Metabolic and functional responses to extracellular Mg2+concentration ([Mg2+]o) were studied in perfused rat heart. Elevations of [Mg2+]ofrom 1.2 to 2.4, 5.0, and 8.0 mM dose dependently reduced contractile function and myocardial oxygen consumption (MV˙o2) up to 80%. Intracellular Mg2+concentration ([Mg2+]i) remained stable (0.45–0.50 mM) during perfusion with 1.2–5.0 mM [Mg2+]obut 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 Pideclined by up to 50%. Free energy of ATP hydrolysis (Δ GATP) increased from −60 to −64 kJ/mol. Adenosine efflux declined in parallel with changes in MV˙o2and [AMP]. At comparable workload and MV˙o2, the effects of [Mg2+]oon cytosolic free energy were mimicked by reduced extracellular Ca2+concentration ([Ca2+]o) or Ca2+antagonism with verapamil. Moreover, functional and energetic effects of [Mg2+]owere reversed by elevated [Ca2+]o. Despite similar reductions in preischemic function and MV˙o2, metabolic and functional recovery from 30 min of global ischemia was enhanced in hearts treated with 8.0 mM [Mg2+]ovs. 2.0 μM verapamil. It is concluded that 1) 1.2–8.0 mM [Mg2+]oimproves myocardial cytosolic free energy indirectly by reducing metabolic rate and Ca2+entry; 2) [Mg2+]idoes not respond rapidly to elevations in [Mg2+]ofrom 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+]oprovides superior protection during ischemia-reperfusion compared with functionally equipotent Ca2+channel blockade.