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November 1994, Volume 44, Issue 11

Original Article

Effects of Aspirin and Indomethacin on Ventricular Arrhythmias Comparative Study

A. Shabbir Ali Bhatti  ( Department of Pharmacology and Therapeutics, Allama Iqbal Medical College, Lahore. )
Hidayat Hussain Khan  ( Department of Pharmacology and Therapeutics, Allama Iqbal Medical College, Lahore. )


The effects of aspirin and indomethacin on the ventricular arrhythmias produced by ligation (ischaemia) and unligation (reperfusion) of the circumflex branch of the left coronary vessel were evaluated in fifty male rabbits weighing 1.5 - 2 kg. Pretreatment of animals with aspirin (50 mg/kg i/v) suppressed all arrhythmias during ischaemia. Low dose of aspirin (12.5 mg/kg i/v) produced no mortality. Indomethacin (2.5 mg/kg) was unable to control ischaemia and reperfusion-induced ventricular arrhythmias. However, higher doses of indomethacin (50 mg/kg) suppressed ischaemia-induced arrhythmias to some extent but the mortality rate was increased (37%). Fragment of ventricular fibrillation was zero during ischaemia after treatment with aspirin and indomethacin but reperfusion-induced ventricular fibrillation was not controlled by any of these drugs. Aspirin (12.5 mgfkg, 50 mg/kg) and indomethacin (2.5 mg/kg) signifi­cantly suppressed ischaemia - induced tachyarrhythmias while reperfusion induced tachyarrhythmias were suppressed only by aspirin. There was no significant effect on the mean arterial pressure after these drug treatments(JPMA 44:261,1994).


Common ventricular anhythmias are ventricular ex­trasystoles, ventricular lachycardia and fibrillation. The com­mon causes include acute or chronic ischaemia, digitalis toxicity, effects of anti-arrhythniic drugs and tricyclic antide­pressants. Ischaemia and reper fusion both produce increase in heart rate (tachyarrhythmias) due to the endogenous release of catecholamine. Moreover, ischaemia and reperfusion are potent stimuli for prostaglandin synthesis by heart1,2. Prostaglandins are released from ischaemic myocar­dium and nonsteroidal anti-inflammatory drugs (NSAJD) block its release3. NSAIDs differ in potency and degree of prostaglandin synthesis inhibition4. Studies have shown that thromboxane A2 is released during ischaemia and reperfu­sion5. Aspirin like drugs are potent inhibitors of thromboxane A2 (TxA2). Antagonists of TxA2 seem to afford a direct cardio protective effect during occlusion. The protective effect of aspirin may be due to inhibition of synthesis and release of TxA2 from myocardium6. This study attempts to evaluate the effects of aspirin and indomethacin on ventricular arrhythmias produced during ischaemia and reperfusion by ligating the circumflex branch of left coronary artery in male rabbits.

Materials and Methods

Male rabbits of species, oryctolagus, cuniculus weigh­ing 1.5-2 kg were used in our experimental model. Pentobar­bitone sodium (30 mg/kg.i/v) was used as anesthetic agent, both for induction and maintenance. Ventilator (volume-oper­ated) was adjusted at 32 strokes/min, 16-20 mI/stroke of air. Mean arterial pressure was recorded by direct cannulation of femoral artery and connecting it to the pressure transducer of harvard oscillograph (speed 50 mm/sec). Parameters recorded included heart rate (HR), mean arterial pressure (MAP) and ECG changes. Animals in which surgical procedure produced arrhyth­mias or severe fall in mean arterial pressure were discarded. Circumflex branch of left coronary artery was ligated close to auricle to produce ischaemia and unligated to produce reperfusion7. Ischaemiaof 15 minutes was produced followed by a period of reperfusion of 30 min. Aspirin 12.5 mg/kg, 50 mg/kg I/V and indomethacin 2.5 mg/kg, 10 mg/kg I/V were given 15 ruins prior to the ligation of vessel. Indomethacin infusion 180 ug/kgwas maintained throughout the experiment to keep the plasma level constant. The rabbits were divided into five groups, 1,11,111, IV, V. Group I (n=20) was selected as control. This group under­went same surgical procedure and was given no drug. Group II (n=6) was given aspirin 12.5 mg/kg i/v slowly before the ligation of Cx branch of left coronary artery (Cx, LCA). Group III (n=7) was given aspirin, 50 mg/kg I/V before ligation of Cx, LCA. Group IV (n=9) was given indomethacin 2.5 mg/kg I/V before ligation of Cx, LCA. Group V(n8) was given indomethacin 10 mg/kg I/V slowly before ligation of Cx, LCA
Statistical Analysis.
The results were estimated and expressed as X±S.E (X= mean S.E. = Standard error). Treatments were estimated at 5% level of significance. Wherever necessary paired or unpaired “t” test was used. Percentages of the ventricular arrhythmias were compared.


The following results of heart rate, mean arterial pressure and E.C.Gs were observed in Group Ito V. Group I
During 15 mins ischaemia ventricular ectopic beats (VEBs) were produced in 10% ventricular tachycardia (VT) in 15% and VF  (Ventricular fibrillation) in 15% of the animals. During 30 mins reperfusion, VEBs were produced in 10%, VT in 15% and VF in  30% of the animals (Table I).

There was 10% mortality during ischaemia and 15% mortality during reperfusion (Table II).

During  ischaemia heart rate (H.R.) was 380+11.40/min and mean arterial pressure (MAP) was 37.16+87 mmHg. During reperfusion,  H.R. was 390+21.09/min and MAP was 40.83+10.31 mmHg (Tables III and IV).

Group II
During 15 mins ischaemia VEBs were produced in 17% of the animals and no VT, VF or Blocks were produced. During  reperfusion VF was produced in 17% of the animals and no VEBs VT or Blocks were occurred (Table V).
There was no mortality  (Table II). During 15 min ischaemia and 30 min reperfusion heart rate was significantly reduced i.e., 21.57% and 20.51% and  MAP was not affected significantly i.e., -9.84% and -16.33% (Tables III and IV).
Group III
During 15 mins ischaemia there was no ventricular arrhythmia. But during 30 min reperfusion VEBs occured in 28%, VT in 14% and VF in 14% (Table I). There was 14% mortality (Table II). During 15 mins ischaemia and 30 mins reperfusionHRwas not significantly affectedi.e, +l.57%and +4.18% and similarly in MAP there was 36.32% and 2.44% positive change (Tables III, IV).
Group IV
During 15 mins ischaemia VEBs occurred in 33% and atrioventricular block (AV block) in 11%. During 30 min reperfusionVEB, VF and AV block occurred in 11%, 33% and 11% of the animals (Table I). There was 11% mortality during ischaemia (Table II). During 15 min ischaemiaH.R. andMAP were changed -12.10% (P<0.05) and +3.14% respectively. During 30 min reperfusion H.R and MAP were not affected significantly i.e., 0.51% and +6.53% respectively (Tables III, IV).
Group V
During 15 mins ischaemia only VEBs occurred in 12% of the animals. During 30 mins reperfusion VEB, VT and VF occurred in 62%, 50% and 25% of the animals respectively (Table I). There was 12% mortality during ischaemia and 37% during reperfusion (Table II). Heart rate during ischaemia and reperfusion were not significantly changed i.e., +3.94% and +7.69% respectively (Table Ill). Mean arterial pressure was changed +7.18% and -13.47% during ischaemia and reperfu­sion respectively (Table IV). These changes were not statisti­cally significant (P>0.05).


This study was undertaken to see the effects of various nonsteroidal anti-inflammatory drugs (NSAIDs) on the ven­tricular arrhythmias. Ventricular arrhythmias are produced as a result of increased irritability of myocardium. These may be produced due to abnormal automaticity or due to abnormal conduction, especially re-entry. Useful antiarrhythniic drugs are usually depressant of cardiac functions, a factor of considerable importance in the patient of impaired cardiac functions. Ventricular arrhythmias particularly reperfusion induced arrhythmias are very resistant to most of conventional anti- arrhythmic drugs6. Salicylates6 have no significant effects on the normal haemodynamic parameters8. Certain similarities between acute myocardial in­farction and acute inflammatory reactions have led to the notion that steroids and non-steroidal anti-inflammatory agents might protect ischaemic myocardium9,10. It is also reported that calcium ions are released during ischaemia and reperfusion11. In any inflammatory reaction prostaglandins are produced and lysosornal enzymes are liberated. Throm ­boxane is also released due to tissue damage. Thromboxane A2 is potent agent for platelet aggregation. It means several factors act for the genesis of irritability of the myocardium after ischaemia and reperfusion. Aspirin has been found to decrease the intensity of tachyarrhythmias during occlusion and reperfusion. The protective effect may be due to inhibition of synthesis and release of thromboxane A2 from myocar­dium4. Salicylates like calcium channel blockers depress the slow inward current in both SA nodes cells and atrial muscle fiber of rabbit heart12,13. Although nonsteroidal anti- inflam­matory agents appear to act by inhibition of prostaglandin biosynthesis, these differ in anti-inflammatory potency and degree of prostaglandin synthesis inhibition14. Indomethacin (2.5 mg/kg) is unable to control ischaemia induced and reperfusion induced arrhythmias. Higher doses (10 mg/kg) though control ischaemia induced arrhythmias to some extent but mortality rate is increased. Large doses of indomethacin (50 mg/kg) produced unwanted effects i.e., increased yen­tricular arrhythrnias and this may be due to lysis of lysosomes as large doses of NSAIDs have been reported to produce lysis of lysosomes15,16. Both ischaemia and reperfusion act as stimuli for the genesis of ventricular arrhythmias. Most severe arrhythmias that occur after occlusion period of 5-15 min are 50-56% ventricular fibrillation. Reperfusion ventricular fibrillation occurs much less commonly when reperfusion was delayed from 30-60 minutes6. Ventricular fibrillation is the worst type of ventricular arrhythmia. Its control is important to protect the animal from death. Previous experimental studies have shown that most of the conventional anti-arrbythniic drugs fail to suppress reperfusion ventricular fibrillation17. NSAJDs have also failed to suppress ventricular fibrillation. Non-stemidal anti-inflammatory drugs especially aspirin (12.5 mg/kg) controls ischaemia induced ventricular arrhythmias and su­pra sventricular tachyarrhythmias without affecting haemody­namic parameter significantly and there is no mortality. On the other hand low dose of indomethacin (2.5 mg/kg) controls supra ventricular tacbyarrhythniias but fails to suppress yen­tricular arrhythmias. When we used large dose of in­domethacin (10 mg/kg) ventricular arrhytlunias were sup­pressed but mortality rate increased and moreover supra ven­tricular tachyarrhythmias were not affected significantly.


Authors are thankful to Prof. Maqsood Ahmed Cheema, Ex Head of Department of Pharmacology and Therapeutics of K. E. Medical College for his expert opinions and technical advice in this study.


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