Effects Of CGRP And OFQ On Cardiac Function And Ischemia-induced Ventricular Arrhythmia Of Isolated Ischemia/Reperfusion (I/R) Rat Heart

Objective:we established the current study to investigate the role of calcitonin gene-related peptide (CGRP), and orphanin (OFQ) on cardiac function and ventricular arrhythmia in isolated rat heart model of ischemia/reperfusion (I/R). The purpose is to compare and explore the effect of CGRP and OFQ on the myocardial ischemia/reperfusion, which further explore the neurogenic mechanism of the organ injury in rats.Background:Acute myocardial ischemia due to coronary circulation and myocardial changes in coronary blood flow which caused by the imbalance between the demand resulting from myocardial injury. Myocardial ischemic disease has become a major killer of human health. Acute myocardial ischemia can produce myocardial injury and cardiac arrhythmia, severe cardiac arrhythmia in acute myocardial ischemia in patients which have become the leading cause of death. The existing research shows that CGRP and OFQ involved in the regulation of the cardiovascular system. In the event of acute myocardial ischemia, the levels of these active substances have increased in the myocardial tissue, suggesting that CGRP and OFQ to participate and influence the pathological changes of acute myocardial ischemia in the process. At present, little is known about the regulatory effects on cardiac function in organ level and the mechanism of action.Method:The experiment was carried out in two parts:In part one, the effects of CGRP on cardiac function and ischemia-induced ventricular arrhythmia was investigated in three steps:1. Observed pretreatment withCGRP(10-6 mol·L-1,10-7 mol·L-1,10-8mol·L-1),the change of cardiac function and ventricular arrhythmia of isolated ischemia/reperfusion (I/R) rat heart and to observe the impact when joint use of CGRP (10-7 mol·L-1) and CGRP receptor antagonist CGRP8-37 (10-6 mol·L-1) on CGRP (10-7 mol·L-1)-induced cardiac function and ventricular arrhythmia.2. Observed after-treatment for CGRP (10-7 mol·L-1), the change of cardiac function and ventricular arrhythmia of isolated ischemia/reperfusion (I/R) rat heart and to observe the impact when joint use of CGRP (10-7 mol·L-1) and CGRP receptor antagonist CGRP8-37 (10-6 mol·L-1) on CGRP (10-7 mol·L-1)-induced cardiac function and ventricular arrhythmia.3. Observed the different effect of pretreatment and after-treatment with CGRP (10-7 mol·L-1) on the cardiac function and ventricular arrhythmia of isolated ischemia/reperfusion (I/R) rat heart.In part two,the effects of OFQ on cardiac function and ischemia-induced ventricular arrhythmia was investigated in three steps:1. Observed pretreatment with OFQ (10-6 mol·L-1,10-7 mol·L-1),the change of cardiac function and ventricular arrhythmia of isolated ischemia/reperfusion (I/R) rat heart and to observe the impact when joint use of OFQ (10-6 mol·L-1) and OFQ receptor antagonist UFP101 (10-5 mol·L-1) onOFQ (10-6 mol·L-1)-induced cardiac function and ventricular arrhythmia.2. Observed after-treatment for OFQ (10-6mol·L-1), the change of cardiac function and ventricular arrhythmia of isolated ischemia/reperfusion (I/R) rat heart and to observe the impact when joint use of OFQ (10-6 mol·L-1) and UFP101 (10-5 mol·L-1) on OFQ(10-6 mol·L-1)-induced cardiac function and ventricular arrhythmia.3. Observed the different effect of pretreatment with OFQ (10-6 mol·L-1) and after-treatment for OFQ (10-6 mol·L-1) on the cardiac function and ventricular arrhythmia of isolated ischemia/reperfusion (I/R) rat heart.The hearts from male SD rats (weighing 250-280g) were perfused with a Langendorff apparatus and the changes of cardiac function parameters including left ventricular systolic pressure (LVSP), left ventricular end-diastrolic pressure(LVEDP), left ventricular developed pressure(LVDP=LVSP-LVEDP), heart rate(HR),+dp/dtmax and-dp/dtmax were investigated. Ventricular arrhythmias, including single, multiple ventricular rhythm, ventricular tachycardia and ventricular fibrillation. Result:In part one of the experiments we found:1. cardiac functiona. Compared with group NOR, pretreatment with CGRP(P-CGRP) can produce following result:CGRP (10-7 mol·L-1) significantly enhanced the change rate of HR, LVDP (P<0.05). group CGRP (10-6 mol·L-1)can prominently reduce the LVDP,HR and enhance LVEDP(p<0.05). CGRP (10-8 mol·L-1) produce lower HR,LVEDP (P<0.01). Compared with group CGRP (10-7 mol·L-1), group CGRP (10-7 mol·L-1)+CGRP8-37 (10-6 mol·L-1) significantly reduce LVSP, HR and enhance LVEDP(P<0.01).b. Compared with group NOR, after-treatment with CGRP (10-7 mol·L-1) (A-CGRP) show lower LVSP, LVDP, HR,±dp/dtmax (P< 0.01). Compared with group A-CGRP (10-7 mol·L-1), group A-CGRP (10-7 mol·L-1)+CGRP8-37(10-6 mol·L-1) significantly enhanced LVSP, LVDP, HR,±dp/dtmax and enhance LVEDP(P<0.01).c. Compared with group P-CGRP (10-7 mol·L-1), A-CGRP (10-7 mol·L-1) produced lower LVSP, LVDP, HR,±dp/dtmax and higher LVEDP (P< 0.01)2. ventricular arrhythmiaa. Compared to group NOR, cardiac ventricular arrhythmia was significantly decreased in group P-CGRP (10-7 mol·L-1) in the first 10 minines of reperfusion (P< 0.01),but no significant difference in group P-CGRP (10-6 mol·L-1,10-8 mol·L-1). Group P-CGRP (10-7 mol·L-1)+CGRP8-37(10-6 mol·L-1) could increase ventricular arrhythmia compared with the effect of P-CGRP (10-7 mol·L-1) (P< 0.01)b. Compared to group NOR, group A-CGRP (10-7 mol·L-1) has the trend of decreasing ventricular arrhythmia, group A-CGRP (10-7 mol·L-1)+CGRP8-37(10-6 mol·L-1) could reverse this trend,but p>0.05.In part two of the experiments we found:1. cardiac functiona. Compared with group NOR, pretreatment with OFQ(P-OFQ) can produce following result:P-OFQ (10-6 mol·L-1) significantly increase the change rate of LVSP,LVEDP(P<0.05) and decrease HR(P<0.01). Group P-OFQ (10-7mol·L-1) could reduce+dp/dtmax(P<0.05) and enhance LVEDP (P<0.01),while showed no effect on other indicaters. Group P-OFQ (10-6 mol·L-1)+UFP(10-5 mol·L-1) significantly induced LVSP, LVDP,±dp/dtmax and enhanced LVEDP (P<0.01).b.Compared with group NOR, A-OFQ (10-6 mol·L-1) showed lower LVSP, LVEDP(P<0.05). A-OFQ (10-6 mol·L-1)+UFP(10-5 mol·L-1) showed higher LVSP, LVDP, LVEDP,-dp/dtmax than group A-OFQ (10-6 mol·L-1) (P<0.01).c. Compared with group P-OFQ (10-6 mol·L-1), A-OFQ (10-6 mol·L-1) produced lower LVSP, LVEDP, HR,±dp/dtmax and higher HR,-dp/dtmax (P< 0.01)2. ventricular arrhythmiaa. Compared to group NOR, cardiac ventricular arrhythmia was significantly decreased in group P-OFQ (10-6 mol·L-1) in the first 10 minines of reperfusion (P < 0.01),but no significant difference in group P-OFQ (10-7mol·L-1). Group P-OFQ (10-6 mol·L-1)+UFP(10-5 mol·L-1) could increase ventricular arrhythmia compared with the effect of P-OFQ (10-6 mol·L-1) (P< 0.01)b.There was no significantly difference in the change of cardiac ventricular arrhythmia in group A-OFQ (10-6 mol·L-1) and A-OFQ (10-6 mol·L-1)+UFP(10-5 mol·L-1).Conclusions:1. Preventive health for CGRP had positive inotropic action and chronotropic effect on cardiac function for isolated rat heart ischemia-reperfusion,while therapeutic for CGRP had negative inotropic action and chronotropic effect. Its antagonist CGRP8-37can antagonize these effects. It suggest that Specific receptor of CGRP may be involved in the regulation of CGRP on cardiac function. The surrounding environment of Myocytes may affect the different role of CGRP.2. Preventive given orphanin (OFQ) has a negative chronotropic and positive inotropic effect on the health of isolated rat heart after ischemia-reperfusion cardiac function.Its antagonist UFP-101 could antagonize the positive inotropic effect. Therapeutic with OFQ has a negative inotropic role, and this effect can also be reversed by UFP-101.3. Preventive and therapeutic for CGRP may reduce the occurrence of ventricular arrhythmias, its antagonist CGRP8-37can antagonize these effects. Preventive for orphanin (OFQ) can reduce the occurrence of ventricular arrhythmia and its antagonist UFP-101 can reverse the effect. Endogenous CGRP and OFQ might be involved in the regulation of ventricular arrhythmias through their specific receptor.