Magnesium attenuates endothelin-1-induced vasoreactivity and enhances vasodilation in mouse pulmonary arteries: Modulation by chronic hypoxic pulmonary hypertension

Abstract

Pulmonary hypertension (PH) is characterized by enhanced vasoreactivity and sustained pulmonary vasoconstriction, arising from the aberrant Ca²⁺ homeostasis in pulmonary arterial smooth muscle cells. In addition to Ca²⁺, magnesium, the most abundant intracellular divalent cation, also plays critical roles in many cellular processes that regulate cardiovascular functions. Recent findings suggested that magnesium regulates vascular functions by altering the vascular responses to vasodilator and vasoactive agonists, and affects endothelial function by modulating endothelium-dependent vasodilation in hypertension. Administration of magnesium also decreased pulmonary arterial pressure and improved cardiac output in PH animal models. However, the role of magnesium in the regulation of pulmonary vascular function related to PH has not been studied. This study examined the effects of magnesium on endothelin-1 (ET-1)-induced vasoconstriction, acetylcholine (Ach)-induced vasodilatation, and the generation of nitric oxide (NO) in pulmonary arteries (PAs) of normoxic and chronic hypoxia (CH)-treated mice. Our data showed that removal of extracellular magnesium suppressed vasoreactivity of PAs to both ET-1 and Ach. High concentration of magnesium (4.8 mm) inhibited ET-1-induced vasoconstriction in endothelium intact or disrupted PAs of normoxic and CH mice, and enhanced the Ach-induced NO production in PAs of normoxic mice. Moreover, magnesium enhanced Ach-induced vasodilatation in PAs of normoxic mice, and the enhancement was completely abolished after CH exposure. Hence, this study demonstrated that increasing magnesium concentration can attenuate ET-1-induced contractile response, and improve vasodilatation via release of NO from endothelium; and chronic exposure to hypoxia can cause endothelial dysfunction resulting in the suppression of magnesium-dependent modulation of vasodilatation.

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