Loe-dose Sevoflurane Effects Right Ventricular Contractility In Pulmonary Arterial Hypertension Rats Through SERCA2-PLB Pathway

Objective:To observe the effects of low-dose sevoflurane on the right ventricular (RV) function in pulmonary arterial (PA) hypertension rats, and to investigate the role of SERCA2-PLB pathway in the mechanism.Methods:Adult male Sprague-Dawley rats were divided randomly into control group and model group, The rats in model group were received a single subcutaneous injection of monocrotaline (60mg/kg), the same volume solvent was performed in the control group. Twenty-eight days later, the rats in control group and model group were divided randomly into two groups with or without sevoflurane inhalation, respectively. The rats in sevoflurane inhalation group were anesthetized and underwent dose-responses to sevoflurane inhalation (0.5%、1.0%、1.5%), the rats in another group were accepted the same anesthesia and instrumentation but without sevoflurane inhalation. The femoral artery and femoral vein were catheterized for fluid infusion and systemic arterial pressure monitoring. Pulmonary artery were catheterized to monitor pulmonary arterial pressure in experiment1, and a conductance catheter was inserted into the RV to evaluate RV function in experiment2. Various hemodynamic parameters and PV Loops were recoreded at baseline(0/T0)、0.5%(T1)、1.0%(T2)、1.5%(T3). Arterial blood samples were collected for blood gas analysis before and after sevoflurane inhalation. RV contractility was assessed by end-systolic elastance (Ees)、 preload recruitable stroke work(PRSW) and dp/dtmax-end diastolic volume relationship(dp/dtmax-EDV), RV afterload was assessed by effective pulmonary arterial elastance (Ea), and RV-PA coupling efficiency was assessed by the Ees/Ea ratio. After sacrifice of the rats, the hearts were removed for morphometric analysis. The RV hypertrophy was assessed by the ratio of RV over left ventricular wall thickness and the weight of RV over left ventricle ratio. HE staining was performed to observe the tissue morphology. The expression of SERCA2and PLB in the RV were surveyed by Western blot analysis.Results:1. Rats injected with monocrotaline presented with increased pulmonary arterial pressure and RV hypertrophy, increased Ea、 Ees、PRSW and dp/dtmax-EDV (P<0.05for all variables), without change in cardiac output(CO) and Ees/Ea ratio (P>0.05). The ratio of RV over left ventricular wall thickness and the weight of RV over left ventricle ratio were increased obviously (P<0.001).2. Sevoflurane produced dose-dependent decreased of systolic and pulmonary hemodynamics, i.e., MAP、mPAP and HR (P<0.05for all variables), and increased R/L ratio (P<0.001).3. Sevoflurane had similar effect on RV function in the control and model rats. In the control group, sevoflurane decreased Ees、PRSW、 dp/dtmax-EDV and CO (P<0.001for all variables), decreased Ees/Ea ratio(about24%at1.5%, P<0.001), but without change in Ea(P>0.05). In the model group, sevoflurane had similar RV effects as in the control group, but Ea decreased (P=0.004).4. Western blotting:Compared with that in control group, the expression of SERCA2in the model group decreased (P<0.001), and the expression of PLB increased (P<0.001), SERCA2/PLB ratio increased significantly (P<0.001). Sevoflurane reduced the expression of SERCA2and increased the expression of PLB both in control and model group, with SERCA2/PLB ratio decreased.Conclusion:1. Sevoflurane impairs RV contractility and RV-PA coupling in puimonary hypertension rats.2. SERCA2-PLB pathway is involved in the effect of pulmonary arterial hypertension on RV function。3. Sevoflurane reduces the expression of SERCA2in RV, witch may related to decreased RV contractility.