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 ::  Introduction
 ::  Material And Methods
 ::  Results
 ::  Discussion
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ARTICLE
Year : 1979  |  Volume : 25  |  Issue : 3  |  Page : 147-153

An experimental investigation to correlate changes in plasma fibrinolytic activity with isoprenaline induced myocardial damage


Department of Pharmacology, L.L.R.M, Medical College, Meerut-250102, India

Correspondence Address:
K K Saxena
Department of Pharmacology, L.L.R.M, Medical College, Meerut-250102
India
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Source of Support: None, Conflict of Interest: None


PMID: 529166

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 :: Abstract 

Administration of different doses of isoprenaline in albino rats produced varying grades of myocardial necrosis with concomitant changes in euglobulin clot lysis time which is a measure of plasma fibrinolytic activity (PFA). A positive and strong correlation was observed between changes in PFA and severity of myocardial necrosis. Experiments in young rats and propranolol pre-treated animals rule out the possibility of isoprenaline being responsible in bringing about changes in PFA. The measurement of PFA appears to be of prognostic significance in myocardial infarction as discussed.



How to cite this article:
Saxena K K, Gupta B, Kulshrestha V K, Prasad D N. An experimental investigation to correlate changes in plasma fibrinolytic activity with isoprenaline induced myocardial damage. J Postgrad Med 1979;25:147-53

How to cite this URL:
Saxena K K, Gupta B, Kulshrestha V K, Prasad D N. An experimental investigation to correlate changes in plasma fibrinolytic activity with isoprenaline induced myocardial damage. J Postgrad Med [serial online] 1979 [cited 2019 Dec 12];25:147-53. Available from: http://www.jpgmonline.com/text.asp?1979/25/3/147/42131



 :: Introduction Top


That the fibrinolytic activity in blood undergoes changes in various diseases is well known. It has been demonstrated to be deranged in various pathological conditions viz. occlusive vascular disease, [7], [11],[12],[13], [16],[18],[23],[24],[26],[30],[31] diabetes mellitus, [2],[11],[12] obesity, [12], [28] pulmonary vascular disease, [10] blood dyscrasias, [37] abnormal pregnancy, [3],[17] trauma [32] and neoplastic diseases. [29]

Following myocardial infarction fibrinolytic activity has consistently been demonstrated to decline. [5],[6],[15],[21],[25],[22] On the other hand serum enzymes like glutamic oxalo-acetic transaminase (GOT),lactate dehydrogenase (LDH), a-hydroxy-butyrate dehydrogenase (α-­ HBDH) and creatine phosphokinase (CPK) have been claimed to rise after myocardial damage [1],[9],[19],[22],[38],[39] Re­cently severity of myocardial damage has been shown to be reflected in the rise of serum enzymes [36],[38] and their levels in blood have been used as a prognostic in­dicator of survival of patients of myo­cardial infarction. [8] However, no such study appears to have been carried out regarding fibrinolytic activity in ralation to myocardial damage. In the present in­vestigation, therefore, an attempt was made to explore any possible relationship between changes in fibrinolytic activity and severity of myocardial damage.


 :: Material And Methods Top


Porter strain rats of either sex weighing 260 ± 10 g (older rats) and young rats of either sex of the same strain and weighing 80 ± 5 g were employed in the study. The animals were housed under controlled conditions of temperature and humidity and were fed a commercial rat diet.

Three independent sets of experiment, were performed to induce myocardia necrosis and to estimate the concomitant changes in the plasma fibrinolytic acti­vity. The experiments were as follows:

(A) Effect of graded doses of isoprena­lin in older rats

Older rats were divided into six group of ten animals each. Five groups out of these were administered different dose; of isoprenaline hydrochloride subcutane­ously (s.c.) for two consecutive days tc induce myocardial necrosis. Five doses of isoprenaline spaced at equal in­terval were selected between 85.0 and 0.02 mg/kg (the doses capable of produc­ing maximal and minimal cardiac necrosis, respectively) to induce myocar­dial necrosis of variable grades. [33] The sixth group was treated with matching volume of saline and served as control.

(B) Effect of isoprenaline in young rats

Young rats were divided into two groups of ten animals each. Animals of one group were injected with 85.0 mg/kg of isoprenaline s.c. for two consecutive days, while the animals of the other group were injected with the matching volume of saline.

(C) Effect of isoprenaline-challenge following propranolol pre-treatment it older rats

Thirty rats of higher weight were divided into three equal groups. Animals in the first group were administered pro­pranolol hydrochloride 5.0 mg/kg, orally for seven consecutive days and the second group with the matching volume of saline. On day sixth and seventh, animals of both the groups were challenged with isoprenaline (85.0 mg/ kg s.c.). [34] The animals of the third group received propranolol HC1 (5.0 mg/kg, orally) for seven consecutive days to study the per se effect of pro­pranolol on plasma fibrinolytic activity (PFA).

Fortyeight hours after the first injec­tion of isoprenaline/saline, animals were anaesthetized with pentobarbitone sodium (40.0 mg/kg, i.p.) ; blood (5.0 ml) was collected from the abdominal aorta in a citrated all glass syringe for determina­tion of PFA by estimating euglobulin clot lysis time (ELT) . [4] The animals were then sacrificed and their hearts were autopsied.

Gradation of myocardial necrosis

Frontal sections of the heart cut at were stained with haematoxylin and eosin. Based on the gross and micro­scopic appearances the heart lesions were graded on a five point scale from grade 0 to grade 4. [33]


 :: Results Top


(A) Effect of graded doses of isoprena­line on myocardial necrosis and plasma fibrinolytic activity (PFA)

The distribution of grades of lesions and values of euglobulin clot lysis time (ELT) are summarized in [Table 1]. With doses of isoprenaline employed in the present study, varying grades of myo­cardial necrosis (from 0 to 4) and dif­ferent values of ELT were obtained. The changes in ELT observed exhibited a steady increase with the severity of necrosis. Pearson's coefficient of correla­tion (r) between values of ELT and grades of myocardial necrosis was found to be ± 0.8783 (p <0.001) which is highly suggestive of a positive correlation [Figure 1]. Regressiin line of these para­meters plotted by the method of least squares demonstrates a linear correlation with slope and intercept being 88.04 and 44.8, respectively. Pearson's coefficients of correlation (r) between doses of isoprenaline and ELT, and between doses of isoprenaline and grades of myocardial necrosis were + 0.5647 (p < 0.001) and + 0.5638 (p < 0.001), respectively. In saline treated animals (control) ELT was 81.1 ± 15.9.

(B) Effect of isoprenaline on PFA in young rats

ELT in the young animals treated with saline only was 74,0± 13.8 while in isoprenaline challenged rats the ELT was 82.0 ± 14.6 (p > 0.05). None of the animals in this group developed myo­cardial necrosis of any grade.

(C) Effect of propranolol pre-treatment on isoprenaline induced myocardial necrosis and PFA

The distribution of grades of lesions and the changes in ELT following isoprenaline challenge in saline as well as propranolol protected animals are shown in [Table 2]. The grades used to assess the lesions do not conform to a normal dis­tribution curve and hence Fisher's exact probability test; [35] a nonparametric test, was applied to compare the results, ob­tained. For application of Fisher's exact probability test, each set of results was arbitrarily arranged into two groups; group A containing 0,1 and 2 grades and group B containing 3 and 4 grades. The results obtained with propranolol pre­treatment were then compared with the results of isoprenaline alone and the pro­bability of difference was calculated. Pro­pranolol pre-treatment significantly pro­tected animals from the isoprenaline in­duced myocardial necrosis (p < 0.001) in these animals ELT also showed corres­ponding change [Table 2]. Propranolol was devoid of any per se effect on ELT as the ELT in propranolol treated animals was 79.0 ± 16.1 which is not significantly different (p > 0.05) from the control.


 :: Discussion Top


A decline in fibrinolytic activity in blood following myocardial infarction was first observed by Hume [15] and this has been confirmed subsequently by numerous workers. [5],[6],[21],[25],[22] However, it appears that no effort, clinical or ex­perimental, has been made to analyse the relationship between the severity of myocardial damage and the decrease in plasma fibrinolytic activity (PFA).

In the present study administration of different doses of isoprenaline produced variable grades of myocardial necrosis in albino rats. The PFA in these animals as measured by recording the euglobulin clot lysis time was found to be significant­ly decreased depending upon the severity of myocardial necrosis as judged by gross as well as microscopic examination of heart at autopsy. Positive and strong cor­relation was observed between doses of isoprenaline and grades of myocardial necrosis, grades of myocardial necrosis and PFA and also between doses of iso­prenaline and PFA. Pearson's coefficient of correlation (r) between these para­meters was found to be + 0.5638 (p < 0.001) + 0.8783 (p < 0.001) and + 0.5647 (p < 0.001), respectively.

The foregoing observations obviously suggest that changes in PFA may be either due to isoprenaline or myocardial necrosis, however, further experiments rule out the possibility of the former. In young rats isoprenaline administration failed to produce myocardial necrosis and FFA was found to be within normal limits. Propranolol pre-treatment in older rats partially protected the animals from isoprenaline induced myocardial necrosis and the PFA exhibited corresponding decline. These observations clearly pre­clude the possibility of any per se effect of isoprenaline on PFA and the correla­tion observed between these parameters may be due to dependence of severity of myocardial necrosis on the doses of iso­prenaline employed. Thus, the role of isoprenaline being ruled out in influenc­ing PFA, the only other factor responsible for producing changes in PFA in the pre­sent experimental set up is myocardial damage. A positive and strong correlation between grades of myocardial necrosis and decline in PFA clearly suggest that the severity of myocardial damage is re­flected in PFA. Further, measurement of - ELT indicates the plasminogen activator activity, [14],[20],[27] therefore, it appears that severity of myocardial lesion is also related to plasminogen activator activity in plasma.

 
 :: References Top

1.Agress, C. M., Jacobs, H. I., Glassner, H, F., Lederer, M. A., Clerk, W. G., Wrob­lewski, F., Karmen, A. and LaDue, J. S.: Serum transaminase levels in experimental myocardial infarction, Circulation, 11: 711-713, 1955.  Back to cited text no. 1    
2.Bogie, W. and Peers, M.: Fibrinolytic acti­vity and treatment of diabetes, Lancet, I: 1000, 1974.  Back to cited text no. 2    
3.Bonnar, J., Davidson, J. F., Podgeon, C., McNicol, G. P. and Douglas, A. S.: Fibrin degradation products in normal and ab­normal pregnancy and parturition, Brit. Med. J., 3: 137-140, 1969.  Back to cited text no. 3    
4.Buckell, M.: The effect of citrate on euglo­bulin methods of estimating fibrinolytic activity, J. Clin. Path., 2: 403-405, 1958.  Back to cited text no. 4    
5.Chakrabarti, R. and Fearnley, G. R.: Phenformin plus ethyloestrenol in survi­vors of myocardial infarction, Lancet, II: 556-559, 1972.  Back to cited text no. 5    
6.Chakrabarti, R., Hocking, E. D. and Fearnley, G. R.: Reaction pattern to three stresses-electroplexy, surgery and myo­cardial infarction-of fibrinolysis and plasma fibrinogen, J. Clin. Path., 22: 659-662, 1969.  Back to cited text no. 6    
7.Chakrabarti, R., Hocking, E. D., Fearnley, G. R., Mann, R. D., Attwell, T. N. and Jackson, D.: Fibrinolytic activity and coronary artery disease, Lancet, 1: 987­990, 1968.  Back to cited text no. 7    
8.Chapman, B. L. and Gray, C. H.: Prog­nostic index for myocardial infarction treated in a coronary care unit, Brit. Heart J„ 35: 135-141, 1973.  Back to cited text no. 8    
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14.Flute. P. T.: "The Fibrinolytic System of Human Plasma." Thesis for M.D. Degree, University of London, 1960.  Back to cited text no. 14    
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17.Jones, P.: Fibrinolytic system in eclamp­sia, Brit. Med. J . , 2: 222-223, 1971.  Back to cited text no. 17    
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19.Konttinen, A. and Halonen, P. I.: Serum. Alpha-hydroxybutyric dehydrogenase (HBD) in myocardial infarction: compa­rison with glutamic oxaloacetic transami­nase (GOT) and lactic dehydrogenase (LDH), Am. J. Cardiol., 10: 525-531, 1962.  Back to cited text no. 19    
20.Kowalski, E., Kopec, M. and Niewia­rowski, S.: An evaluation of the euglobu­lin method for the determination of fibrinolysis, J. Clin. Path., 12: 215-218, 1959.  Back to cited text no. 20    
21.Lackner, H. and Mersky, C.: Variation in fibrinolytic activity after acute myocar­dial infarction and after the administration of oral anticoagulant drugs and intra­venous heparin, Brit. J. Haematol., 6: 402-423, 1960.  Back to cited text no. 21    
22.LaDue, J. S., Wroblewski, F. and Karmen, A.: Serum glutamic oxaloacetic transaminase activity in human acute transmural myocardial infarction, Science, 120; 497-499, 1954.  Back to cited text no. 22    
23.23.Menon, I, S., McCollum, J. P. K. and Gibson, A. L,: Blood fibrinolytic activity in deep vein thrombosis, Lancet, I: 242­243, 1971.  Back to cited text no. 23    
24.Mittal, M. M., Gupta, N. N. and Malhotra, R. M. L.: A study of plasma fibrinogen content and its fibrinolytic activity in acute cerebral infarction, J. Assoc. Phys. India, 18: 787-793, 1970.  Back to cited text no. 24    
25.Mittal, M. M., Gupta, N. N. and Malhotra, R. M. L.: Study of plasma fibrinogen content and its fibrinolytic activity following acute myocardial in­farction, J. Assoc, Phys. India, 18: 795­801, 1970.  Back to cited text no. 25    
26.Murakami, M., Matsuda, T., Nishio, T., Hiramaru, M., Manmi, S. and Takase, M.: Changes in platelet adhesiveness, blood coagulation and fibrinolysis before and after the development of myocardial infarction, Japan. Heart J., 11: 450-459, 1970.  Back to cited text no. 26    
27.Norman, P. S.: Plasmin system I. Mea­surement of human and animal plasmino­gen; Measurement of an activator in human plasma, J. Expt. Med., 106: 423­437, 1957.  Back to cited text no. 27    
28.Ogston, D. and McAndrew, G. M.: Fibrinolysis in obesity, Lancet, II: 1205­1207, 1964.  Back to cited text no. 28    
29.Omar, J. B., Saxena, H., Mital, H. S., Rohatgi, V. K. and Gopal, M. G.: Fib­rinolytic activity in malignant neoplastic diseases, J. Assoc. Phys. India, 19: 293­296, 1971.  Back to cited text no. 29    
30.Pandolfi, M., Nilsson, I. M., Robertson, B. and Isacson, S.: Fibrinolytic activity of human veins, Lancet, 11: 127-128, 1967.  Back to cited text no. 30    
31.Pandolfi, M., Isacson, S. and Nilsson, I. M.: Low fibrinolytic activity in the walls of veins of patients with thrombosis, Acta, Med. Scandinav., 186: 1-5, 1969.  Back to cited text no. 31    
32.Rawles, J. M., Warlow, C. and Ogston, D.: Fibrinolytic capacity of arm and leg veins after femoral shaft fracture and acute myocardial infaction, Brit. Med. J., II: 61-62, 1975.  Back to cited text no. 32    
33.Rona, G., Chappel, C. I., Balaze, T. and Gaudry, R.: An infarct like myocardial lesion and other toxic manifestations pro­duced by isoproterenol in the rat, Arch. Path., 67: 443-455, 1959.  Back to cited text no. 33    
34.Saxena, K. K., Srivastava, V. K., Gupta, B., Srivastava, R. K. and Prasad, D. N.: Propranolol and experimental myo­cardial necrosis, Indian J. Physiol. & Pharmacol., 21: 401-402, 1977.  Back to cited text no. 34    
35.Siegal, S.: "Non-parametric Statistics for the Behavioural Sciences", McGraw-Hill Book Co. Inc., New York, 1956, p. 96.  Back to cited text no. 35    
36.Sobel, B. E. and Shell, W. E.: Serum enzyme determinations in the diagnosis and assessment of myocardial infarction, Circulation, 45: 471-482, 7,972.  Back to cited text no. 36    
37.Thiele, G. Z.: - Increased fibrinolytic activity in thrombocytopenia and its therapeutic modification by PAMBA Aerzti Forthild, 63: 1296-1298, 1969.  Back to cited text no. 37    
38.Witteveen, S. A. G. J., Hemker, H. C., Hollaar, L. and Hermens, W. T.: Quantitation of infarct size in man by means of plasma enzyme levels, Brit. Heart J., 37: 795-803, 1975.  Back to cited text no. 38    
39.Wroblewski, F.: Clinical significance of serum enzyme alterations associated with, myocardial infarction, Amer. Heart J., 54: 219-224, 1957.  Back to cited text no. 39    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2]



 

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