Coronary microvascular protection with Mg²⁺: effects on intracellular calcium regulation and vascular function

Abstract

The use of Mg2+-supplemented hyperkalemic cardioplegia preserves microvascular function. However, the mechanism of this beneficial action remains to be elucidated. We investigated the effects of Mg2+ supplementation on the regulation of intracellular calcium concentration ([Ca2+]i) and vascular function using an in vitro microvascular model. Ferret coronary arterioles (80–150 μm in diameter) were studied in a pressurized (40 mmHg) no-flow, normothermic (37°C) state. Simultaneous monitoring of internal luminal diameter and [Ca2+]iusing fura 2 were made with microscopic image analysis. The microvessels ( n = 6 each group) were divided into four groups according to the content of MgCl2 (nominally 0, 1.2, 5.0, and 25.0 mM) in a hyperkalemic cardioplegic solution ([K+] 25.0 mM). After baseline measurements, vessels were subjected to 60 min of hypoxia with hyperkalemic cardioplegia (equilibrated with 95% N2-5% CO2) containing each concentration of Mg2+([Mg2+]) and were then reoxygenated. During hyperkalemic cardioplegia, [Ca2+]iincreased in a time-dependent manner in all groups. In the lower [Mg2+] cardioplegia groups, [Ca2+]iwas significantly increased at the end of the 60-min cardioplegic period (247 ± 44 nM and 236 ± 49 nM in [Mg2+] 0 and 1.2 mM groups, respectively; both P < 0.05 vs. baseline) with 19.6–17.2% vascular contraction. Conversely, there was no significant [Ca2+]iincrease in the higher [Mg2+] cardioplegia groups and less vascular contraction (5.4–4.1%, both P < 0.05 vs. [Mg2+] 1.2 mM group). After reperfusion, agonist (U-46619, thromboxane A2 analog)-induced vascular contraction was significantly enhanced in the lower [Mg2+] cardioplegia groups (both P < 0.05 vs. control) but was normalized in the higher [Mg2+] cardioplegia groups. Intrinsic myogenic contraction was significantly decreased in the lower [Mg2+] cardioplegia groups (both P < 0.05 vs. control) but was preserved in the higher [Mg2+] cardioplegia groups. These results suggest that supplementation of the solution with >5.0 mM [Mg2+] may prevent hyperkalemic cardioplegia-related intracellular Ca2+ overloading and preserve vascular contractile function in coronary microvessels.

Preventive magnesium supplement reduces ischemia-induced hearing loss and blood viscosity in the guinea pig

“…This is also true of the vasodilative effect of Mg shown in several vascular systems [1,2,13,19,27]. Animal studies have shown that solutions >5 mmol/l Mg may prevent isolated coronary microvessels of ferrets from Ca 2+ -overloading during hypoxia and preserve vascular function during reoxygenation [19]. In our present study, the serum Mg level of the high Mg group was only 1.24 mmol/l.…”

“…However, the Mg values in serum were markedly increased (up to 4 mmol/l) in these studies. This is also true of the vasodilative effect of Mg shown in several vascular systems [1,2,13,19,27]. Animal studies have shown that solutions >5 mmol/l Mg may prevent isolated coronary microvessels of ferrets from Ca 2+ -overloading during hypoxia and preserve vascular function during reoxygenation [19].…”

Vascular changes after cardiopulmonary bypass and ischemic cardiac arrest: roles of nitric oxide synthase and cyclooxygenase

“…The mechanism of the positive effect of blood is uncertain but may be due to its potent inhibitory effects on oxygen-derived free radical generation, improved oxygenation of tissues (thereby decreasing the amount of vascular ischemia), buffering capacity of histidine and other blood proteins or preservation of morphological integrity of the endothelium (6,8). The addition of blood or magnesium to the cardioplegic solution prevents the depolarization and intracellular calcium accumulation during ischemic arrest, most likely by limiting calcium entry to the cytosol from the sarcoplasmic reticulum and extracellular space (56), and by limiting the derangement in responses mediated by the endothelium and those acting directly through the vascular smooth muscle (57). In addition, the use of continuous warm blood cardioplegia has been shown to better preserve coronary endothelium-dependent relaxation (53), although other studies have failed to demonstrate an improved effect over standard intermittent, cold blood cardioplegia (58).…”

Mg2+ blocks myogenic tone but not K+-induced constriction: role for SOCs in small arteries

“…Indeed, blood vessel tone can be modulated by [Mg 2ϩ ] o (1,23,36). Reduction of [Mg 2ϩ ] o increases tone.…”

“…Reduction of [Mg 2ϩ ] o increases tone. Conversely, elevation of [Mg 2ϩ ] o relaxes VSM: it dilates small spontaneously constricted arteries (i.e., those with MT) and attenuates agonist-evoked vasoconstriction (1,23 currents and Ca 2ϩ entry through LVGCCs in VSM or other cell types. Dihydropyridines (DHPs) such as nifedipine (Nif) are widely viewed as selective blockers of LVGCCs (10,34,38) and thus are potentially useful in distinguishing the role of LVGCCs from other channels, such as SOCs, in phenomena such as MT.…”