Nitric oxide, endothelium-derived hyperpolarizing factor, and smooth muscle-dependent mechanisms contribute to...

Magnesium (Mg²⁺ ) is a vasorelaxant. The underlying physiological mechanisms driving this vasorelaxation remain unclear. Studies were designed to test the hypothesis that multiple signaling pathways including nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) in endothelial cells as well as Ca²⁺ antagonization and TRPM7 channels in vascular smooth muscle cells mediate Mg²⁺ -dependent vessel relaxation.

To uncover these mechanisms, force development was measured ex vivo in aorta rings from mice using isometric wire myography. Concentration responses to Mg²⁺ were studied in intact and endothelium-denuded aortas. Key findings were confirmed in second-order mesenteric resistance arteries perfused ex vivo using pressure myography. Effects of Mg²⁺ on NO formation were measured in Chinese Hamster Ovary (CHO) cells, isolated mesenteric vessels, and mouse urine.

Mg²⁺ caused a significant concentration-dependent relaxation of aorta rings. This relaxation was attenuated significantly in endothelium-denuded aortas. The endothelium-dependent portion was inhibited by NO and cGMP blockade but not by cyclooxygenase inhibition. Mg²⁺ stimulated local NO formation in CHO cells and isolated mesenteric vessels without changing urinary NOx levels. High extracellular Mg²⁺ augmented acetylcholine-induced relaxation. SK_Ca and IK_Ca channel blockers apamin and TRAM34 inhibited Mg²⁺ -dependent relaxation. The endothelium-independent relaxation in aorta rings was inhibited by high extracellular Ca²⁺ . Combined blockade of NO, SK_Ca , and IK_Ca channels significantly reduced Mg²⁺ -dependent dilatation in mesenteric resistance vessels.

In mouse conductance and resistance arteries Mg²⁺ -induced relaxation is contributed by endothelial NO formation, EDHF pathways, antagonism of Ca²⁺ in smooth muscle cells, and additional unidentified mechanisms.