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

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