Effects Of Magnesium On The Contractile Response And Endothelium-dependent Relaxation In Pulmonary Arteries Of Pulmonary Hypertension Rats Induced By Monocrotaline

Pulmonary hypertension（PH）is a pathophysiological syndrome characterized by increased pulmonary vasoconstriction,pulmonary vascular remodeling,and free calcium ion concentration([Ca²⁺]_i)in pulmonary arterial smooth muscle cells（PASMCs）.Increased pulmonary vascular tension is a key factor in pulmonary vascular remodeling during PH.Mg²⁺is an important cation in the body,which is necessary for the normal life activities of cells and plays an important role in regulating vascular smooth muscle tension and endothelial cell function.The regulatory effect of Mg²⁺on vascular tension and reactivity can affect systemic pressure,which is the core of hypertension etiology.Epidemiological,experimental and clinical studies have confirmed that Mg²⁺plays an important role in hypertension vascular physiology.Mg²⁺has been proved to reduce pulmonary arterial pressure and improve cardiac output in the pulmonary arterial hypertension（PAH）model in rats,but the role of Mg²⁺in the regulation of PAH related pulmonary vascular function is still rare.In addition,studies have shown that the wall structure,vasoreactivity and proliferative capacity of the large proximal pulmonary arteries（PA）and the small distal pulmonary artery（sPA）are significantly different.There are significant differences in the reactivity to many vasoactive substances between them.In this study,In this study,the PAH model induced by monocrotaline（MCT）was established to observe the changes of the reactivity of PA and sPA to calcium channel activators during PAH and to compare the effects of Mg²⁺on the contraction of PA and sPA were induced to KCl,cyclopiazonic acid（CPA）,1-Oleoyl-2-acetyl-sn-glycerol（OAG）and endothelin-1（ET-1）.ET-1-induced intact PA and sPA were used to establish the cumulative concentration-response curves of ET-1.We observe the effect of Mg²⁺on endothelium-dependent vasodilation of PA and sPA during PAH,to study the mechanism of Mg²⁺regulating pulmonary vascular function in PAH,and provide a new theoretical basis for the treatment of PAH.Objective:To observe the effects of Mg²⁺on pulmonary vasoconstrictive effect and endothelium-dependent diastolic effect induced by various vasoactive drugs in the process of PAH,and to study the mechanism of Mg²⁺regulating pulmonary artery function and its changes in PAH,so as to provide new scientific research theoretical basis for the treatment of PAH.Methods:（1）Identify whether the MCT-induced PAH models were successfully prepared by detecting right ventricular pressure（RVP）and right ventricular mass index（RVMI）.（2）Use traditional vascular ring tension detection technique to measure the vascular effects of PA in CON and MCT rats.（3）Use DMT620M microvessel tension detection technique to determine the vascular effects of sPA in CON and MCT rats.Results:（1）The RVP and RVMI in MCT group were significantly higher than that in CON group,suggesting that the PAH models were successfully prepared.（2）The dehydration weight of unit vascular rings of PA and sPA was significantly greater than that of CON group,and internal circumference of vascular was reduced compared with CON group and ring Resting wall tention of vascular ring was increased compared with CON group,indicating pulmonary vascular hyperplasia and narrowing of lumen in MCT group.（3）The tension was standardized by unit weight of vessel ring dehydration.The results showed that sPA was more responsive to KCl,CPA,OAG and ET-1 than PA.（4）In normal-Mg²⁺solution（1.2 mM）,the response induced by KCl of PA and sPA in MCT group was not significantly changed.The maximal KCl response of PA and sPA in CON group and MCT group were significantly inhibited in high-Mg²⁺（4.8 mM）solution and in Mg²⁺-free solution.The attenuation of the maximal KCl response of PA in MCT group were more pronounced in high-magnesium solution.（5）In normal-Mg²⁺solution,the CPA response of PA and sPA in MCT group was increased compared with CON group.High Mg²⁺significantly inhibited the contraction of CPA induced endothelium-disrupted（EC^-）PA and sPA in CON group and MCT group.In the absence of Mg²⁺,the CPA responses of PA and sPA increased in CON group,while in MCT group showed no significant changes.（6）In normal-Mg²⁺solution the response induced by OAG of PA and sPA in MCT group was increased compared with CON group.High Mg²⁺significantly inhibited the contraction of OAG induced EC^-PA and sPA rings in CON group and MCT group.（7）In normal-Mg²⁺solution the response induced by ET-1 of EC^-and endothelium-intact（EC⁺）PA and sPA in MCT group was increased compared with CON group.The maximal ET-1 response of PA and sPA in CON group and MCT group were significantly inhibited in high-Mg²⁺solution and in Mg²⁺-free solution.High Mg²⁺further inhibited the contractile effects of PA and sPA in MCT group.（8）In normal-Mg²⁺solution,the vascular response of EC⁺PA to ET-1 in CON group and MCT group was lower than that in the EC^-group,while the vascular response of EC⁺sPA in CON group and MCT group was significantly lower than that in the EC^-group.The inhibitory effect of high Mg²⁺on EC⁺PA and sPA in CON group was more significant than that of EC^-PA and sPA,but the depressed effect of high Mg²⁺on EC⁺PA in MCT group was not different.However,The attenuation of high Mg²⁺on EC⁺sPA of MCT group was more significant than that of CON group.Conlcusions:（1）The reactivity of PA and sPA to CPA,OAG and ET-1 in PAH models was significantly higher than that in CON group.The reactivity of sPA to various angioagonists during PAH was higher than that of PA.（2）High Mg²⁺may inhibit the contraction of PA and sPA by inhibiting the Ca²⁺influx mediated by these three different types of calcium channel agonists in combination with the Ca²⁺competitive action,or by affecting the agonist-contraction coupling and altering the reactivity of the vessel to the vascular agonist.（3）High Mg²⁺can direct effects on vascular smooth muscle cells（VSMCs）and vascular endothelial cells（VECs）cause vasodilation,also can promote endothelium-dependent relaxing function by regulating endothelial function.