| Haloperidol (Hal) is an antipsycotic agent, but our past researches showed that Hal had vasodilation and anti-myocardial ischemia effects. However, its adverse effects on extrapyramidal system limited large sample observation. It was imaged to change the structure of Hal . So a polar group was linked to hydrogen atom of piperidine in Hal. A newly-structure compound was synthesized . It is named as quateranary ammonium salt derivative(F2) of haloperidol , N-n-butyl haloperidol iodide. Because the lipid solubility was lessened, it was impossible to pass through blood -brain barrier and difiuse into brain. So the central nerve reaction might be avoided, but the obvious cardial and vascular effects were preserved. Our previous researches also have shown that F2 can antagonize the reduction of coronary flow induced by pituitrin on isolated heart of guinea-pig. It can also block the pig coronary arterial strips contraction induced by KC1 . In the study by using laser scanning confocal microscopy, the results have shown that F2 can decrease the intracellular calcium fluorescence intensity. Its mechanism of reducing the intracellular calcium level may be due to the effect of blocking the calcium channel. F2 could open the potassium channel in the experimentby the use of whole-cell patch clamp recording technique. In order to father study the effects of F2 in vivo and the mechanisms of vasodilation and anti-myocardial ischemia , an in vivo animal model of myocardial ischemia and reperfusion injury was designed to study the effects of F2 on myocardial ischemia and reperfusion injury by using verapamil as positive control. The effects of F2 on L-type calcium current were investigated with single enzymatically -dissociated ventricular myocyte by using patch clamp techniques in whole-cell recording configuration. The results are reported as follows.The effects of F2 on myocardial ischemia and reperfusion injury 1. The effects of F2 on myocardial enzymes (CK, CK-MB, LDH, HBDH, GOT) , SOD and MDA in ischemic and reperfused rat heartsThe in vivo animal model of myocardial ischemia and reperfusion injury was reconducted by occluding the left anterior descending branch of coronary artery for 30 min and removing the ligation later to reperfuse for 30 min. Ver (2mg kg"1) and different dosages of F2 (Img kg"1, 2mg' kg"1, 4mg kg"1, respectively) was intravenously injected before heart ischemia. Serum Creatine Kinase (CK), Creatine Kinase isoenzyme MB(CK-MB), Lactate dehydrogenase (LDH), a -Hydroxybutyrate dehydrogenase (HBDH), Grutamic-oxalacetic transaminase (GOT), Superoxide dismutase (SOD) activity and Malondiadehyde (MDA) contents were measured .The results showed that CK, CK-MB, LDH,HBDH, GOT, MDA were increased and SOD was decreased in the I/R group(vs sham proup, p<0.01). Ver, used as positive control, could decrease the concentration of CK, CK-MB, LDH, HBDH, GOT , MDA and increase the SOD activity(vs I/R proup, p<0.01). F2 also reduced the release of CK, CK-MB, LDH, HBDH, GOT from ischemic and reperfused rat hearts, increased the activity of SOD and decreased the MDA contents in dose-dependent manner (p<0.05, or p<0.01 vs I/R group) .The effect of F2 (4mg kg"1) on CK-MB was remarkable than Ver (2mg kg1) QK0.05).2. The effects of F2 on the pathological changes of myocardium in ischemic and reperfused rat heartsThe in vivo animal model of myocardial ischemia and reperfusion injury was reconducted by occluding the left anterior descending branch of coronary artery for 30 min and removing the ligation later to reperfuse for 30 min. Ver (Img'kg"1) and different dosages of F2 (Img kg"1, 2mg" kg"1, 4mg' kg"1, respectively) was intravenously injected before heart ischemia. After reperfusion had been finished, small pieces of myocardium at cardial apex were collected immediately and were cut into fragments(diameter=lmm). Then they were fixed in 2.5% glutaraldehyde, post-fixed with 2% osmium tetroxide, dehydrated with the graded series of ethanol, passed through propyleneoxide, and then embedded in PDAP. Ultra... |
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