Effects Of Magnesium Sulfate On Hemodynamics And Vasoactive Factors In Rabbit With Pulmonary Arterial Hypertension

Background and ObjectivePulmonary arterial hypertension (PAH) is a common clinical disease due to various causes which lead to the pulmonary arterial pressure continuously increases and develops progressively. The normal pulmonary circulation is of low resistance and low pressure, and the artery systolic pressure of the resting pulmonary is 18～25mmHg, and the mean pulmonary arterial pressure of it is 12～16mmHg. PAH can causes acute pulmonary heart disease even right ventricular failure, it can endanger the patient's life, therefore the therapy of PAH is an important clinical issue. There are a lot of causes to PAH during perioperative period, and pulmonary thromboembolism (PTE) is the commonest cause of PAH. The mechanism of PAH due to PTE includes mechanical plug and the role of vasoactive factors. In the past, it was believed that the former plays an important role in the formation and development of PAH. But subsequently many studies and experimental results did not support this theory. Now it is believed that the vasoactive factors play an important role in the formation and development of PAH, especially in the early period. It has been reported that the concentration of vasoconstrictive factors endothelin-1 (ET-1) and thromboxane A₂ (TXA₂), and vasodilatation factor prostacyclin (PGI₂) changed in occurrence of PAH. Accordingly, study the changes of the vasoactive factors in the occurrence of PAH, and how to relax the blood vessels and reduce pulmonary artery pressure with drugs, it is an important issue. Magnesium sulfate is a vasodilator, Magnesium ion (Mg²⁺) is a natural antagonist to calcium (Ca²⁺), and high concentration of Mg²⁺ blocks the influx of Ca²⁺, and it can also inhibit the hypoxic pulmonary vasoconstriction (HPV), through which relaxes the vessels; It can reduce the pulmonary vascular contractile response to norepinephrine, histamine and other vasoactive substances and promote the angiectatic response of pulmonary vessels; Anti-thrombosis; It promotes the secretion of prostaglandins and metabolins, and inhibits the release of catecholamine, and inhibits the vascular contraction. Magnesium sulfate has been reported to be used in the therapy of persistent pulmonary arterial hypertension of newborn (PPHN). However, magnesium sulfate has not been reported for the therapy of PAH of adults or PAH during perioperative period. As PGI2 and TXA2 are extremely unstable in vivo, we measure their stable metabolites 6-keto-prostaglandin Fla(6-keto-PGFla)and thromboxane B₂ (TXB₂) to explore their pathophysiological changes in the formation and development of PAH due to PTE.The purpose of this study is to establish the model of rabbit pulmonary arterial hypertension due to pulmonary thromboembolism, and to investigate the changes of hemodynamics and concentration of plasma ET-1, 6-keto-PGFla, TXB₂ in pulmonary arterial hypertension due to PTE, and the effects of magnesium sulfate on them, and to provide a theoretical base for the reasonable use of magnesium sulfate in the clinical therapy of pulmonary arterial hypertension due to pulmonary thromboembolism.Materials and Methods40 Chinese big-ear rabbits were randomly divided into four groups: control group (nl=10), magnesium sulfate group I , II, III(n2=n3=n4=10). The rabbits were anesthetized with 3% pentobarbital sodium intravenous injection. Insert a catheterization to the left carotid artery to monitor systemic arterial pressure and Insert a catheterization to the pulmonary artery to monitor pulmonary artery pressure. after the coagulation of rabbit venous blood, it was heated by aqueous water bath, and then made the thrombus. All groups were injected with four thrombuses in 3 minutes with the help of 5 ml saline injection. Injected autologous thrombus through the right internal jugular vein catheterization to establish the pulmonary arterial hypertension model of rabbit. After the injection, magnesium sulfate I, II, III treatment groups were infused (micro pump)with 10% magnesium sulfate injection at the bolus doses of 150mg·kg-1 ,200mg·kg-1 and 250mg·kg-1 respectively in 15minutes,and then at the maintenance dose of 150 mg·kg-1·h-1, 200 mg·kg-1·h-1 and 250 mg·kg-1·h-1 respectively at the end of the experiment and control group with saline. Before injection of thrombus (T1), 15 minutes after injection of thrombus (T2), 30 minutes (T3),60 minutes (T4), 90 minutes (T5), 120 minutes (T6). Records T1-T6 systemic mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP). Collected3.0 ml blood sample, separated and stored it according to instruction. The concentration of ET-l,6-keto-PGFl and. TXB2 were measured by radioimmunoassay (RIA). Did the anatomy and pathological section of lung after the end of experiment, and observed the pathological changes of lung after PTE. Parameters measured using parameters±standard deviation ( x|-±s ). Statistical analysis was analyzed with software SPSS 10.0 using Student-Newman-Keuls (SNK) test and analysis of variance of repeated measurement. P<0.05 is considered as statistically significant.Results1. hemodynamic and pathological changes1.1 MPAPSelf comparisons: After the injection of thrombus, MPAP of the control group rose significantly, and MPAP of T2～T6 were significantly higher than that of T1 (P<0.05), and it achieved peak at T3, and at the end of the experiment (T6), it was still significantly higher than that of T1 (P<0.05). With magnesium sulfate group I MPAP of T2-T5 were significantly higher than that of T1 (P<0.05). With magnesium sulfate group III MPAP of T6 was significantly lower than that of T1 (P<0.05).Comparisons between groups: With magnesium sulfate group I, there were no significant differences compared with that of control group (P>0.05).With magnesium sulfate group II, III, their MPAP of T2-T6 were significantly lower than those of control group at the same timepoint (P<0.05).With magnesium sulfate group III MPAP of T3 ,T5 were significantly lower than those of group I of the same timipoint (P<0.05), and MPAP of T6 was significantly lower than that of group II at the same timepoint (P<0.05).1.2 MAPSelf comparisons: After the injection of thrombus MAP of the control group descended significantly, and MAP of T5,T6 were significantly lower than that of T1 (P<0.05). With magnesium sulfate group I, MAP of T5, T6 were significantly lower than that of T1 (P<0.05). With magnesium sulfate group III MAP of T3-T6 were significantly lower than that of T1 (P<0.05).Comparisons between groups: With magnesium sulfate group I, there were no significant differences compared with control group at the same timepoint (P>0.05). With magnesium sulfate group III MAP of T6 was significantly lower than that of control group and magnesium sulfate group II (P<0.05).1.3 Pathological changesThe pathological results are consistent with the pathological changes of pulmonary arterial hypertension due to pulmonary embolism.2. Vasoactive factor2.1 ET-1Self comparisons: After the injection of thrombus, ET-1 concentration of the control group rose gradually, ET-1 concentration of T6 was significantly higher than that of T1 (P <0.05). With magnesium sulfate group I , II there were no significant differences between ET-1 concentration of each timepoint and that of T1 (P> 0.05). With magnesium sulfate group III ET-1 concentration of T6 were significantly higher than that of T1 (P <0.05).Comparisons between groups: With magnesium sulfate group II ET-1 concentration of T6 was significantly lower than that of control group of T6 (P <0.05).With magnesium sulfate group III ET-1 concentration of T6 was significantly lower than that of magnesium sulfate group I, II (P <0.05).2.2 6-keto-PGFlaSelf comparisons: After the injection of thrombus, 6-keto-PGFla concentration of the control group rose significantly, and it achieved peak at T3, and descended subsequently (P<0.05). 6-keto-PGFla concentration of magnesium sulfate group I, II, IIIboth achieved peak at T3. With magnesium sulfate group I 6-keto-PGFla concentration of T2-T5 were significantly higher than that of T1 (P<0.05). With magnesium sulfate group II, 6-keto-PGFla concentration of T2～T6 were significantly higher than that of T1 (P<0.05). With magnesium sulfate groupIII 6-keto-PGFla concentration of T3 was significantly higher than that of T1 (P<0.05).Comparisons between groups: With magnesium sulfate group II, 6-keto-PGFla concentration of T3, T6 were significantly higher than those of control group at the same timepoint (P<0.05), and 6-keto-PGFla concentration of T6 was significantly lower than that of magnesium sulfate group I (P<0.05). With magnesium sulfate group III, 6-keto-PGFla concentration of T4, T5 were significantly lower than those of magnesium sulfate group II at the same timepoint (P<0.05)2.3 TXB2Self comparisons: After the injection of thrombus, TXB2 concentration of the control group rose, TXB2 concentration of T2-T6 were significantly higher than that of T1 (P<0.05), and it achieved peak at T4, and it descended subsequently. With magnesium sulfate group I TXB2 concentration of T3-T6 were significantly higher than that of T1 (P<0.05). With magnesium sulfate group III TXB2 concentration of T5,T6 were significantly higher than those of T1 (P<0.05).Comparisons between groups: With magnesium sulfate group II TXB2 concentration of T3-T6 were significantly lower than those of control group at the same timepoint (P<0.05), and TXB2 concentration of T3-T5 were significantly lower than those of magnesium sulfate group I at the same timepoint (P<0.05). With magnesium sulfate group III, TXB2 concentration of T3, T4 were significantly lower than those of control group at the same timepoint (P<0.05).Conclusions1. Changes of concentration of plasma ET-1, 6-keto-PGFla and TXB2 are involved in the pathophysiological process of pulmonary arterial hypertension due to pulmonary thromboebolism.2. Magnesium sulfate regulates the pulmonary arterial pressure of pulmonary arterial hypertension due to pulmonary thromboebolism through affecting the concentration of plasma ET-1,6-keto-PGFla and TXB2.3. In rabbit undergoing pulmonary arterial hypertension, the micro pump infusion of magnesium sulfate ,at the maintenance dose of 200 mg·kg-1·h-1 after the bolus dose of 200 mg·kg-1 ,reduces the mean pulmonary arterial pressure significantly, while impacting on systemic mean arterial pressure slightly. It is a reasonable dose in the therapy of rabbit undergoing pulmonary arterial hypertension due to pulmonary thromboebolism.