| Haloperidol (Hal) is an antipsychotic agent. Our previous research showed that Hal could noncompetitively antagonize the contraction of coronary artery induced by phencyclidine, agonists of opioid receptor, and noradrenaline, etc. However, it was not used as an anti-myocardial ischemia drug due to its extrapyramidal adverse reactions. In consideration of this, we synthesized a series of quaternary ammonium salt derivatives of Hal, with polarity increased so that they do not pass the blood-brain barrier. One of these compounds with serial number F2 (N-n-butyl haloperidol iodide) was screened, and was found to maintain the vasodilating effects but have no side reactions. In this article, both the protective effects of F2 on ischemia-reperfusion injury and its mechanism were studied. Multiple aspects such as the evaluation of hemodynamics, various enzymes and anti-oxygen free radicals in myocardial tissue were assessed. Moreover, the effects of F2 on potassium channel were studied to explore the mechanisms of its cardiovascular activity using patch clamp techniques in whole-cell configuration.1. The protective effects of F2 on myocardial ischemia-reperfusion injuryRabbits of either sex weighing between 2.0 to 2.6 kg were anesthetized with intravenous pentobarbital sodium (30 mg/kg). A cannula with 40 lU/ml of sodium heparin linked to pressure transducer was inserted into the femoral artery to monitor the mean arterial pressure. A heparinized catheter was inserted into left ventricle through right common carotid artery for measuring the left ventricular pressure. Thoracotomy was performed through the fourth left intercostal space adjacent to the sternum, and the pericardium was widely opened and sewn to thoracic wall. A silk ligature was placed under the left ventricular branch of the coronary artery (LVBCA) approximately 5mm below the left auricle of the heart. Ischemia was induced by ligated the LVBCA. 40 minutes later, the ligature was cut and reperfusion was obtained for another 40 minutes. The ECG of limb lead II was used to document the process of myocardial ischemia and reperfusion. Ninety rabbits were randomly assigned to one of nine groups: (1) Sham-operated group (Sham, n=10), (2) Control group (I/R, n=10), (3) Solvent group (PEG, n=10), (4) Verapamil group(Ver, n=10), groups (5)9 F2 of five different dosages (all groups, n=10). Saline, solvent polyethylene glycol 400 (PEG 400), verapamil and F2 of five different dosages (0.25 mg/kg, 0.5 mg/kg , 1 mg/kg , 2 mg/kg , 4 mg/kg) were injected through the auricular vein 5 min before ischemia. The changes of hemodynamics, including heart rate (HR), mean aortic pressure (MAP), left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP) and dP/dt max, were recorded with MS302 recording-and-analyzing system software during the experiment.At the end of the experiment, tissue samples from ischemic zones were homogenized to 10% tissue homogenate with a glass grinder in ice water. After centrifugation at 2500g for 10min, the supernatants weredecanted to determine the activities of superoxide dismutase (SOD), creatine kinase (CK), Ca2+-ATPase, Na+, K+-ATPase and the contents of malondialdehyde (MDA).The results of experiment were as follows:1.1. Effects of F2 on hemodynamics of myocardial ischemia-reperfusion injury in rabbitsCoronary occlusion caused a significant decrease in MAP, LVSP and dP/dtmax and a significant increase in LVEDP in all 8 groups compared with Sham group (P<0.05 ) . However, there was no significant difference among the I/R, PEG and all treatment groups (P>0.05). After reperfusion, MAP, LVSP and dP/dt max in I/R and PEG groups decreased progressively and LVEDP increased progressively, but there was no group difference (P>0.05). However, these hemodynamic indexes in Ver and F2 groups had obvious improvement compared with I/R group, but they were still worse than those of Sham group.In addition, HR in all groups showed an obvious decrease immediately after c...
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