Magnesium is a divalent cation with relaxant proper-
ties. Various mechanisms have been proposed to explain
the effects of magnesium on vascular tone.
The main ac-
tion of magnesium on smooth muscle is thought to occur
through the inhibition of calcium influx into the smooth
muscle cell and blockade of calcium release from the sar-
The entrance of calcium into en-
dothelial cells is an obligatory step for production of the
endothelium-dependent vasorelaxants nitric oxide,
and endothelium-derived hyperpolarizing
Nitric oxide is a free radical produced during the
-citrulline by nitric oxide syn-
The endothelial isoform of NOS is cal-
cium-calmodulin dependent and thus requires calcium
for its activation and production of nitric oxide.
Magnesium can modulate vascular tone at the level of
smooth muscle and at the level of endothelial cells by an-
tagonizing calcium entry.
Magnesium inhibits calcium
entry in the vascular smooth muscle and thus causes va-
sorelaxation. On the other hand, when an agonist is pres-
ent to activate calcium entry into the endothelial cells, in-
hibition of calcium entry by magnesium would decrease
production of relaxing factors such as nitric oxide,
prostacyclin, and endothelium-derived hyperpolarizing
factor and thereby promote contraction.
Nitric oxide acts on the vascular smooth muscle through
numerous pathways, including activation of guanylate cy-
clase and increase in cyclic guanosine monophosphate
Nitric oxide, through its direct ef-
fects, as well as those mediated by cGMP, decreases cal-
cium entry and increases calcium reuptake in the vascu-
lar smooth muscle cells, thereby causing relaxation.
relaxant effect of magnesium is also mediated by inhibi-
tion of calcium entry.
Thus nitric oxide and magnesium
may act synergistically at the level of calcium regulatory
mechanisms in the vascular smooth muscle. Vascular re-
activity changes with advancing gestation.
From the Department of Obstetrics and Gynecology, The University of
Texas Medical Branch,
and the Department of Obstetrics and Gynecol-
ogy, University of Modena and R. Emilia.
Received for publication July 13, 2000; revised October 10, 2000;
accepted October 30, 2000.
Reprint requests: Robert E. Garfield, PhD, Division of Reproductive Sci-
ences, Department of Obstetrics and Gynecology, The University of Texas
Medical Branch, 301 University Blvd, Rte J-62, Galveston, TX 77555-
Copyright © 2001 by Mosby, Inc.
0002-9378/2001 $35.00 + 0 6/1/112587
Endothelium dependence and gestational regulation of inhibition
of vascular tone by magnesium sulfate in rat aorta
Monica Longo, MD,
Venu Jain, MD, PhD,
Yuri P. Vedernikov, MD, PhD,
Fabio Facchinetti, MD,
George R. Saade, MD,
and Robert E. Garfield, PhD
Galveston, Texas, and Modena, Italy
OBJECTIVE: The aim of this study was to investigate the role of nitric oxide in the vasorelaxant effect of
magnesium sulfate during pregnancy.
STUDY DESIGN: Segments of 3 mm of the aorta, with or without intact endothelium, from 16- or 22-day-
pregnant rats were mounted in organ chambers with standard Krebs solution or low-magnesium Krebs solu-
tion for measurement of isometric tension. The rings were contracted with phenylephrine, and cumulative
concentration-response curves for magnesium were determined after incubation with various inhibitors.
RESULTS: Magnesium relaxed the aortic rings from pregnant rats in a concentration-dependent manner.
The relaxation was significantly lower on day 22 of gestation than on day 16 of gestation. Removal of the en-
dothelium or incubation with 10
-arginine methyl ester (a nitric oxide synthase inhibitor),
-mol/L 6-anilino-5,8-quinolinedione (a guanylate cyclase inhibitor), or 10
-mol/L indomethacin (a cy-
clooxygenase inhibitor) significantly decreased the relaxant effect of magnesium on aortic rings from 16-day-
pregnant but not 22-day-pregnant rats. Treatment with minimally effective concentrations of a nitric oxide
donor (3 × 10
-mol/L sodium nitroprusside) or a cyclic guanosine monophosphate analog (10
8-bromo-cyclic guanosine monophosphate) restored the response to magnesium.
CONCLUSIONS: The relaxant effect of magnesium on rat aortic rings was dependent on both endothelium
and gestational age and was lower at term than during late pregnancy. The endothelium appears to potenti-
ate the vasorelaxant effects of magnesium through the nitric oxide–cyclic guanosine monophosphate and cy-
clooxygenase systems. (Am J Obstet Gynecol 2001;184:971-8.)
Key words: Endothelium, magnesium, nitric oxide, pregnancy, rat aorta