Effects Of Substance P And OFQ On Cardiac Function Of Isolated Rat Heart

Objective: The aim of the study was to investigate the effect of Substance P (SP) and orphanin (OFQ)on cardiac function of isolated rat heart, exploring the interaction of cardiac sensory nerve and adrenergic nerve in regulation of cardiac function.Background: Increased evidence indicated the regulatory effects of SP and OFQ on cardiovascular system. Recent studies found that the concentration of these bioactive compounds was increased in myocardium when heart plunged into acute infarction, indicating involvement of SP and OFQ in pathological process of acute myocardial ischemia. Little is known about the regulatory effects on cardiac function in organ level and the mechanism of action.Methods: The experiment was carried out in two parts:In part one, the effects of SP on cardiac function was investigated in five steps:1. The effects of NK-1 receptor antagonist, [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-Substance P (10-7 mol·L-1,10-8 mol·L-1,10-9mol·L-1)on cardiac function of isolated rat heart were tested.2.The effects of SP(10-6 mol·L-1,10-7 mol·L-1,10-8 mol·L-1) on norepinephrine (NE) induced changes in cardiac function of isolated rat heart were investigated;3.The effects of NK-1 receptor antagonist, [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-Substance P (10-7 mol·L-1,10-8 mol·L-1,10-9mol·L-1) on NE+ SP induced changes in cardiac function of isolated rat heart were investigated.4.The effects of NK-2 receptor antagonist, MEN10376 on NE+ SP induced changes in cardiac function of isolated rat heart were investigated.5. The effects of NK-1 receptor antagonist, [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-Substance P (10-7 mol·L-1,10-8 mol·L-1,10-9mol·L-1) on NE induced changes in cardiac function of isolated rat heart were investigated.In part two the effects of OFQ on cardiac function was investigated in two steps:1. The effects of OFQ(10-6 mol·L-1,10-7 mol·L-1,10-8mol·L-1)on cardiac function of isolated rat heart was examined. OFQ receptor antagonist UFP-101(10-6 mol·L-1)was used to analyze the changes in the effects on OFQ(10-6 mol·L-1) on cardiac function of isolated rat heart.2. The effects of OFQ(10-6 mol·L-1,10-7 mol·L-1,10-8 mol·L-1) on norepinephrine (NE) induced changes in cardiac function of isolated rat heart were investigated. OFQ receptor antagonist UFP-101(10-6 mol·L-1)was used to examine the changes in the effects of OFQ(10-6 mol·L-1)on NE induced action on cardiac function of isolated rat heart;The hearts from male SD rats (weighing 250-280g) were perfused with a Langendorff apparatus and 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.Results: In part one of the experiments we found: a.D-SP(10-8M) significantly enhanced the change rate of LVDP, LVSP (P<0.01), while there was no significantly difference in the change of HR and LVEDP, Compared to the control (P>0.05). D-SP(10-7M)and D-SP(10-9M)did not show significant effect (P>0.05).b. NE(10-5M)SP(10-6M) , NE(10-5M)SP(10-7M) , NE(10-5M)SP(10-8M)group induced elevation of LVEDP, compared with that induced by NE(10-5M) (P<0.05), leaving LVSP,LVDP and HR not significantly changed (P>0.05).c.Compared to NE(10-5M)SP,NE(10-5M)SP(10-7M)D-SP(10-7M) showed lower LVEDP and HR(P<0.05),while LVSP and LVDP were not significantly changed(P>0.05), while NE(10-5M)SP(10-7M)D-SP(10-8M) and NE(10-5M) SP(10-7M) D-SP(10-9M) showed no significant effect (P>0.05). NE(10-5M) SP(10-8M) D-SP(10-7M) produced lower LVEDP (P<0.01) but showed no effect on LVSP,LVDP and HR (P>0.05). There was no significantly difference in NE(10-5M) SP(10-8M) M(10-7M) (P>0.05), compared with NE(10-5M)SP.d.Compared to NE(10-5M), NE(10-5M)D-SP(10-7M) significantly enhanced the LVSP and LVDP(P<0.01) but no significant difference in LVEDP and HR (P>0.05) was detected;NE(10-5M)D-SP(10-8M)and NE(10-5M)D-SP(10-9M)did not show any significant effect (P>0.05).In part two of the experiments we found:a. Compared to the control,OFQ(10-6M)and OFQ(10-8M)significantly enhanced the LVDP ,LVSP (P<0.01);OFQ(10-7M)and OFQ(10-8M)could reduce LVEDP(P<0.05)and enhanced -dp/dtmax(P<0.05);OFQ(10-6M), OFQ(10-7M) reduced HR (P<0.05) and enhanced +dp/dtmax(P<0.05).b. OFQ(10-6M)+ OFQ receptor antagonist UFP-101(10-6M)produced lower LVSP,LVDP,+dp/dtmax and -dp/dtmax(P<0.05), while There was no significantly difference in LVEDP and HR (P>0.05), compared with the effect of OFQ(10-6M).c. Compared with NE(10-5M),NE(10-5M)OFQ(10-6M)produced lower LVEDP(P<0.05)LVSP, LVDP, HR, +dp/dtmax and -dp/dtmax were higher(P<0.05);NE5OFQ8 showed higher LVSP and LVDP(P<0.05),and LVEDP, HR, +dp/dtmax and -dp/dtmax had no significantly difference(P>0.05).d. Compared with NE(10-5M)OFQ(10-6M),NE(10-5M)OFQ(10-6M)UFP(10-6M) enhanced LVEDP greatlly(P<0.01)and LVSP, LVDP, HR, +dp/dtmax and -dp/dtmax became lower(P<0.01).Conclusions: (1)Endogenous SP is possibly involved in regulation of systole and diastolic cardiac function. NK-1 receptor may mediate the effect of SP on cardiac function. SP may regulate cardiac function by modulating the function of adrenergic nervous system. (2)OFQ had positive inotropic action and negative chronotropic effect on isolated rat heart,and the positive inotropic action could be reversed by UFP-101;OFQ could enhanced the positive inotropic and chronotropic effect of NE and this action could be be reversed by UFP-101.