Protective effects of captopril against ischemic stress - Role of cellularMg

Magnesium (Mg) deficiency enhances tissue sensitivity to ischemic damage, a n effect reversed not only by Mg, but also by sulfhydryl (SH)-containing co mpounds. We therefore created an in vitro model of red blood cell ischemia to investigate whether the protective effects of these compounds might be r elated to effects on intracellular free Mg (Mg-i) content. P-31-nuclear mag netic resonance (NMR) spectroscopy was used to measure the high-energy meta bolites ATP and 2,3-diphosphoglycerate (DPG) and Mg-i and inorganic phospha te (P-i) levels in erythrocytes before and for 6 hours after progressive ox ygen depletion in the presence or absence of SH-compounds, including captop ril, N-acetyl-L-cysteine (NAC), penicillamine, and N-(2-mercaptopropionyl)- glycine (MPG). Under basal aerobic conditions, captopril increased Mg-i in a dose- and time-dependent fashion (174.5+/-5.3 to 217.1+/-5.1 mu mol/L, P< 0.05 at 100 mu mol/L, 60 minutes). The SH compounds NAG. penicillamine, and MPG but not the non-SI I compound enalaprilat also significantly raised Mg -i in erythrocytes (P<0.05). With oxygen deprivation, a consistent decrease occurred in both ATP and 2,3-DPG levels associated with a rise in P-i and in the P-i/2,3-DPG ratio used as an index of high-energy metabolite depleti on. Captopril, compared with control, retarded the rise in P-i and reduced the P-i/2,3-DPG ratio (P<0.008 and P<0.025 at 4 and 6 hours. respectively). Furthermore, the higher the initial Mg-i and the greater the captopril-ind uced rise in Mg-i, the greater the metabolite-protective effect (r=0.799 an d r=0.823, respectively: P<0.01 for both). Altogether, the data suggest tha t Mg influences the cellular response to ischemia and that the ability of S H compounds such as captopril to ameliorate ischemic injury may at least in part be attributable to the ability of such compounds to increase cytosoli c free Mg levels.