Effects Of Low-dose Sevoflurane On PAH Rats’Circulatory Function Through INOS/sGC Signaling Pathway

Objective:In this study, we induced experimental PAH rats with a single intraperitoneal injection of monocrotaline to observe the effects of different doses sevoflurane on rats’ circulatory function. And we explored the role of iNOS/sGC signaling pathway in the effects of sevoflurane on PAH rats’ circulatory function.Methods:1.Induction of experimental pulmonary arterial hypertension:30male SD rats were randomly assigned to group M (n=15) or group C(n=15), In group M, rats were intraperitoneal injected with60mg/Kg monocrotaline, In group C, rats were treated with the solvent. Four weeks later, animals were anesthetized and treated with thoracotomy. And the hemodynamic data were continuously recorded, the RV/(LV+S) ratio and the RV/LV wall thickness ratio were calculated, HE staining.was performed to evaluate the pathology changes of the pulmonary artery.2.Effects of low-dose sevoflurane inhalation on rats’ hemodynamics:75male SD rats were randomly assigned to group M (n=45) or group C(n=30), PAH modle induction as described above. Four weeks later, animals were anesthetized and treated with thoracotomy. Each rat was exposed to stepwise increasing doses (0.5%,1.0%, and1.5%) of sevoflurane, and the effects of different doses sevoflurane on rats’circulatory function were observed.3.Immunoassay of protein iNOS&sGC in right ventricle myocardium:Western blot was performed to assess the expression level of protein iNOS and sGC in RV myocardium.Results:1. Induction of experimental pulmonary arterial hypertension:①Hemodynamics:Mean pulmonary arterial pressure was higher in group M;③Mean RV weight of group M was statistically heavier than group C, as was the ratio of the right over left ventricle wall thickness (P<0.05);③HE staining:Compared with group C, rat in group M had a thicker pulmonary arterial wall and its small pulmonary artery was more stenosed.2. Effects of low-dose sevoflurane inhalation on rats’hemodynamics:①As the doses of sevo stepwise increased, the mPAP, heart rate, dp/dtmax, MAP of rat in group M gradually decreased, and the cardiac output, eject fraction, stroke volume increased at dose of0.5%, but decreased at1.0%and1.5%, and group C had a similar result.②PAH rats preserved more cardiac output, stroke volume, myocardial contractility and heart rate;3. Immunoassay of protein iNOS&sGC in right ventricle myocardium:①The expression level of iNOS is higher in group M (P<0.05);②The expression level of iNOS was up-regulated after low-dose sevoflurane inhalation in both group M and group C.③The expression level of sGC was down-regulated after low-dose sevoflurane inhalation in group M (p<0.05), but remained unchanged in group C (P>0.05).Conclusions:1. The experimental PAH model can be successfully induced by60mg/Kg monocrotaline.2.In both PAH and normal rats, the circulatory function was suppressed by low-dose sevoflurane, however PAH were more tolerant to low-dose sevoflurane inhalation,3. The expression level of sGC was down-regulated after low-dose sevoflurane inhalation in PAH rats, and this may be one of the reasons why PAH rats were more tolerant to low-dose sevoflurane inhalation.