Remodeling And The Effects Of Telmisartan On Intramyocardial Small Arteries In Diabetic Spontaneously Hypertensive Rats

ObjectiveTo investigate features and cytological mechanisms of intramyocardial small arteries (IMSAs) remodeling in diabetic spontaneously hypertensive rats(DSHR), and to study the effects of telmisartan.Methods12-week-old male SHRs were randomized to 4 groups (all n=10), including untreated SHR group,DSHR group, telmisartan low dose(TelL) group,telmisartan high dose(TelH) group.Rats of TelL and TelH received telmisartan 0.5 mg? kg-1?d-1,5mg?kg-1?d-1 by intragastric administration respectively. Age and sex matched Wistar Kyoto rats were served as control group {WKY group and Diabetic WKY (DWKY)group,all n=10}. All animals were transiently anesthetized with ether by inhalation to allow injection of either STZ or its vehicle into the intraperitoneal. Diabetes was induced by a single intraperitoneal injection of STZ (50 mg/kg) dissolved in citrate buffer (pH 4.4). Control rats were injected with citrate buffer alone.After 8 weeks intervention,hemodynamics index of rats were measured before rats being sacrificed. Morphological characteristics were evaluated with HE, Sirus-red, elasticity fibrin and collagen fibrin double staining (P/VB). Wall area (WA), lumen area (LA) and percent wall area (%WA) of IMSAs were assessed with the compute-assisted image analysis system.Type III collagen expression of different group were studied by SP immunohistochemical methods.The apoptosis and proliferation of intramyocardialarterial smooth muscle cells were detected by in situ end labeling technique (TUNEL) and proliferating cell nuclear antigen (PCNA) immunohistochemistry staining respectively. Mast cells were demonstrated with toluidine blue staining.Results1. Glucose:There was no difference between glucose of SHR group and WKY group, similar results were also seen for DSHR group when compared with DWKY group, Injecting animals with STZ resulted in a diabetic state with an elevated glucose(P <0.01) .2. Changes of hemodynamics: Mean arterial pressure(MAP),left ventricular systolic pressure(LVSP),left ventricular end-diastolic pressure(LVEDP)and the maximum rate of left ventricular pressure rise (dp/dtmax) of SHR group were much higher than those of WKY group (P <0.01);LVSP and dp/dtmax of DWKY group were lower than those of WKY group;LVSP and dp/dtmax of DSHR group were much lower than those of SHR and DWKY group (P <0.01);MAP of DSHR and SHR are kept on the same level.3. WA and %WA:Compared with WKY group, WA and %WA of IMSAs were increased and LA was decreased in SHR group (P <0.01 for each);Similar results were also seen for DWKY when compared with WKY group;Compared with SHR group and DWKY group, WA and %WA of IMSAs were increased and LA was decreased in DSHR group (P <0.01 for each);WA and %WA in TelH group were lower, but LA was greater than DSHR group (P<0.01 for each). Compared with DSHR group, LA were greater and %WA were reduced in TelL group (P <0.05 for each), but WA was no difference between both groups.4. PI and AI:The proliferation index (PI) and the apoptosis index (AI) of intramyocardial arterial media in SHR group and DWKY group were strikingly higher than that in WKY group(P <0.01 for each); Similar results were also seen for DSHR group when compared with DWKY group and SHR group(P<0.01) . AI of IMSAs media in SHR group and DWKY group were both higher than that in WKY group(P <0.01).5. IMSAs density: There was a significant decrease in myocardial arteriolar density in DSHR when compared to SHR and DWKY rat(P <0.01). 6. The mean integrated optical density(IOD)of type III collagen: The mean IOD of type III collagen in LV of DSHR group were remarkably higher than that of SHR group(P <0.01).7. IOD of type III collagen in LV of DSHR were positively correlated with %WA of IMSAs (r=0.842).8. Effects of Telmisartan: When glucose of DSHR was compared with telmisartan groups, there was no difference among the groups; LVSP, and dp/dtmax of TelH group were significantly increased compared to those of DSHR group;However, the same effects were scarcely found in TelL group, except LVEDP(P <0.01).LVEDP of both group were significantly decreased compared to that of DSHR group; PI of TelH and TelL group were remarkably lower than that of untreated DSHR(P <0.01),and there was a significant difference between both group(P <0.01),AI of TelH and TelL group were remarkably higher than DSHR group (P <0.01 and P <0.05),AI of TelH group was greater than TelL group(P <0.01); The number of IMSAs in TelL and TelH group were greater than DSHR group. The number of IMSAs in TelL was smaller than that in TelH group (P <0.01). The mean IOD of type III collagen of TelL and TelH group were lessened when compared with DSHR group (P <0.01, for each).Conclusions1. The apparent changes of IMSAs remodeling were observed in 20-week-old SHR/DWKY and DSHR. The combination of hypertension and diabetes was accompanied by higher IMSAs remodeling than that seen with either disorder alone. This remodeling was represented with increasing in the vessel media wall area and type III collagen expression of perivascular and rarefaction of IMSAs.2. Both proliferation and apoptosis of VSMC in arterial media may play an important role in the pathogenesis of IMSAs remodeling in SHR/DWKY and DSHR.3. Telmisartan could attenuate significantly the IMSAs remodeling in DSHR. The mechanisms might involve the following factors lowing blood pressure, inhibiting expression of type III collagen, decreasing proliferation and increasing apoptosis of VSMC, and reversing rarefaction of IMSAs.