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Ann Thorac Surg 1998;65:967-972
© 1998 The Society of Thoracic Surgeons

Hypomagnesemia Inhibits Nitric Oxide Release From Coronary Endothelium: Protective Role of Magnesium Infusion After Cardiac Operations

^a Section of Cardiovascular Surgery, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA

Accepted for publication October 10, 1997.

Address reprint requests to Dr Schaff, Section of Cardiovascular Surgery, Mayo Clinic, 200 First St SW, Rochester, MN 55905. %

	Abstract

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Postoperative hypomagnesemia is common in patients who have undergone cardiac operations and is associated with clinically significant morbidity resulting from atrial and ventricular dysrhythmias. Magnesium supplementation may increase the cardiac index in the early postoperative period.

Methods. The action of the magnesium cation on coronary vascular reactivity was studied. Segments of canine epicardial coronary artery were suspended in organ chambers to measure isometric force (95% O₂/5% CO₂, 37°C).

Results. In coronary segments constricted with prostaglandin F₂ (2 x 10^-6 mol/L), acetylcholine and adenosine diphosphate (10^-9 to 10^-4 mol/L) induced vasodilation in arteries with endothelium (n = 10, each group; p < 0.05). Acetylcholine-mediated vasodilation was blocked by N^G-monomethyl-L-arginine (10^-4 mol/L) and N^G-nitro-L-arginine (10^-4 mol/L), two inhibitors of nitric oxide synthesis from L-arginine (n = 10, p < 0.05). The removal of magnesium from the organ chamber solution impaired vasodilation in response to acetylcholine and adenosine diphosphate. However, normal endothelium-dependent vasodilation could be restored by return of magnesium to the bathing solution. Vascular relaxation in response to bradykinin (10^-9 to 10^-6 mol/L), which was found to induce endothelium-dependent vasodilation independent of nitric oxide production, was unaffected by magnesium removal (n = 10).

Conclusions. Hypomagnesemia selectively impaired the release of nitric oxide from the coronary endothelium. Because nitric oxide is a potent endogenous nitrovasodilator and inhibitor of platelet aggregation and adhesion, hypomagnesemia could promote vasoconstriction and coronary thrombosis in the early postoperative period.

	Introduction

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Magnesium is a key ionic modulator of blood vessel tone [1]. Indeed, magnesium ion has been characterized as an endogenous calcium channel blocker [2] that relaxes vascular smooth muscle and attenuates the vasoconstriction induced by agonists such as serotonin [3, 4]. Hypomagnesemia is present in up to 94% of patients after cardiopulmonary bypass [5–7] and is associated with clinically significant morbidity resulting from cardiac dysrhythmias and a decreased cardiac index [5–7]. However, patients who undergo cardiac operations and receive magnesium supplementation intravenously during the perioperative period have fewer clinically important atrial and ventricular dysrhythmias and also demonstrate an increased cardiac index [5–7].

To investigate the mechanisms responsible for the protective effect of magnesium infusion after cardiac operations, we studied the action of the cation on the production of coronary artery–derived vasodilators [8]. The coronary endothelium produces nitric oxide, which is the active component of one endothelium-derived relaxing factor [9]. In addition to functioning as an endogenous nitrovasodilator [9], nitric oxide inhibits platelet aggregation [10] and platelet adhesion [11] and promotes platelet disaggregation [10] in the coronary artery. If the production of nitric oxide depended on magnesium ion, hypomagnesemia could inhibit the protective vasodilatory and thrombolytic action of the radical in the coronary circulation and put the blood vessels at risk for ischemic events such as vasospasm and thrombosis [12].

	Material and methods

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Animal preparation
Heartworm-free mongrel dogs (25 to 30 kg) of either sex were anesthetized with pentobarbital sodium (30 mg/kg given intravenously) and exsanguinated through the carotid arteries. The chest was opened and the still-beating heart was harvested and immersed in cool, oxygenated physiologic salt solution of the following composition: NaCl, 118.3 mmol/L; KCl, 4.7 mmol/L; MgSO₄, 1.2 mmol/L; KH₂PO₄, 1.22 mmol/L; CaCl₂, 0.5 mmol/L; NaHCO₃, 25.0 mmol/L; Ca ethylenediamine tetraacetic acid, 0.016 mmol/L; and glucose, 11.1 mmol/L (control solution). The procedures and handling of the animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Mayo Foundation as consistent with the principles set forth in the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences (National Institutes of Health publication no. 85-23, revised 1985).

In vitro experiments
The left circumflex coronary artery carefully was dissected free of connective tissue. Segments of blood vessel (4 to 5 mm in length) were prepared from the artery. The segments were assigned randomly to the experimental conditions so that, at most, one pair of segments per artery (with and without endothelium, from each animal) was assigned to the same experimental condition. In some segments, vascular smooth muscle function was tested without the influence of the endothelium; in these rings, the endothelium was removed by gently rubbing the intimal surface of the blood vessel with a pair of watchmaker’s forceps. This procedure removes endothelium but does not affect the ability of vascular smooth muscle to contract or relax.

Coronary arterial segments, with and without endothelium, were suspended in organ chambers (25 mL) filled with control solution maintained at 37°C and bubbled with 95% O₂/5% CO₂ (pH = 7.4) [13]. Each ring was suspended by two stainless steel clips passed through the lumen. One clip was anchored to the bottom of the organ chamber and the other was connected to a strain gauge for measurement of isometric force (Grass FTO3; Grass Instrument Company, Quincy, MA). The rings were placed at the optimal point of their length–tension relation by progressively stretching them until contraction in response to potassium ions (20 mmol/L), at each level of distention, was maximal [13]. In all experiments, the presence or absence of endothelium was confirmed by determining the response to acetylcholine (ACh; 10^-6 mol/L) in rings contracted with potassium ions (20 mmol/L) [13].

After optimal tension was achieved, the arterial segments were allowed to equilibrate for 30 to 45 minutes before the administration of drugs. When hemoglobin (10^-5 mol/L), N^G-monomethyl-L-arginine (L-NMMA; 10^-4 mol/L), or N^G-nitro-L-arginine (NO-ARG; 10^-4 mol/L) was used, the compound was added to the organ chamber at least 10 minutes before constriction of the vascular tissue with prostaglandin F₂. When methylene blue (10^-6 mol/L) was used, the tissue was incubated with the compound for at least 30 minutes before contraction with prostaglandin F₂. Magnesium-free solution was obtained by removing magnesium sulfate (1.2 mmol/L) from the control solution. When magnesium-free solution was used, the vascular preparations were exposed to the solution at least 30 minutes before experimentation. When magnesium-containing solution was restored to the vascular preparations, the tissue was exposed to the solution at least 30 minutes before experimentation. In all experiments, indomethacin (10^-6 mol/L) was used to prevent the synthesis of endogenous prostanoids.

Drugs
The following drugs were used: ACh chloride, adenosine diphosphate (ADP), bradykinin, calcium ionophore A23187, indomethacin, isoproterenol hydrochloride, methylene blue, prostaglandin F₂, sodium fluoride (Sigma Chemical Company, St. Louis, MO), and L-NMMA and NO-ARG (Calbiochem, San Diego, CA). All the drugs were prepared with distilled water except for indomethacin, which was dissolved in Na₂CO₃ (10^-5 mol/L), and the calcium ionophore, which was dissolved in dimethyl sulfoxide, with further dilutions made in distilled water. Oxyhemoglobin was prepared using the method of Gillespie and Sheng [14]. All drug concentrations are expressed as final molar concentration in the organ chambers.

Data analysis
Changes in wall tension are expressed as a percentage of the maximal tension achieved after exposure to prostaglandin F₂, a convention that corrects for variability among animals in the response of the tissue to prostaglandin. In all experiments, n refers to the number of animals from which vascular segments were taken. Results are expressed as mean plus or minus standard error of the mean. All tests were two-sided at an alpha level of 0.05. For vascular relaxation, the negative logarithm of the effective molar concentration (-log mol/L) of agonist that caused 50% inhibition of contraction to prostaglandin F₂ was calculated from concentration-response curves, and the mean of these values is presented. Statistical evaluation of the data was performed using the Student’s t test for either paired or unpaired observations. Values were considered to be statistically significant when the p value was less than 0.05.

	Results

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
After the contraction of arteries with prostaglandin F₂ (2 x 10^-6 mol/L), the progressive addition of ACh (10^-9 to 10^-4 mol/L) induced relaxation in coronary segments with endothelium but not in segments without endothelium (n = 10, p < 0.05) (Fig 1). Because all experiments were performed in the presence of indomethacin (10^-6 mol/L), endothelium-dependent relaxation was not caused by prostanoids. However, the incubation of vascular segments with NO-ARG (10^-4 mol/L) or L-NMMA (10^-4 mol/L), two inhibitors of nitric oxide synthesis from L-arginine [15, 16], completely abolished endothelium-dependent relaxation in response to ACh (n = 10, each group) (Fig 2; Table 1). The addition of hemoglobin (10^-5 mol/L), a scavenger of the nitric oxide radical [14], also inhibited endothelium-dependent relaxation in response to ACh (n = 10) (Table 1). In addition, the incubation of vascular segments with methylene blue (10^-6 mol/L), the inactivator of soluble guanylate cyclase, inhibited vasodilation in response to ACh (n = 10) (Table 1).

View larger version (18K): [in this window] [in a new window]   Fig 1. Concentration-response curves for acetylcholine in canine coronary arteries. Segments were contracted with prostaglandin F2 (2 x 10-6 mol/L). Results are expressed as mean plus or minus standard error of the mean. Magnesium Free denotes experiments performed in the absence of magnesium sulfate (1.2 mmol/L). Maximum reversal of the prostaglandin contraction in control arteries with endothelium was 100%, whereas the magnesium-free group only relaxed to a maximum of 41.67% ± 7.91% (n = 10, each group; p < 0.05).

View larger version (9K): [in this window] [in a new window]   Fig 2. Effect of acetylcholine (ACh) and bradykinin (BK) on isometric tension of canine coronary arteries in the presence of NG-monomethyl-L-arginine (L-NMMA; 10-4 mol/L) (original trace). Segments of coronary artery, with (E+) and without (E-) endothelium, were suspended in organ chambers to measure isometric force. NG-monomethyl-L-arginine was added to the organ chamber at least 10 minutes before contraction with prostaglandin F2 (PGF2) (2 x 10-6 mol/L). When the contraction induced by PGF2 was stable, the vessels were exposed to a single dose of ACh (10-4 mol/L) followed by BK (10-6 mol/L).

View larger version (18K): [in this window] [in a new window]   Fig 3. Concentration-response curves for adenosine diphosphate (ADP) in canine coronary arteries with and without endothelium. Segments were contracted with prostaglandin F2 (2 x 10-6 mol/L). Results are expressed as mean plus or minus standard error of the mean. Magnesium Free denotes experiments performed in the absence of magnesium sulfate (1.2 mmol/L). Values for 50% inhibition (-log mol/L) of contraction in control and magnesium-free experiments with endothelium are 6.61 ± 0.10 and 5.18 ± 0.22, respectively (n = 10, p < 0.05).

View larger version (17K): [in this window] [in a new window]   Fig 4. Concentration-response curves for the calcium ionophore A23187 in canine coronary arteries with and without endothelium. Segments were contracted with prostaglandin F2 (2 x 10-6 mol/L). Results are expressed as mean plus or minus standard error of the mean. Magnesium Free denotes experiments performed in the absence of magnesium sulfate (1.2 mmol/L). Values for 50% inhibition (-log mol/L) of contraction in control and magnesium-free experiments with endothelium are 7.39 ± 0.13 and 7.41 ± 0.07, respectively (n = 10, each group; p = not significant).

View larger version (19K): [in this window] [in a new window]   Fig 5. Concentration-response curves for sodium fluoride (NaF) in canine coronary arteries with and without endothelium. Segments were contracted with prostaglandin F2 (2 x 10-6 mol/L). Results are expressed as mean plus or minus standard error of the mean. Magnesium Free denotes experiments performed in the absence of magnesium sulfate (1.2 mM). Values for maximal relaxation to 9.5 mmol/L of NaF in control and magnesium-free experiments with endothelium were 50.7% ± 6.3% and 182.1% ± 22.3% of the initial prostaglandin F2 contraction, respectively (n = 10, each group; p < 0.05).

View larger version (12K): [in this window] [in a new window]   Fig 6. Effect of acetylcholine on isometric tension of canine coronary arteries (original trace). Segments of coronary artery, with (E+) and without (E-) endothelium, were suspended in organ chambers to measure isometric force and then contracted with prostaglandin F2 (PGF2; 2 x 10-6 mol/L). When the contraction induced by PGF2 was stable, the vessels were exposed to increasing concentrations of acetylcholine. Magnesium Free denotes experiments performed in the absence of magnesium sulfate (1.2 mmol/L).

Isoproterenol (10^-9 to 10^-4 mol/L; n = 10) induced concentration-dependent vasodilation of coronary artery segments with endothelium. The removal of magnesium from the bathing medium did not alter smooth muscle relaxation in response to isoproterenol. The values for 50% inhibition (-log mol/L) of contraction in the control and magnesium-free experiments were 7.60 ± 0.11 and 7.76 ± 0.09, respectively (n = 10, each group; p = not significant).

	Comment

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
The major findings of this study are as follows: (1) removal of magnesium from the extracellular bathing solution inhibits coronary artery endothelium production of nitric oxide by the receptor-mediated agonists ADP and ACh; (2) removal of magnesium does not affect the ability of the coronary endothelium to produce nitric oxide (vasodilation in response to the receptor-independent calcium ionophore was normal); (3) lack of magnesium inhibits vasodilation to sodium fluoride, a pertussis toxin–sensitive G-protein agonist in the canine coronary artery; (4) bradykinin induces endothelium-dependent vasodilation of the coronary artery that is unaffected by blockers of nitric oxide synthesis and scavengers of the radical; (5) vasodilation in response to bradykinin is unaffected by a lack of magnesium; and (6) removal of magnesium does not affect the ability of the vascular smooth muscle to relax in response to isoproterenol.

Magnesium infusion after extracorporeal circulation protects against clinically important cardiac dysrhythmias and may decrease the risk of cardiac failure [5–7]. Because most patients have hypomagnesemia after cardiopulmonary bypass [5, 6] and because the level of hypomagnesemia is related directly to the incidence of postoperative cardiac dysrhythmias [6, 7], it seems likely that the beneficial effect of magnesium infusion is its correction of preexisting deficits. The cardiovascular actions of magnesium are multiple, including effects on the myocardial conduction system, myocyte, and vascular smooth muscle [19]. In addition, as demonstrated in the present study, magnesium has a profound effect on the expression of nitric oxide production by the coronary endothelium.

The coronary endothelium exerts a protective action against vasospasm and thrombosis by producing the nitric oxide radical [12]. The fact that nitric oxide is produced by the intima is confirmed once again by the finding that removal of the endothelium abolishes vasodilation in response to certain agonists. Nitric oxide, which also is the active component of nitrovasodilators such as nitroglycerin [8], induces vasodilation through the activation of soluble guanylate cyclase in the vascular smooth muscle [8, 9]. Methylene blue, an inactivator of soluble guanylate cyclase, abolished the vascular smooth muscle relaxation caused by nitric oxide and inhibited the vasodilation induced by ACh in the present study. Further confirmation that ACh-mediated vasodilation is caused by nitric oxide is provided by the finding that hemoglobin, which scavenges the nitric oxide radical [14], abolished the vasodilation induced by ACh.

In the endothelial cell, nitric oxide is produced from L-arginine [8]. This metabolic pathway can be inhibited by two substituted derivatives of L-arginine: L-NMMA and NO-ARG [15, 16]. In the present study, L-NMMA and NO-ARG inhibited the endothelium-dependent vasodilation induced by ACh, providing clear evidence that ACh-mediated vasodilation of the epicardial coronary artery is caused by endothelium-derived nitric oxide.

Adenosine diphosphate and the calcium ionophore A23187 are two additional compounds that have been used extensively as tools to generate nitric oxide production by the endothelium. Adenosine diphosphate is physiologically the most important platelet-derived compound to release nitric oxide in response to platelet aggregation [17]. Thus, with a normally functioning endothelium, platelet aggregation and adhesion are inhibited by negative feedback secondary to platelet-derived ADP-stimulated nitric oxide production [12, 17]. Impairment of nitric oxide production by the endothelium might be expected to interrupt the protective feedback, and platelet aggregation and adhesion could proceed unchecked [12, 13]. In addition, because magnesium antagonizes vascular smooth muscle constriction [3, 4, 20] and has been implicated in the prevention of platelet aggregation [21], hypomagnesemia may contribute to postoperative coronary vasospasm (Fig 7).

View larger version (17K): [in this window] [in a new window]   Fig 7. Possible mechanism of coronary vasospasm resulting from hypomagnesemia.

Receptor-mediated release of nitric oxide is modulated by G proteins [22]. G proteins are the vital link between cellular receptors and intracellular metabolic pathways [23], such as nitric oxide production. Indeed, dysfunction of endothelial cell G proteins has been implicated in atherosclerosis and in the development of vasospasm after intimal regeneration [12]. In the present study, magnesium removal inhibited endothelium-dependent relaxation in response to sodium fluoride, which acts on a pertussis toxin–sensitive G protein in the coronary endothelium to promote vasodilation [18]. This supports the concept that hypomagnesemia does not impair the ability of the endothelial cell to produce nitric oxide but rather selectively disrupts the signal transduction pathway that leads to production of the radical. The present study suggests that endothelial dysfunction in the absence of magnesium may occur at the level of receptor-associated G proteins [12]. Further, the restoration of normal endothelium-dependent vasodilation in response to all the agonists tested on return of magnesium demonstrates that this impairment in receptor-dependent production of nitric oxide is rapidly reversible.

In the present study, bradykinin induced endothelium-dependent relaxation of the coronary artery. However, bradykinin-mediated vasodilation was not inhibited by methylene blue, hemoglobin, L-NMMA, or NO-ARG. These findings indicate that there is an additional nitric oxide–independent vasodilator produced by the endothelium, possibly hyperpolarizing factor [24]. The removal of magnesium did not affect the ability of bradykinin, which also is receptor-mediated, to promote vasodilation. This indicates that hypomagnesemia selectively inhibits receptor-dependent nitric oxide production, whereas bradykinin-induced production of an alternative relaxing factor remains unaltered. This alternative mechanism of endothelium-dependent vasodilation could be an important and complementary pathway of protection against coronary vasospasm.

	Acknowledgments

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Supported in part by Mayo Foundation and CNPq Conselho de Nacional de DesenvolumimentoCientifico e Technologico, São Paulo, Brazil.

	Footnotes

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
This article has been selected for the open discussion forum on the STS Web site: http://www.sts.org/annals

	References

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Paul J. Pearson John F. Seccombe Hartzell V. Schaff Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pearson, P. J. Articles by Schaff, H. V. Search for Related Content PubMed PubMed Citation Articles by Pearson, P. J. Articles by Schaff, H. V.