Magnesium homeostasis in the mammalian heart

Howarth, Frank Christopher (1994) Magnesium homeostasis in the mammalian heart. Doctoral thesis, University of Central Lancashire.

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The magnesium ion (Mg2 ) is involved in a variety of physiological and biochemical processes including the activation of over 300 enzymes and the control of transmembrane movement of cations. In most mammalian cells intracellular Mg2+ is kept well below electrochemical equilibrium. In cardiac muscle cells recent studies suggest that the intracellular and extracellular concentrations of Mg2+ are around I and 0.5 mIs4, respectively. The equilibrium potential for Mg2 is approximately - 10
mV. In resting muscle the membrane potential is far more negative than this and M g2+ extrusion must take place aganist an electrochemical gradient. Factors which may be important in preserving intracellular Mg2+ include; changes in membrane potential which occur during the action potential, intracellular buffering, intracellular compartmental redistribution, the permeability characteristics of the plasma membrane and transport stystems in the plasma membrane.
The aims of the study are to investigate the effects of extracellular Mg2+ on contractility and coronary flow and the effects of hormonal and extracellular cationic control of Mg2+ homeostasis in the rat heart. Subsequently, the effects of dietary
magnesium on the magnesium, calcium, sodium and potassium content of the heart (and other tissues) in young rats is also investigated. Perfusion of the isolated heart with elevated extracellular Mg2+ (1.2 - 7.2 mM) caused a profound reduction in the force of contraction and an associated increase in the coronary flow rate. The selective 13-adrenoceptor agonist isoprenaline (10 M), evoked a large Mg2+ efflux and an associated increase in the force and rate of contraction in the isolated perfused heart.
Quantitativley, similar increases in Mg2+ efflux were seen during stimulation of the isolated heart with the adenylate cyclase activator, forskolin (10 M). Stimulation of superfused electrically paced ventricle segments with either isoprenaline, noradrenaline or adrenaline (10-6 M) also evoked a large net Mg2+ efflux. The isoprenaline-evoked Mg2+ efflux was significantly reduced during treatment of the heart with either the 0- antagonist, propranolol (I o-5 M), or the Ca2 -channel blocker, verapamil (1 o-5 M) Stimulation of mag-ftira-2 AM loaded cardiac myocytes in suspension with
isoprenaline did not result in any change in intracellular M g2+. Elevations of extracellular Na+ concentration (as NaCl or sodium isethionate), elevated chloride (as choline chloride) and sucrose (at concentrations osmotically equivalent to elevated Na+) all evoked large Mg2+ eftiuxes in the isolated perfused heart. The elevated Na (as NaCl) -evoked Mg 2 efflux was partially, though not significantly, inhibited by the Na channel blocker, amiloride (10 M) and propranolol (lOs M). During stimulation of the heart with elevated Na+ there was no increase in lactate dehydrogenase activity indicating that the release of Mg2+ was not due to cell damage. Treatment of the heart with verapamil (I o-6 M), which dramatically reduced the force of contraction, had little effect on the Mg2+ efflux evoked by elevated Na+ (as sodium sulphate).
Acute perfusion of the isolated heart with nominally Mg2+ free physiological solution over 15 min caused a significant reduction in the magnesium content of the heart, thereafter, magnesium was well conserved. Magnesium deficient diets fed to young rats over a period of approximately one month caused reduction in food consumption, retardation of growth, reductions in some organ weights and various cationic disturbances in the heart and other tissues. In the heart there were no significant changes to sodium or potassium but there was a significant increase in calcium and reduction in magnesium.
Collectively, these results suggest that magnesium is well conserved in the heart and that the catecholamines and changes in extracellular osmolarity may be important physiological regulators of magnesium homeostasis in the heart.

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