Effect Of Different Immunosuppressive Agents In Therapeutic Doses On Heart, Blood Pressure And Bood Cell In Unilateral Nephrectomized Rats

Objective: To observe the effect of the first therapeutic dose of cyclosporin A (CsA),tacrolimus (FK506) and rapamycin (Rapa) in unilateral nephrectomized rats onmyocardial enzymes, cardiac histopathology and ultrastructure, blood pressure and heartrate, blood cells. In addition, to learn how effects have changed after the CSA and FK506in conjunction with diltiazem,Methods: The therapeutic doses of CsA, FK506, Rapa and diltiazem (Dil) after renaltransplantation in patients were converted into rats’ dose by the conversion formula.56unilateral renal male SD rats were randomly divided into normal group, control group,CsA (25mg kg-1D-1) group, FK506(0.8mg kg-1D-1) group, Rapa (0.2mg kg-1D-1) group，CsA+Dil (25mg kg-1D-1+8mg kg-1D-1) group, FK506＋Dil (0.8mg·kg-1·d-1＋8mg·kg-1·d-1) group，with8rats in each group(n=8). The drug dosage wasreviseed according to the body weight of each rat. Each rat was record before theexperiment and twice a week during the experiment. After8weeks administration, wehave measured blood pressure (systolic, diastolic) rats with rat tail sphygmomanometercuff, simultaneously recorded heart rate. We have taken blood under ether anesthesia, anddetected the myocardial enzymes index (It contains CK, CK-MB, LDH and AST etc.) andblood cell index (It contains RBC, WBC, HGB, PLT, HCT, MCV, MCH, BASO#, EOS#,NEUT#and LYM#etc.) in blood. And to observe the cardiac histopathology through HEstaining light-microscopy and ultrastructure changes through transmission electronmicroscope.Results:1.Compared the normal group’s blood pressure, heart rate, the myocardial enzymesindex (It contains CK,CK-MB,LDH and AST etc.) and blood cell index (It containsRBC,WBC,HGB,PLT,HCT,MCV,MCH,BASO#,EOS#,NEUT#and LYM#etc.) with thecontrol groups’ before and after the experiment, there is no statistically significantdifference between them (P>0.05). 2. There is no statistically significant difference on body weight between each groupbefore gastric feeding drug or placebo (P>0.05).But after8weeks.3.Rats of CsA group’s and Rapa group’s systolic pressure(SBP) obviously higherthan normal group’s, control group’s,FK506group’s, CsA＋Dil group’s and FK506＋Dilgroup’s (P<0.05). The CsA group’s SBP has increased greater than the Rapa group’s(P<0.05). Rats of CsA group’s,Rapa group’s and FK506group’s Diastolic pressure (DBP)obviously higher than normal group’s, control group’s,, CsA＋Dil group’s and FK506＋Dil group’s (P<0.05). The FK506group’s DBP has increased greater than the Rapagroup’s (P<0.05).4.Rats of CsA group’s and FK506group’s heart Rate obviously faster than normalgroup, control group, Rapa group, CsA＋Dil group’s and FK506＋Dil group’s (P<0.05).There is no statistically significant difference on heart Rate between CsA group andFK506group (P>0.05).5.Rats of CsA group’s CK、CK-MB、LDH are obviously much higher than normalgroup’s, control group’s, FK506group’s, Rapa group’s and CsA+Dil group’s (P<0.05).CsA group’s and CsA+Dil group’s AST obviously much higher than the rats of othergroups (P<0.05). There is no statistically significant difference on AST between CsAgroup and CsA+Dil group (P>0.05).6. Rats of CsA group’s and FK506group’s RBC, HGB obviously less than the rats ofother groups (P<0.05).There is no statistically significant difference on RBC, HGBbetween CsA group and FK506group. CsA group’s and Rapa group’s PLT lower than therats of other groups (P<0.05). But only CsA group has statistically significant differenceon PLT compared with others. Rats of CsA group’s and FK506group’s WBC obviouslymuch higher than the rats of other groups (P<0.05).And the magnitude of CsA group’sWBC increase greater than the FK506group’s (P<0.05).7. Rats’ cardiac histopathology change: There are different degrees of myocardialinjury in CsA group: myocardial cells are swelling, and myocardial stripes are blur.Thereare a lot of eosinophilic granular degeneration in cytoplasm, and it is obvious that muchvacuolar degeneration surrounding the nucleus. Occasionally, some rats’ cardiac from CsA group exist hyaline scarring. Some rat’s heart membrane and valve appear mucousdegeneration, and the end of heart tendon cable performs coagulation necrosis. Rapagroup, FK506group, CsA+Dil group and FK506+Dil group are similar to the normalgroup’s and the control group’s myocardial pathology, only a few vacuolar degenerationsurrounding the nucleus.8.Rats’ cardiac ultrastructural performance as follows: muscle fibers arrange in neatlines Z with myofascial complete consecutive, and partial myofibrils are milddissoluted.Oval nuclei is in the central of cell, intercalated disc is closely connected.There is a lot of dilated sarcoplasmic reticulum in cytoplasm, and light degree of loosechange happened in mitochondria.Conclusions:1.Therapeutic doses of CsA take into effect on blood pressure in rats (includingsystolic and diastolic) that make the BP significantly increased, Rapa also mildlyincreased blood pressure (systolic and diastolic), but FK506only elevated diastolic bloodpressure, the CsA has the Maximum impact on blood pressure in these three drugs. CsAand FK506combined with calcium antagonists, causing blood pressure approaching tonormal levels. Patients with hypertension are suitable for useing Rapa or FK506-basedimmunosuppressive regimen with less impact on blood pressure or combination withcalcium channel antagonists.2. Therapeutic dose of CsA FK506can increase heart rate in rats, thus the renaltransplant patients with sinus tachycardia, atrial fibrillation, atrial flutter, ventricularfibrillation and ventricular flutter and other arrhythmias should choose the Rapa-basedimmunosuppressive regimen with less impact on the appropriate rhythm election.3. Therapeutic dose of CsA causes cardiac enzymes (CK, CK-MB, LDH and ASTetc.)elevated, and light-microscopy and electron-microscopy presenting ultrastructuralpathology has prompted varying degrees of damage occurred in myocardium, if the patientwith coronary heart disease, viral myocarditis, hypertrophic cardiomyopathy and otherheart disease, etc., should avoid choosing CsA-based immunosuppressive regimen, shouldtake appropriate choice to FK506or Rapa-based immunosuppressive regimen. 4、CsA and FK506lead to reduction about the number of RBC,HGB; CsA causesPLT decrease; CsA and FK506cause leukocytosis, the former mainly to the number oflymphocytes, the latter mainly to the number of monocytes; Rapa, CsA+Dil and FK506+Dil may lead neutropenia. In the application of these drugs, we need to pay attention tochanges in blood-related, and in a timely manner to the appropriate treatment, due to thelack of domestic and foreign research data, reports and related mechanisms no systematicexposition, some of the experimental data and clinical practice findings differ clinical datafor further experimental investigation and larger sample confirmed.