Effect of magnesium treatment on the electrophysiological changes of the heart in experimental hypertension

Hypertension is one of the major risk factors of cardiac hypertrophy and heart failure and Mg2+ is suggested to be a contributing factor in the progression of these diseases. In this study, we aimed to unravel the electrophysiological changes produced in the cardiac myocytes and to establish the relationship between intracellular free Mg2+ levels with these changes in L-NAME induced hypertension model. Hypertension was induced by administration of 40 mg/kg of L-NAME in drink water for six weeks, while MgO treated rats fed with a diet supplemented with 1 g/kg of MgO. Elevated blood pressure, with application of L-NAME for six weeks, was reversed to control levels with MgO treatment, thereby cardiac hypertrophy developing secondary to hypertension was prevented. Cytosolic free Mg2+ levels of ventricular myocytes were significantly decreased with hypertension and MgO treatment restored these changes to control levels. Hypertension significantly decreased the fractional shortening with slowing of contraction kinetics and elicited prolonged Ca2+ transient decay time, despite unchanged Ca2+ transient amplitudes in left ventricular myocytes. Thus 6 week MgO treatment was capable of restoring hypertension-induced contractile dysfunction in ventricular myocytes. Hypertension prolonged repolarization phase of action potential and Mg2+ significantly restored repolarization duration in ventricular myocytes from MgO-treated hypertensive rats. In addition, L-NAME induced hypertension suppressed Ito and Iss currents. Though magnesium treatment corrected Ito currents to control levels; it did not affect Iss currents significantly. On the other hand, hypertension dependent decrement in intracellular Mg2+ level did not result in a significant change in L-type Ca2+ currents, SR Ca2+ content and NCX activity. Moreover, hypertension mediated increase in oxidative stress and protein oxidation mitigated with MgO treatment. In summary, it is likely that Mg2+ affects electrical and mechanical changes observed in hypertensive rat ventricular myocytes. Accordingly hypertension induced Mg2+ deficiency leads to upregulated oxidative stress and functional abnormalities in myocardium while MgO treatment ameliorates that electropyhsiological changes via activation of enzyme-linked antioxidant mechanisms. As a result, changes in intracellular Mg2+ balance may contribute to the pathophysiology of chronic heart diseases. Key Words: Hypertension, L-NAME, Mg2+, Excitation-Contraction Coupling, ROS