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 contracti le 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 unaffec ted by [Mg2+](o), phosphocreatine (PCr) increased up to 25%, and P-i d eclined by up to 50%. Free energy of ATP hydrolysis (Delta G(ATP)) inc reased from -60 to -64 kJ/mol. Adenosine efflux declined in parallel w ith changes in M(V) over dot o(2) and [AMP]. At comparable workload an d M(V) over dot o(2), the effects of [Mg2+](o) on cytosolic free energ y were mimicked by reduced extracellular Ca2+ concentration ([Ca2+](o) ) or Ca2+ antagonism with verapamil. Moreover, functional and energeti c effects of [Mg2+](o) were reversed by elevated [Ca2+](o). Despite si milar reductions in preischemic function and M(V) over dot o(2), metab olic and functional recovery from 30 min of global ischemia was enhanc ed 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 cytosoli c 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 metabol ic responses to [Mg2+](o); 3) adenosine formation in rat heart is indi rectly reduced during elevated [Mg2+](o); and 4) 8.0 mM [Mg2+](o) prov ides superior protection during ischemia-reperfusion compared with fun ctionally equipotent Ca2+ channel blockade.