Vol. 87, Issue 5, 1589-1594, November 1999
Developmental change in magnesium sulfate-induced relaxation
of rabbit pulmonary arteries
Jean-Francois
Tolsa,
Yuansheng
Gao, and
J. Usha
Raj
Department of Pediatrics, Harbor-UCLA Medical Center, University of
California, Los Angeles, School of Medicine, Torrance, California
90502
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ABSTRACT |
Magnesium causes
a variety of vascular smooth muscle to relax. The present study was
designed to determine whether there is a developmental change in the
magnesium-induced response of pulmonary vasculature. Isolated pulmonary
arteries (PA) of newborn (1- to 3-day-old) and juvenile (4- to
6-wk-old) rabbits were suspended in organ chambers filled with modified
Krebs-Ringer bicarbonate solution (95%
O2-5%
CO2, 37.0°C), and their
isometric tension was recorded. In arteries preconstricted with
endothelin-1 to a similar tension level,
MgSO4 caused greater relaxation of
juvenile rabbit PA than that of the newborn rabbit PA. Verapamil, a
voltage-dependent Ca2+ channel
blocker, attenuated magnesium-induced relaxation in juvenile rabbit PA
but not in newborn PA. The uptake of
Ca2+ of juvenile rabbit PA was
inhibited by MgSO4, and the
inhibition was attenuated by verapamil. The uptake of
Ca2+ of newborn rabbit PA was
smaller than that of the juvenile PA and was not significantly affected
by MgSO4 and verapamil. These results demonstrate that there is a developmental increase in the
dilator effect of MgSO4 in rabbit
PA. In newborn rabbit PA, an incomplete maturation of the
voltage-dependent Ca2+ channels
may contribute to the smaller vasodilation induced by MgSO4.
perinatal pulmonary circulation; verapamil; voltage-dependent
calcium channels; vasorelaxation
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INTRODUCTION |
MAGNESIUM IS THE SECOND most plentiful cation of the
intracellular fluid. It plays an important role in neurochemical
transmission, muscular excitability, and regulation of vascular tone
(3, 4, 6, 7, 19, 20). In a variety of blood vessels, an increase in
extracellular magnesium concentration inhibits vascular contractile
tension (2, 4, 5, 24, 32, 33). Magnesium has been shown to reduce acute
hypoxia-induced pulmonary vasoconstriction (1, 9, 10) and to attenuate
experimentally induced pulmonary hypertension (21). In clinical
studies, intravenous magnesium has been proposed as effective in the
treatment of persistent pulmonary hypertension in term (1, 30) and
preterm (39) neonates.
Substantial evidence suggests that magnesium may modulate vasoactivity
by affecting the influx of extracellular
Ca2+ (3, 4, 6-8, 34).
Agonists may stimulate the entry of extracellular
Ca2+ through voltage-dependent
Ca2+ channels and
receptor-operated Ca2+ channels
(26, 29). In cardiac, uterine, basilar arterial, and airway smooth
muscle, extracellular magnesium has been shown to block
voltage-dependent Ca2+ channels
(12, 25, 28). In whole-cell patch-clamp studies done on capillary
endothelial cells, high extracellular magnesium concentrations have
been shown to reversibly depress the
Ca2+ current (11). It is possible,
therefore, that inhibition of voltage-depedent
Ca2+ channels by magnesium may be
one of the mechanisms by which the pulmonary vasculature relaxes during
intravenous treatment with magnesium. However, the effect of magnesium
on Ca2+ entry in newborn pulmonary
vessels is not known and is likely to be different from that in the
adult, as the structure and pharmacology of
Ca2+ channels in newborn pulmonary
vessels may be variable during the perinatal period as of the anatomic,
functional, and pharmacological changes after the birth process in the
first weeks of life (17, 18).
In the present study, we hypothesize that there is a developmental
change in voltage-dependent Ca2+
channels. Such a difference affects relaxation of pulmonary vessels induced by magnesium. We tested this hypothesis in isolated pulmonary arteries of newborn and juvenile rabbits.
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METHODS |
Tissue preparation.
Forty newborn rabbits (1-3 days old, either sex, 73.8 ± 2.2 g)
and twenty-two juvenile rabbits (4-6 wk old, either sex, 1.75 ± 0.06 kg) were used. They were New Zealand White rabbits purchased from Irish Farms (Norco, CA). The newborn rabbits were killed by
pentobarbital sodium (300 mg/kg ip) and by exsanguination. The juvenile
rabbits were anesthetized with ketamine hydrochloride (30 mg/kg im) and
killed by pentobarbital sodium (30 mg/kg) given by ear vein injection
and by exsanguination.
The lungs were removed immediately and placed in a cold modified
Krebs-Ringer bicarbonate solution of the following composition (mM):
118.3 NaCl, 4.7 KCl, 2.5 CaCl2,
1.2 MgSO4, 1.2 KH2PO4,
25.0 NaHCO3, and 11.1 glucose. As
defined by Weibel and Taylor (38), who designated the left and right
main branches of pulmonary arteries as the first, third, and fourth
generation, pulmonary arteries were dissected from the lungs, cleaned
of visible connective tissue, and cut into rings. The
diameters of the rings were 0.62 ± 0.02 mm
(n = 24) for the newborns and 1.54 ± 0.09 mm (n = 22) for the juveniles.
Organ chamber studies.
Rings of pulmonary arteries were suspended in organ chambers filled
with 10 ml of the modified Krebs-Ringer solution described in
Tissue preparation, maintained at
37.0°C, and aerated with 95%
O2-5%
CO2 (pH 7.4). Each
ring was suspended by two stirrups passed through the lumen. One
stirrup was anchored to the bottom of the organ chamber, and the other
was connected to a force displacement strain-gauge transducer (model
FT03C, Grass Instruments, Quincy, MA) for the measurement of isometric
force (15). A permanent record of the force developed by each ring was
obtained by using a multichannel recorder. At the beginning of every
experiment, pulmonary artery rings were brought to their optimal
resting tension by stretching the tissues progressively until their
contractile response to 100 mM KCl was maximal. The optimal resting
tensions of the vessel rings were 0.50 ± 0.05 g/mm2 smooth muscle
cross-sectional area (CSAsm;
n = 24) for the newborns and 0.27 ± 0.03 g/mm2
CSAsm
(n = 22) for the juveniles; the method
to determine the CSAsm is
described in Determination of
CSAsm. One hour of
equilibration was allowed after tissues were brought to their optimal
resting tension (15).
Experimental protocols.
To determine the developmental change in voltage-dependent
Ca2+ channels of pulmonary
vessels, the response of these vessels to KCl (20-100 mM) was
examined. It is known that potassium causes vasoconstriction
predominantly by increasing the influx of
Ca2+ into cells through
voltage-dependent channels (26). The response of these vessels to
endothelin-1 (10
10 M to 3 × 107 M) was also
determined. Endothelin causes vasoconstriction not only by stimulating
the influx of extracellular Ca2+
but also by mobilizing the intracellular
Ca2+, sensitizing of myofilaments
to Ca2+, and by other mechanisms
(27).
To determine the vasodilator effect of magnesium, pulmonary vessels of
newborn and juvenile rabbits were preconstricted with different
concentrations of endothelin-1 (3 × 109 to
108 M) to a similar tension
level. After the contraction became stable, the effect of
MgSO4 (2-8 mM) was determined.
To evaluate the role of voltage-dependent
Ca2+ channels in the vasorelaxant
effect of magnesium, pulmonary vessels of newborn and juvenile rabbits
were pretreated with verapamil
[105 M; a
voltage-depedent Ca2+ channel
blocker (29)] or solvent (distilled water, 0.58% of organ
chamber volume). These vessels were contracted with different concentrations of endothelin-1 (3 × 109 to 2 × 108 M) to a similar tension
level, and then the effect of
MgSO4 was evaluated.
To eliminate a possible involvement of prostanoids and
endothelium-derived nitric oxide (14, 15), all the experiments mentioned above were performed in the presence of indomethacin (3 × 105 M) and
nitro-L-arginine
(104 M), inhibitors of
cyclooxygenase (36) and nitric oxide synthase (22), respectively. These
inhibitors had no significant effect on the resting tension and
endothelin-induced contraction of pulmonary arteries of newborn and
juvenile rabbits (data not shown).
Determination of CSAsm.
To properly compare the constriction of pulmonary arteries of newborn
and juvenile rabbits, vessel tensions have been standardized as
previously described (14). First, the total tissue cross-sectional area
(CSAtot) was obtained by the
following formula: CSAtot = wet
weight of vessel (mg) / vessel density
(mg/mm3) / optimal length of
the vessel (mm). The vessel density was obtained by dividing the
blotted wet weight of the vessel from its volume. The volume was
determined by measuring the volume of Krebs-Ringer bicarbonate solution
displaced by the vessel rings after the tissues were placed in a 1-ml
graduated cylinder with an accuracy of 0.01 ml. The optimal length was
determined, with the aid of a magnifying eyepiece and a micrometer with
an accuracy of 0.01 mm, by measuring the distance between two stirrups
passed through the lumen of the vessel ring under the optimal resting tension of the vessel.
After the CSAtot was obtained, the
CSAsm/CSAtot
ratio was obtained by counting the total area and the area occupied by
smooth muscle cells on a histological transverse section of the
pulmonary arteries (5-µm thickness) viewed under a microscope. The
histological sections were treated with either hematoxylin and eosin or
Van Giesson stains to discriminate between smooth muscle cells and other components. The
CSAsm/CSAtot
ratios obtained from hematoxylin and eosin and from Van Giesson stains
were averaged. The mean values were multiplied by the
CSAtot to obtain the
CSAsm of the vessel.
Ca2+ uptake.
Ca2+ uptake was determined by
using methods described by Godfraind (16) and by Turlapaty and Altura
(32). Pulmonary artery rings were weighed and then placed in 10-ml
vials containing a HEPES buffer containing the following composition
(mM): 144.0 NaCl, 5.8 KCl, 2.5 CaCl2, 1.2 MgSO4, 5.0 HEPES, 11.1 D-(+)-glucose, 105 M indomethacin, and
104 M
nitro-L-arginine. The HEPES
buffer was maintained at 37.0°C and aerated with 95%
O2-5%
CO2 (pH 7.4).
After a 1-h equilibration, vessel rings were exposed to
45Ca2+
(3 µmCi; specific activity: 10.82 mCi/mg; NEN Life Products, Boston, MA). Five minutes later, endothelin-1 (3 × 109 M and
108 M for vessels of
juvenile rabbits and newborn rabbits, respectively) was added to the
vials. Twenty minutes later, different concentrations of
MgSO4 or solvent were
administrated. In some experiments, the effect of magnesium on
Ca2+ uptake was determined in the
presence of verapamil (105
M). In these experiments, verapamil was added at least 45 min before
incubation with Ca2+.
Twenty minutes after the administration of
MgSO4, vessel rings were taken out
and placed individually into tubes containing 10 ml of an ice-cold
Ca2+-free HEPES solution
containing 50 mM LaCl3 for 60 min.
Then, the tissues were washed with the same ice-cold
LaCl3 solution (16). Afterward,
pulmonary artery rings were blotted and transferred into tubes
containing 5 ml EDTA (5 mM) and left overnight at room temperature. The
next day, 5 ml of EDTA solution were mixed with 10 ml of scintillant
(Ecolite+, ICN Biomedical, Irvine, CA) and the radioactivity was
counted. The results of each determination have been converted to the
apparent tissue content of
45Ca2+
according to the following formula (16)
where
cpm is counts per minute.
Drugs.
The following drugs were used: EDTA, HEPES, indomethacin,
LaCl3, verapamil (Sigma Chemical,
St. Louis, MO); endothelin-1 (Peptides International, Louisville, KY);
and
NG-nitro-L-arginine
(RBI, Natick, MA). Indomethacin was prepared with an equimolar
amount of
Na2CO3.
This concentration of
Na2CO3 did not significantly affect the pH of the solution in the organ chambers (15). All the other drugs were dissolved by using distilled water. Concentrations are expressed as final molar concentration in the
organ chamber or in the incubation vial.
Data analysis.
Contractions are expressed in grams per millimeter
CSAsm. Relaxations were expressed
as percentage of tension elicited by pretreatment with endothelin-1.
Data are shown as means ± SE. When mean values of two groups were
compared, Student's t-test for
unpaired observations was used. When the mean values of the same group
before and after stimulation were compared, Student's t-test for paired observations was
used. Comparison of mean values of more than two groups was made with
one-way ANOVA test, with Student-Newman-Keuls test for post hoc testing
of multiple comparison. Statistical significance was accepted when the
P value (2 tailed) was <0.05. In all
experiments, n represents the number
of rabbits studied.
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RESULTS |
Organ chamber studies.
The wet weights, optimal length, and
CSAsm of vessel rings used in the
study were significantly different between pulmonary arteries of
newborn rabbits and those of juvenile rabbits. There is no significant
difference in the tissue densities and in the CSAsm/CSAtot
ratio between these two vessel types (Table
1).
KCl (20-100 mM) and endothelin-1
(1010 M to 3 × 107 M) caused a greater
increase in tension in pulmonary arteries of juvenile rabbits than in
those of newborn rabbits. In pulmonary arteries of the newborn rabbits,
the maximal contraction induced by KCl was ~30% of that induced by
endothelin-1. For the vessels of juvenile rabbits, there is no
significant difference in the maximal contraction between that induced
by KCl and that by endothelin-1 (Fig. 1).
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Fig. 1.
Contractions of pulmonary arteries of newborn and juvenile rabbits
evoked by KCl and endothelin-1. Values are means ± SE;
n = 6 for each group. SMA, smooth
muscle area. * Significant difference between vessels from
newborn and juvenile rabbits, P < 0.05.
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The effect of MgSO4 was examined
in arteries preconstricted with different endothelin-1 concentrations
(3 × 109 M to
108 M) to a similar tension
level (1.14 ± 0.18 g/mm2
CSAsm and 1.28 ± 0.22 g/mm2
CSAsm for the vessels from newborn
and juvenile rabbits, respectively; n = 6-7, P < 0.05). After the
contraction became stable, the administration of
MgSO4 induced a
concentration-dependent relaxation. The relaxation was significantly
greater in arteries of juvenile rabbits than in those of newborn
rabbits (Fig. 2).
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Fig. 2.
Relaxations of pulmonary arteries of newborn and juvenile rabbits
induced by MgSO4. Experiments were
performed during contraction to endothelin-1. Values are means ± SE; n = 6-7 for each group.
* Significant difference between vessels from newborn and
juvenile rabbits, P < 0.05.
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Verapamil [105 M; a
voltage-dependent Ca2+ channel
blocker (29)] had no significant effect on the basal tension of
pulmonary arteries of newborn and juvenile rabbits. After a 45-min
exposure to verapamil, the vessels were contracted with endothelin-1 (3 × 109 to 3 × 108 M) to a
tension similar to vessels that were not treated with verapamil (data
not shown, n = 6 for each group;
P < 0.05). In pulmonary arteries of
juvenile rabbits, pretreatment with verapamil significantly reduced the
vasodilator effect of MgSO4 (8 mM), whereas verapamil had no significant effect on the relaxation induced by MgSO4 in pulmonary
arteries of the newborns (Fig. 3).
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Fig. 3.
Relaxations of pulmonary arteries of newborn and juvenile rabbits
induced by MgSO4 at 8 mM under
control conditions or in presence of verapamil
(105 M). Experiments were
performed during contraction to endothelin-1. Values are means ± SE; n = 6 for each group.
* Significantly different from newborn,
P < 0.05.  Significantly
different from control, P < 0.05.
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Ca2+ uptake.
Under control conditions (1.2 mM
MgSO4), the
Ca2+ uptake of pulmonary
arteries of newborn and juvenile rabbits for 45 min was 0.23 ± 0.02 mmol/kg wet wt tissue (n = 7) and 0.34 ± 0.03 mmol/kg wet weight tissue (n = 8),
respectively. These values are significantly different
(P < 0.05).
MgSO4 induced a
concentration-dependent inhibition in the
Ca2+ uptake of the juvenile
pulmonary arteries but had no significant effect on the
Ca2+ uptake of the newborn
pulmonary arteries (Fig. 4).
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Fig. 4.
Effect of MgSO4 on
Ca2+ uptake of pulmonary arteries
of newborn and juvenile rabbits. Values are means ± SE;
n = 7-8 for each group.
* Significantly different from newborn,
P < 0.05. Significantly
different from control (1.2 mM
MgSO4),
P < 0.05.  Significantly
different from vessels treated with 4.0 mM
MgSO4,
P < 0.05.
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In vessels pretreated with verapamil
(105 M), the
Ca2+ uptake of pulmonary arteries
of newborn and juvenile rabbits was similar [0.21 ± 0.01 mmol/kg wet weight tissue (n = 7) and
0.24 ± 0.02 mmol/kg wet wt tissue
(n = 8), respectively]. In the
presence of verapamil, the reduction in the
Ca2+ uptake of pulmonary arteries
of juvenile rabbits caused by
MgSO4 (8 mM) was significantly
attenuated. Verapamil had no significant effect on the
Ca2+ uptake of pulmonary arteries
of newborn rabbits (Fig. 5).
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Fig. 5.
Effect of MgSO4 (8 mM) on
Ca2+ uptake of pulmonary arteries
of newborn and juvenile rabbits under control conditions or in the
presence of verapamil (105
M). Values are means ± SE; n = 7-8 for each group. * Significantly different from control,
P < 0.05.
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DISCUSSION |
Magnesium as a vasodilator has been reported in a variety of vessel
types (6). However, few studies have been done in isolated pulmonary
vessels. Villamor et al. (37) found that, in 10- to 17-old-day piglets,
magnesium is a weak dilator of isolated pulmonary arteries. The maximal
reduction in tension of preconstricted pulmonary arteries is <20%.
Such an observation is in line with our present finding in pulmonary
arteries of newborn rabbits. In contrast, magnesium caused
marked relaxation of pulmonary arteries of juvenile rabbits.
These results demonstrate that there is a developmental increase in the
vasorelaxant effect of magnesium in the rabbit lungs.
A rise in intracellular Ca2+ in
smooth muscle cells is thought to be one of the key events for the
initiation and the maintenance of contraction, with the inverse being
true for relaxation (35). When stimulated with a variety of
vasoconstrictors, extracellular Ca2+ may enter into the cell
through voltage-dependent Ca2+
channels and receptor-operated
Ca2+ channels (26, 29). In airway
smooth muscle, electrophysiological studies have shown that magnesium
inhibits voltage-dependent Ca2+
channel current. The inhibition is quantitatively similar to MgSO4-induced relaxation of
trachea smooth muscle strips (28). In the present study,
MgSO4-induced relaxation of
pulmonary arteries of juvenile rabbits was attenuated by verapamil, a
voltage-dependent Ca2+ channel
blocker (29). Furthermore, the inhibition of
Ca2+ uptake caused by
MgSO4 in the juvenile pulmonary
arteries was attenuated by verapamil. Hence, inhibition of
Ca2+ entry through
voltage-dependent Ca2+ channels
may contribute to vasodilation of pulmonary arteries of juvenile
rabbits caused by magnesium.
The voltage-dependent Ca2+
channels seem to be less well developed in pulmonary arteries of
newborn rabbits in comparison to those of the juveniles. A similar
suggestion was advanced earlier for newborn piglet arteries (17). It is
well known that contraction of smooth muscle evoked by potassium
results predominantly from extracellular
Ca2+ entry via the
voltage-dependent channels (26). In our study, the maximal contraction
of pulmonary arteries of the newborn rabbits to KCl was only 15% of
that of pulmonary arteries of the juveniles. Furthermore, verapamil
reduced the Ca2+ uptake of the
vessels from juvenile rabbits but had no significant effect on the
Ca2+ uptake of the vessels from
newborn rabbits. In addition, verapamil attenuated
MgSO4-induced relaxation of the
arteries from juvenile rabbits but had no significant effect on
MgSO4-induced relaxation of the
arteries from newborn rabbits. These observations indicate that the
difference in the vasodilation effect of magnesium between the
pulmonary arteries of the newborn rabbits and those of the juveniles is
likely due to a difference related to the voltage-dependent Ca2+ channels.
Magnesium modulates the influx of extracellular
Ca2+ into the cell not only via
the voltage-dependent channels but also via the other pathways (5, 23,
31). For instance, in rat cultured aortic smooth muscle, magnesium
inhibits receptor-mediated
Ca2+-permeable nonselective cation
channels (23). It is interesting to note that the relative role of the
voltage-dependent and receptor-operated Ca2+ channels in the effect of
magnesium differs in vascular smooth muscle of Wistar- Kyoto rats
and spontaneously hypertensive rats. In Wistar-Kyoto rats,
extracellular magnesium modulates cytosolic Ca2+ concentration primarily
through the voltage-dependent
Ca2+ channels. In spontaneously
hypertensive rats, extracellular magnesium affects cytosolic
Ca2+ concentration through
voltage-dependent Ca2+ channels,
non-voltage-dependent Ca2+
channels, and the intracellular
Ca2+ stores (3, 7, 31). The roles
of the later two mechanisms in magnesium-induced vasodilation in the
lungs are not clear.
Clinical studies have shown that
MgSO4 infusion, to achieve a
magnesium blood concentration between 3.5 and 5.5 mmol/l, can be an
effective therapy for persistent pulmonary hypertension in preterm and
term neonates (1, 30, 39). However, and under similar magnesium
concentrations, results obtained from isolated animal newborn pulmonary
arteries of our present study and those of others show that magnesium
has only a moderate vasodilator effect (37). In in vivo studies, the
observed effects of magnesium reflect the actions of magnesium on the
whole pulmonary vascular tree. In contrast, our present results and
those of others are obtained from midsized isolated pulmonary arteries
(37). It is possible that the effect of magnesium is more pronounced in small pulmonary arteries and arterioles, as it has been shown in
monocrotaline-induced pulmonary hypertension (21), or in pulmonary
veins. In ovine arteries, we found that nitric oxide is more potent in
relaxing small-size pulmonary arteries (13). Alternatively, the
voltage-dependent Ca2+ channels of
the pulmonary vasculature of human neonates may be more mature in
comparison to those of newborn rabbits and piglets (17, 18). Our
present study indicates that the voltage-dependent Ca2+ channels play an important
role in the developmental change in magnesium-induced vasodilation in
the rabbit lung. Whether this is the case in humans remains to be determined.
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ACKNOWLEDGEMENTS |
We thank Jean Morris for technical assistance.
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FOOTNOTES |
This study was supported by National Heart, Lung, and Blood Institute
Grants HL-38438 and HL-59435. J.-F. Tolsa was sponsored by Swiss grants
(les Fonds du Département de Pédiatrie et de Perfectionnement du Centre Hospitalier Universitaire Vaudois, la
Société Académique Vaudoise, and la Fondation Emma
Mushamp, Lausanne, Switzerland).
Address for reprint requests and other correspondence: J.-F. Tolsa,
Div. of Neonatology, Dept. of Pediatrics, Centre Hospitalier
Universitaire Vaudois, 1011 Lausanne, Switzerland (E-mail:
Jean-Francois.Tolsa{at}chuv.hospvd.ch).
Received 12 March 1997; accepted in final form 30 June 1999.
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