caused progressively larger, transient increases in [Mg2+]i. These transient changes in [Mg2+]i were completely dependent on [Mg]o but was independent of extracellular calcium ([Ca]o). Although acute imipramine did not alter basal [Mg2+]i, imipramine eliminated the return-to-basal phase of the [Mg2+]i transient induced by low sodium medium. Increasing extracellular magnesium ([Mg]o) caused stepwise increases in [Mg2+]i. CONCLUSIONS: The JEG-3 cells appear to possess a functional Na/Mg exchanger that functions to maintain low [Mg2+]i in cytotrophoblast cells. In addition, [Mg2+]i is acutely regulated by [Mg]o. Because placental trophoblasts are sites of maternal-fetal ion exchange, and [Mg]o is altered in preeclampsia, derangements in or modulation of this exchanger may contribute to complications of pregnancy such as pregnancy-induced hypertension, pre-eclampsia, and preterm labor.