| Objective: Pulmonary hypertension (Pulmonary Hypertention, PH)is characterized with clear etiology unknown and pulmonary arterypressure persistent increased and with a small pulmonary arteryobstruction, is a kind of malignant pulmonary vascular disease with highmorbidity, poor prognosis. Right ventricular dysfunction refers to apathological state of myocardial damage caused by variety of causes,resulting in myocardial structure and function changes, to reduce thepump function of right ventricular, and depends on the filling pressure tocompensate at last. Pathological changes of pulmonary hypertensionmake pulmonary vascular resistances increased and the structions ofpulmonary vascular remodeling and develop into symptoms of circulatorysystem diseases as the main clinical manifestations seriously, eventuallyto the death of right heart failure. The study first used Monocrotaline(Monocrotaline, MCT) to establish the models of the PH and Rightventricular dysfunction, choose β-oxidation inhibitor-Trimetazidine tointervene the models, and to observe pulmonary artery pressures reducedand the right ventricular functions improved or not，to evaluate effectionon vascular endothelial function and right ventricular function ofpulmonary hypertension in rabbits and to investigate the mechanism ofthem further, in order to provide a new target and target direction for thetreatment of pulmonary vascular disease and the right ventriculardysfunction.Methods:24healthy, adult and New Zealand rabbits were randomlydivided into two groups：①The blank group (the blank group, n=12)②The MCT group (the PH group, n=12). Under the same feed and rearing conditions, the high pressure group of rabbits were injected themonocrotaline by the dose of60mg/kg dissolved in ethanol and salinemixed by1:5into the abdominal cavity in the same way, The blank groupwas injected the same dose of a mixture of ethanol and saline into theabdominal cavity once. After feeding for four weeks, began to theDoppler ultrasound examination,to determinate the velocities of tricuspidregurgitations (v), based on pulmonary artery pressure=4V2+right atrialpressure in order to know the models of the PH and the right ventriculardysfunction established or not, and then the PH group were randomlydivided into two groups:①the model group (the control group, n=6)②the Trimetazidine group (the experimental group, n=6), and began tointervene the drug to the experimental group for4weeks. Theexperimental group was given daily Trimetazidine by the dose of5mg/kgdissolved in30ml saline to gavage, while the experimental group wasgiven saline30ml daily in the same way. After feeding of Trimetazidinefor4weeks, terminated the experiment, began to the Doppler ultrasoundexamination again and to determinate the velocities of tricuspidregurgitations (v), based on pulmonary artery pressure=4V2+right atrialpressure in order to know the pressure of the control group and theexperimental group, then anesthetized rabbits trachealed intubation,ventilatored life support, opened chest and approached the right atrialappendage for the determination of the mean right ventricular pressure,calculate the mean pulmonary artery pressure (mPAP). After pressuremeasurement, removed the lungs tissue, cleaned up the residual bloodwith saline fixed in10%formalin solution for48hours, embedded inparaffin, sliced, HE stained, to observe the pathological changes of thelung tissue under light microscope, radiography and contrast. Heart wasremoved, cut off the atrium, separated the right ventricle (RV) and leftventricle plus septum (LV+IVS), and cleaned up the residual blood withsaline and weighed immediately after a dry filter paper,calculated theratio of right ventricular hypertrophy index (RVHI) to determine the presence or absence of right ventricular hypertrophy, then fixed rightventricular wall in10%formalin solution for48hours, embedded inparaffin, sliced, HE stained, resin were mounted, to observe thepathological changes of the heart tissue under light microscope,radiography and contrast. At the end of four and eight weeks,Exsanguinated blood from sets of rabbit ear vein in order to determinatethe plasma levels of BNP, NO and ET-1.Results:1General observation: The spirit of the blank group is good, movedeasily, response sensitively, and normal diet. After the injection ofMonocrotaline for1week, the spirit of the hypertension group was low,lying still, ate less, unresponsive and the ulcers of the MCT injection sitewere seen. After treatment for two weeks, the spirit of the experimentalgroup visible improved the activity increased, diet and stimulationsignificantly increased compared with the previous.2Hemodynamic changes: At the end of four weeks of MCTinjection, began to the Doppler ultrasound examination, tricuspidregurgitations were seen in the hypertension group. Determinated thevelocities of the tricuspid regurgitations, and calculated the meanpulmonary artery pressure, Pulmonary artery pressure (mmHg) of the PHgroup was (32.72±1.53), the pressure were higher than30mmHg. It wasshown that the model of Pulmonary hypertension was establishedsuccessfully. the PH group was divided into a control group and theexperimental group,the pressures of them were(32.73±1.48),(32.70±1.71); compared with the control group, the experimental groupwas no significant difference (P=0.982).The mean pulmonary arterypressure (mPAP) of the PH group were significantly higher than thecontrol group (P<0.05).After feeding of Trimetazidine for4weeks,beganto the Doppler ultrasound examination again, to determinate the velocitiesof tricuspid regurgitations (v), based on pulmonary arterypressure=4V2~+right atrial pressure in order to know the pressure of the control group and the experimental group, they were（38.86±0.65）,（38.09±0.55），At the end of8weeks of the experiment, determinatedthe right ventricular pressure, calculated mPAP, they were（20.44±2.04）,（40.20±1.53）,（39.85±0.86）. Compared with the control group, themPAP of the experimental group did not changed significantly, but had asignificant difference (P<0.05), compared with the control group,although the mPAP of the experimental group was decreased, but doesnot have a statistically significant difference (P>0.05).3Heart right ventricular Tei index: At the end of four weeks of MCTinjection, began to the Doppler ultrasound examination, calculate theright ventricular Tei indexes of the blank group and the PH group, and theTei index were（0.484±0.1196）,（0.598±0.1243）, The right ventricularTei indexes of the PH group were significantly higher (P<0.05) than theblank group, indicating that the right ventricular dysfunction wereestablished successfully.4The right ventricular hypertrophy index (RVHI): At the end of8weeks, after the end of the hemodynamic, weighed and calculated rightventricular hypertrophy index, they were (0.3314±0.15846),(0.4266±0.19754),(0.3735±0.19657).compared with the blank group, RV/(LV+IVS)of the control group was significantly higher (P<0.05), comparedwith the control group, RV/(LV+IVS)of the experimental group waslower than the control group when but significantly lower (P<0.05).5The morphology observation of Lung tissue: Under the naked eye,the lung tissue of the blank group was grayish red, soft, no swelling, nocongestion, the double lung of the control group and the experimentalgroup were seen with visibly dark red and black necrotic areas,the blacknecrotic area of the control group was significantly larger than theexperimental group; Under light microscope, The small pulmonaryvascular wall structure of the blank group was clear, normal wallthickness, The pulmonary vascular wall of the control group was obviousthickening and the lumen was significantly stenosis, even to the occlusion degree and the recanalizated blood vessels were seen, and inflammatorycells infiltrated vessel wall and perivascular. Compared with the controlgroup, the degree of wall thickening mitigate in the experimental groupwas lighten and the lumen area increased, inflammatory cells of vesselwall and perivascular alleviated significantly.6The morphology observation of Heart tissue: Under the naked eye,compared with the blank group, the right ventricular wall of the controlgroup thicken obviously, the thickening of the experimental group wasnot obvious. Under the light microscope, the blank group was seencardiac muscle fibers were bundle and tightly packed. In the controlgroup, we could see that the cardiac myocytes were obviouslyhypertrophy, myocardial fiber disordered, nuclei enlarged and deeplystained, and myocardial cells were obviously edema and myocardialmuscle fibers were discontinuous. In the experimental group, the cardiacmuscle fibers arranged neatly, edema of myocardial cells was mild,uncontinuous myocardial muscle fibers were not seen.7Compared the levels of BNP: After4weeks of the MCT injection,measured the BNP levels (pg/ml) of the blank group and he hypertensiongroup, they were:(134.3±1.31),(184.3±2.30). The PH group wasrandomly divided into a control group and the experimental group, theBNP levels (pg/ml) of the control group and the experimental group were(185±7.53),(183±9.07).Compared with the blank group, the BNP levelsof the hypertension group were significantly higher (P<0.05), with astatistically significant. At the end of8weeks of the experiment, the BNPlevels (pg/ml)of the blank group, the control group and the experimentalgroup were:(135±5.26),(284±3.56),(229±4.49),the BNP levels of thecontrol group were elevated than forward(at4weeks)(P<0.05), the BNPlevels of the experimental group were significantly different from thelevel of the blank group (P<0.05), but compared with the control group itwas significantly lower (P<0.05), with statistical significance.8Compared the levels of ET-1and NO: After4weeks of the MCT injection, measured the ET-1(ng/L) and NO(umol/L)levels of the blankgroup and the PH group, they were(49.26±1.72),(59.05±1.92);(69.19±1.63),(39.54±1.71).The PH group randomly divided into a control groupand the experimental group, the ET-1(ng/L) and NO(umol/L)levels of thecontrol group and the experimental group were (59.24±3.77),(58.87±2.88);(38.33±2.12),(40.80±2.08). Compared with the blankgroup, the ET-1levels of the PH group were significantly higher (P<0.05)and the NO levels of the PH group were significantly lower (P<0.05),with a statistically significant; at the end of4weeks of the experimentcompared to the control group, the ET-1(ng/L) and NO (umol/L) levels ofthe experimental group were no significant difference (P=0.851andP=0.432). At the end of8weeks of the experiment, the ET-1(ng/L) andNO (umol/L) levels of the blank group, the control group and the experimentgroupwere:(48.66±2.09),(70.33±1.93),(62.96±1.48);(66.73±1.70),(32.86±1.57),（59.54±2.17）. The ET-1levels of the control group were elevatedthan forward (at4weeks)(P<0.05) and the NO levels of the controlgroup were lower than forward (at4weeks)(P<0.05), the ET-1and NOlevels of the experimental group were significantly different from thelevel of the blank group (P<0.05), and compared with the control groupthey changed significantly (P<0.05), with statistical significance.Conclusion:1Used MCT to establish the models of Pulmonary Hypertensionand the models of the Right ventricular dysfunction successfully.2When the rabbits existed pulmonary hypertension and rightventricular dysfunction, we could see the secretion of ET-1increasing andNO decreasing, the imbalance of ET-1and NO may be involved in theformation and vicious of pulmonary hypertension and the right heartdysfunction.3When the rabbits existed pulmonary hypertension and rightventricular dysfunction, the structure remodeling of pulmonary vascularsand the right ventricular were seen and we could see the secretion of BNP increasing.4Trimetazidine could improve endothelial function, and couldadjust the secretion imbalances of ET-1and NO, and could reverse thestructural remodeling of pulmonary vasculars, may be to reduce thepulmonary arterial pressure.5Trimetazidine could reverse the structural remodeling of the rightventricular, may be to improve right heart function. |
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