Simulated ischemic conditions (acidosis, altered Mg2+ and ATP) impaired cardiac Ca2+ release channel activity by decreasing Ca2+ sensitivity and increasing Mg2+ inhibition.
Simulated ischemic conditions, including acidosis and altered nucleotide pools, impair cardiac sarcoplasmic reticulum Ca2+ release channel activity through increased inhibition by Mg2+ and altered Ca2+ sensitivity.
In myocardial ischemia, pHi and ATP fall, whereas the free Ca2+ and Mg2+ rise. The effects of these changes on cardiac Ca2+ release channel (ryanodine receptor) activity were investigated in 3Hryanodine binding and single-channel measurements, using isolated membrane and purified channel preparations. In the absence of the two channel ligands Mg2+ and ATP, cardiac Ca2+ release channels were half-maximally activated at pH 7.4 by approximately 4 mumol/L cytosolic Ca2+ and half-maximally inhibited by approximately 9 mmol/L cytosolic Ca2+. Regulation of channel activity by Ca2+ was modulated by Mg2+ and ATP. Single-channel activities were more sensitive to a change of cytosolic pH than SR lumenal pH. Reduction in lumenal and/or cytosolic pH from 7.3 to 6.5 and 6.0 resulted in decreased single-channel activities without a change in single-channel conductance. 3HRyanodine binding measurements also indicated that acidosis impairs cardiac Ca2+ release channel activity. Mg2+ and adenine nucleotide concentrations regulated the extent of inhibition and the Ca2+ dependence of binding. In the presence of 5 mmol/L Mg2+ and 5 mmol/L beta, gamma-methyleneadenosine 5'-triphosphate (AMPPCP, a nonhydrolyzable ATP analogue), the free Ca2+ for half-maximal 3Hryanodine binding was increased from 1.9 mumol/L at pH 7.3 to 36 mumol/L at pH 6.5 and to 89 mumol/L at pH 6.2. These results suggest that ionic and metabolic changes that might be expected to affect sarcoplasmic reticulum Ca2+ release channel activity in ischemic myocardium include an altered Ca2+ sensitivity of the channel, a fall in pH, and a loss of the high-energy adenine nucleotide pool, leading to an increased inhibition by Mg2+.
Xu et al. (1996) studied Myocardial ischemia. Simulated ischemic conditions (low pH, altered ATP, Ca2+, Mg2+) vs. Normal conditions (pH 7.3-7.4) was evaluated on Cardiac Ca2+ release channel (ryanodine receptor) activity and [3H]ryanodine binding. Simulated ischemic conditions (acidosis, altered Mg2+ and ATP) impaired cardiac Ca2+ release channel activity by decreasing Ca2+ sensitivity and increasing Mg2+ inhibition.