花生四烯乙醇胺对大鼠心功能与心肌一氧化氮水平及一氧化氮合酶活性的影响

Effects of Anandamide on the Cardiac Function,Nitric Oxide Content and Nitric Oxide Synthase Activity in the Myocardium of the Rat

目的观察大麻素类物质花生四烯乙醇胺(anandam ide,Ana)对大鼠体外心脏左心室心肌中一氧化氮(NO)含量和一氧化氮合酶(NOS)活性的影响。方法采用Langendorff方法观察Ana对大鼠体外心脏心率(HR)、冠脉流量(CF)、冠脉灌注压(CPP)、左室压最大上升速率(+dp/dtm ax)、左室压最大下降速率(-dp/dtm ax)、左室收缩峰压(LVSP)、左室舒张末压(LVEDP)及左室发展压(LVDP)的影响;NO含量和NOS活性采用联苯胺荧光分光光度法测定。结果Ana可使体外心脏心率、CPP、+dp/dtm ax-、dp/dtm ax、LVSP、LVDP降低,使LVEDP升高,CF增加。选择性大麻素CB1受体拮抗药AM251(1μmol.L-1)可阻断Ana的部分心脏效应;另一选择性大麻素CB2受体拮抗药AM630(1μmol.L-1)对Ana的心脏效应无显著影响。NOS抑制药L-N-硝基精氨酸甲酯(L-NAME)(100μmol.L-1)对Ana的心脏效应也无显著影响。Ana能增强原生型NOS(cNOS)活性,抑制诱生型NOS(iNOS)活性,促进心肌NO的释放。结论Ana使离体大鼠心肌收缩力降低,心率减慢,表现出负性肌力和负性频率作用;Ana可舒张冠脉,增加冠脉流量;大麻素CB2受体可能不参与Ana的这些心脏效应,内源性NO也可能不参与调节Ana的心脏效应;可能存在其他新的作用位点调节Ana的心脏效应。Ana调节心肌NOS同工酶活性,增加cNOS活性,降低iNOS活性,促进NO的释放,可能发挥心肌保护作用,在心肌缺血和高血压治疗中有潜在应用前景。

Objective To survey the effects of anandamide（Ana） on the cardiac function, nitric oxide（NO） content and nitric oxide synthase（NOS） activity in the left ventricular myocardium of the rat in vitro. Methods The Langendorff method was used for surveying the effects of Ana on the heart rate （ HR）, coronary flow （ CF）, coronary perfusion pressure （ CPP）, maximal rate of left ventricular developed pressure（ ＋ dp/dtmax） , maximal rate of left ventricular decline pressure（ -dp/ dtmax） , left ventricular systolic pressure（ LVSP）, left ventricular end-diastolic pressure（LVEDP） and left ventricular developed pressure（I＋VDP） of the rat heart. NO content and NOS activity were assayed with benzidine fluorescence spectrophotometry. Results Ana was shown to decrease HR, CPP, ＋ dp/dt -dp/dt LVSP and LVDP and increase LVEDP and CF. The selective cannabinoid CB1 receptor antagonist AM251 （1μmol· L^-1） blocked a portion of the cardiac effects of Ana. Another selective cannahinoid CB2 receptor antagonist AM630 （11μmol·L^-1 ） and the nitric oxide synthase inhibitor N-omega-nitro-L- arginine methyl ester （L-NAME） （ 100μmol·L^-1） had no significant influence on the cardiac effects of Ana. Ana was shown to enhance the activity of constitutive nitric oxide synthase （cNOS） and inhibit the activity of inducible nitric oxide synthase （iNOS）. Ana could also protnote the release of NO from the myocardium. Conclusion Ana was shown to decrease the myocardial contractility and slow down the heart rate, denoting negative inotropic as well as negative chronotropie action. Ana caused cornary vasodilatation and increased coronary blood flow. Cannabinoid CB2 receptors and endogenous NO probably did not take part in the effects of Ana on the cardiac functions. It is likely that other novel action sites may be present that could modulate the cardiac effects of Aria. By regulating the activity of myocardial NOS isoenzyme, increasing the eNOS activity and decreasing the iNOS activity as well as promoting the myocardial release of NO, Ana seems possible to exert a myocardial protective effect and may have a potential prospect of clinical application in the treatment of myocardial ischemia and arterial hypertension.