| Objectives:In order to study the changes of vascular endothelial function and ERK/CREB signaling pathway in rats with acute myocardial infarction (AMI) and the interventional effects of olmesartan medoxomil , the effects of olmesartan medoxomil on blood pressure, endothelial vasomotor effects of isolated thoracic aorta strips,levels of blood NO,AngⅡ,activities of NOS, myocardial infarct area,the expressions of myocardial ERK mRNA and CREB mRNA were explored.Methods:(1)Development of rat models with AMI and experimental grouping: AMI was induced by ligation of the left coronary artery in male Sprague-Dawley rats. Twenty-four survivors within 24 hours after operation were randomized into three groups: The AMI group(n=8);The OML group(n=8),olmesartan medoxomil(1mg/kg/d)was administered;The OMH group(n=8), olmesartan medoxomil(3mg/kg/d)was administered. The Sham group was served as a control group(n=7). Olmesartan medoxomil was administered through gavage 24 hours after operation for 2 weeks. The Sham group and the AMI group were fed with vehicle in the same volume and the same method.(2)Contents surveyed:①Systolic blood pressures taken through tail artery:They were measured before operation, 24 hours after operation (before gavage) and week 1 and week 2 ;②Levels of serum NO and activities of NOS: Blood samples were drawn through postorbital vein 2 weeks after operation . Levels of serum NO and activities of NOS were measured using nitrate reductase method;③levels of AngⅡ: Blood samples were drawn through postorbital vein 2 weeks after operation . Levels of plasma AngⅡwere measured by radioimmunity assay method;④Vascular vasomotor effects of isolated thoracic aorta strips:Animals were put to death,then thoracic aortas were harvested 2 weeks after operation and were cut into strips for isolated perfusion experiment on contraction to phenylephrine(PE),endothelium-dependent diastole to acetylcholine(Ach)and non-endothelium-dependent diastole to sodium nitroprusside(SNP);⑤Pathological changes of heart tissue and myocardial infarct area: Left ventricles were cut along cross-sections immediately after the death of rats and then made into paraffin sections. The percentage between the lengths of cardiac scar and those of circumference stands for the myocardial infarct area by applying HE staining;⑥Gene expressions of ERK and CREB in myocardium:The mRNA expressions of myocardial ERK and CREB were half-quantitated by reverse transcriptase-polymerase chain reaction(RT-PCR) method. Results:(1) Systolic blood pressures taken through tail artery:Systolic blood pressures taken through tail artery at different time did not have significant differences in different groups; (2) Levels of serum NO and activies of NOS: Compared with those in the Sham group, levels of serum NO and activities of NOS in the AMI group were much lower and the differences were significant;levels of serum NO and activities of NOS in group OML and group OMH were obviously higher compared with those in AMI group,and almost reached the similar levels to Sham group. The levels of NO and acticities of NOS in the OMH group were higher than those in the OML group,but the differences were not significant. (3) Plasma levels of AngⅡ: Compared with those in the Sham group, levels of plasma AngⅡin the AMI group, the OML group and the OMH group were much higher, The differences were significant;The difference between AMI group and OML group were insignificant;The difference between AMI group and OML group were insignificant;the levels of plasma AngⅡin OMH group was distinctly higher than those in AMI group and OML group,p<0.05 . (4) Endothelial vasomotor effects of isolated thoracic aorta strips:Compared with Sham group,EDD in the AMI group decreased seriously,P<0.05;OML group and OMH group were all significantly impaired;After the treatment of olmesartan medoxomil,EDDs in isolated aortic strips improved greatly,there were predominant differences among the two therapic groups and AMI group. OMH group seemed to have a better tendency to improve EDDs than OML group,but the difference was insignificant. On the other hand,contraction to PE and the NEDDs to SNP were not affected in all groups (P﹥0.05);(5) HE dyeing of heart tissue and the calculation of myocardial infarction area:Heart tissue showed normal HE dyeing features in group Sham;On the other hand,at infarction zones in the AMI group,the OML group and the OMH group,myocardial dissolution,fragmentation,inflammatory infiltration, fibroblast infiltration and formation of granalation tissue were obviously seen. At non-infarction zones cardiac muscles arranged regularly;olmesartan medoxomil can decrease the size of myocardial infarct in a dose-dependant manner;(6) Gene expressions of ERK and CREB in myocardium:Expressions of myocardial ERK mRNA and CREB mRNA were low in the Sham group;they were higher in the AMI group;olmesartan medoxomil could decrease the expressions of myocardial ERK mRNA and CREB mRNA in a dose-dependant manner.Conclusions: (1) Endothelial dysfunction (ED) occurs 2 weeks after AMI in SD rats.(2) Plasma AngⅡincreases after AMI and the increase is associated with elevated gene expression of ERK and CREB in myocardium;this hints that the occurrence of ED after AMI may be related to the upregulation of genetic expressions in ERK/CREB signaling pathway by AngⅡthrough AT1R;(3) Olmesartan medoxomil can greatly improve the disordered endothelial function after AMI and decrease the size of myocardial infarction.;(4) Olmesartan medoxomil can decrease the myocardial expressions of ERK mRNA and CREB mRNA in AMI rats in a dose-dependent manner. It hints that olmesartan medoxomil may downregulate the genetic expressions of ERK/CREB signaling pathway through the inhibition of AT1R. But the association between the downregulation and endothelial function needs to be further investigated;(5) The protective effect of olmesartan medoxomil on endothelial function in AMI rats is independent on blood pressure lowering.
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