Nitric oxide, endothelium‐derived hyperpolarizing factor, and smooth muscle‐dependent mechanisms contribute to magnesium‐dependent vascular relaxation in mouse arteries
Olga Kudryavtseva, Kristina S. Lyngsø, Boye L. Jensen, Henrik Dimke
Abstract
Abstract Aim Magnesium (Mg 2+ ) 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 Ca 2+ antagonization and TRPM7 channels in vascular smooth muscle cells mediate Mg 2+ ‐dependent vessel relaxation. Methods To uncover these mechanisms, force development was measured ex vivo in aorta rings from mice using isometric wire myography. Concentration responses to Mg 2+ 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 Mg 2+ on NO formation were measured in Chinese Hamster Ovary (CHO) cells, isolated mesenteric vessels, and mouse urine. Results Mg 2+ 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. Mg 2+ stimulated local NO formation in CHO cells and isolated mesenteric vessels without changing urinary NOx levels. High extracellular Mg 2+ augmented acetylcholine‐induced relaxation. SK Ca and IK Ca channel blockers apamin and TRAM34 inhibited Mg 2+ ‐dependent relaxation. The endothelium‐independent relaxation in aorta rings was inhibited by high extracellular Ca 2+ . Combined blockade of NO, SK Ca , and IK Ca channels significantly reduced Mg 2+ ‐dependent dilatation in mesenteric resistance vessels. Conclusions In mouse conductance and resistance arteries Mg 2+ ‐induced relaxation is contributed by endothelial NO formation, EDHF pathways, antagonism of Ca 2+ in smooth muscle cells, and additional unidentified mechanisms.