- Mg_i²⁺ modulates Ca²⁺ flux in pathophysiologic and physiologic states. Increasing concentrations of Mg_i²⁺ during early ischemia or hypoxia have beneficial effects on L-type Ca²⁺ channels during stress; i.e., Ca²⁺ influx is inhibited.
- Depletion of Mg_i²⁺, as occurs after prolonged ischemia and reperfusion, contributes to progressive Ca²⁺ over-load and subsequent cell damage (discussed subsequently). In addition, loss of Mg_i²⁺ may promote cystolic Ca²⁺ overload from intracellular sources: Elevated concentrations of Mg_i²⁺ inhibit efflux of Ca²⁺ from sarcoplasmic reticulum.

Two mechanisms are believed to be involved in inhibition of Ca²⁺ current by extracellular Mg²⁺:
- effects mediated by cationic screening of fixed negative external surface charges
- competition with permeant ions (Ca²⁺) for a site within the channel itself.

Mg²⁺ and Ischemic-Reperfusion Injury studies in the 1970s showed that myocardial ischemia followed by reperfusion results in cytoplasmic Ca²⁺ overload. There is now general agreement that during and after periods of ischemia, transmembrane Ca²⁺ influx occurs by several routes, and that cytoprotective agents, including Mg²⁺, attenuate the increase in intracellular Ca²⁺ via multiple mechanisms.