Functional and metabolic effects of extracellular magnesium in normoxic and ischemic myocardium

Metabolic and functional responses to extracellular Mg2+ concentration ([Mg2+](o)) were studied in perfused rat heart. Elevations of [Mg2+](o) from 1.2 to 2.4, 5.0, and 8.0 mM dose dependently reduced contractile function and myocardial oxygen consumption (M(V) over dot o(2)) up to 80%. Intracellular Mg2+ concentration ([Mg2+](i)) remained stable (0.45-0.50 mM) during perfusion with 1.2-5.0 mM [Mg2+](o) but increased to 0.81 +/- 0.14 mM with 8.0 mM [Mg2+](o). Myocardial ATP was unaffected by [Mg2+](o), phosphocreatine (PCr) increased up to 25%, and P-i declined by up to 50%. Free energy of ATP hydrolysis (Delta G(ATP)) increased from -60 to -64 kJ/mol. Adenosine efflux declined in parallel with changes in M(V) over dot o(2) and [AMP]. At comparable workload and M(V) over dot o(2), the effects of [Mg2+](o) on cytosolic free energy were mimicked by reduced extracellular Ca2+ concentration ([Ca2+](o)) or Ca2+ antagonism with verapamil. Moreover, functional and energetic effects of [Mg2+](o) were reversed by elevated [Ca2+](o). Despite similar reductions in preischemic function and M(V) over dot o(2), metabolic and functional recovery from 30 min of global ischemia was enhanced in hearts treated with 8.0 mM [Mg2+](o) vs. 2.0 mu M verapamil. It is concluded that 1) 1.2-8.0 mM [Mg2+](o) improves myocardial cytosolic free energy indirectly by reducing metabolic rate and Ca2+ entry; 2) [Mg-2 divided by](i) does not respond rapidly to elevations in [Mg2+], from 1.2 to 5.0 mM and is uninvolved in acute functional and metabolic responses to [Mg2+](o); 3) adenosine formation in rat heart is indirectly reduced during elevated [Mg2+](o); and 4) 8.0 mM [Mg2+](o) provides superior protection during ischemia-reperfusion compared with functionally equipotent Ca2+ channel blockade.