Shiva D. Seth

Role of aspirin in modulating myocardial ischemic reperfusion injury.

The role of low-dose aspirin (3 mg/kg, i.v.) in attenuating ischemic reperfusion injury was studied in a canine model. Regional ischemia for 40 min was produced by temporary occlusion of the left anterior descending coronary artery and thereafter reperfusion instituted for 3 h. Mean arterial pressure (MAP), heart rate (HR), left ventricular end diastolic pressure (LVEDP), positive (+) LV dP/dtmax and negative (−) LV dP/dtmax were monitored alongwith myocardial adenosine triphosphate (ATP), creatine phosphate (CP), glycogen and lactate. Following reperfusion, there was a significant fall in (i) MAP, (ii) (+) LV dP/dtmax and (iii) (−) LV dP/dtmax. LVEDP was corrected after about 2h of reperfusion. Replenishment of only myocardial CP occurred, without any change in ATP and glycogen, although lactate accumulation was corrected.Aspirin administered 15 min before reperfusion (posttreatment) caused normalisation of LVEDP within 15 min and prevented any deterioration in (−) LV dP/dtmax, although it had no effect on MAP and (+) LV dP/dtmax. After 3h of reperfusion (post-treatment), myocardial ATP, CP, glycogen and lactate contents became normal. The number of premature ventricular complexes was significantly reduced after aspirin treatment. The present study indicates that low-dose aspirin post-treatment can ameliorate at least some of the deleterious consequences of reperfusion injury of the myocardium.

Interaction of ouabain and propranolol in the central nervous system. Neurally-mediated effects on the cardiovascular system.

The effect of intracerebroventricular (i.c.v.) ouabain alone and after pretreatment with i.c.v. (+/-)-propranolol, (+)-propranolol, UM-272 (a quaternary analogue of propranolol) and lignocaine, on arterial blood pressure (BP), heart rate (HR) and cardiac rhythm was investigated in chloralose anesthetized, vagotomized cats. Ouabain elicited an increase in BP and HR followed by cardiac arrhythmias of ventricular origin. Pretreatment with (+/-)-propranolol, (+)-propranolol or UM-272 attenuated/prevented the cardiovascular effects of ouabain whereas lignocaine did not modify the response appreciably. Since UM-272, which lacks local anesthetic activity and beta-blocking activity also shared the antagonism with (+/-)-and (+)-propranolol, it is deduced that neither beta-blocking nor local anesthetic activity of propranolol could be responsible for this antagonism. This is supported by the fact that lignocaine which has a comparable local anesthetic effect of propranolol failed to modify significantly the cardiovascular response to ouabain. The antagonism appears to be a direct neural depressant effect independent of local anesthetic action. The neural depressant effect may be due to an interference in depolarization process and/or a neurone-blocking effect.

Antiarrhythmic effects of prostaglandins E2 and I2 on ouabain-induced cardiac arrhythmias in cats: Effect of vagotomy and adrenergic neuron blockade

The effects of i.v. prostaglandins (PGs) E2 and I2 on ouabain-induced cardiac arrhythmias were investigated in chloralose-anaesthetized cats. Bilateral vagotomy and guanethidine-pretreatment interventions were employed to elucidate the involvement of vagal and sympathetic neural influences in these effects. PGE2 (1 micrograms/kg/min i.v. infusion for 5 min) and PGI2 (4-16 microgram/kg i.v. bolus injections) effectively suppressed the ouabain-induced arrhythmias in a control group of cats. The bilateral vagotomy or guanethidine-pretreatment interventions did not significantly alter the antiarrhythmic effects of PGE2 and PGI2. It is concluded that the presence of functionally intact sympathetic and vagal nerve supply to the heart is not a prerequisite for the antiarrhythmic effects of i.v. administered PGE2 and PGI2. The possible role of direct action of these PGs on the myocardium is discussed.

LACK OF ANY ADDITIONAL BENEFIT IN COMBINING ASPIRIN WITH ILOPROST IN A CANINE MODEL OF MYOCARDIAL REPERFUSION INJURY

The effects of iloprost infusion (100 ng/kg/min for 75 min) alone and in combination with aspirin (3 mg/kg IV bolus) were compared in a canine model of myocardial reperfusion injury. Regional ischemia of 40 min was produced by temporary occlusion of the left anterior descending coronary artery, after which the myocardium was reperfused for a period of 3 hours. Mean arterial pressure (MAP), heart rate (HR), left ventricular end diastolic pressure (LVEDP), positive (+) LVdP/dtmax and negative (-) LVdP/dtmax were monitored. Rate pressure product and (-) dP/dt/Pmax were also derived from the above. Myocardial tissue levels of adenosine triphosphate (ATP), creatine phosphate (CP), glycogen and lactate were estimated. Following reperfusion in the saline treated group, there was a significant fall in (i) MAP, (ii) (+) LVdP/dtmax and (iii) (-) LVdP/dtmax. LVEDP was corrected about 2 hours after reperfusion. Despite correction of lactate accumulation, ATP and glycogen were not restored although the CP store was replenished. The hemodynamic profiles in both iloprost and in combination treated groups were similar; (i) depressed MAP (particularly during iloprost infusion) without any significant change in HR (ii) no significant depression in (+) LVdP/dtmax (iii) depression in (-) LVdP/dtmax but not when corrected for lower Pmax and (iv) a significant reduction in the incidence of reperfusion arrhythmias. Similarly, in both the drug/s treated groups, ATP, CP and lactate were normalised although glycogen store was not restored. The results of this study indicate (i) cardioprotective effect of iloprost even when administered prior to reperfusion and (ii) no additional protective effect of combining iloprost and aspirin.

The vagal involvement in the antiarrhythmic and arrhythmogenic effects of prostaglandin F2α on ouabain-induced cardiac arrhythmias in cats

The effects of prostaglandin F2 alpha (PGF2 alpha) on ouabain-induced cardiac arrhythmias were investigated in chloralose-anaesthetized cats. Bilateral vagotomy and atropine intervention were employed to elucidate the involvement of vagal neural influences. PGF2 alpha (2-16 micrograms/kg i.v. bolus) predominantly suppressed the ouabain-induced ventricular and supraventricular arrhythmias and less commonly aggravated them in vagi-intact cats. The antiarrhythmic effect of PGF2 alpha was considerably, but not statistically significantly, decreased while its arrhythmogenic effect was significantly (p less than 0.05) increased in atropine-pretreated group. In vagotomised group PGF2 alpha failed to abolish the arrhythmias but it aggravated them to a degree comparable to that observed in vagi-intact group. It is concluded that the PGF2 alpha exhibits both antiarrhythmic and arrhythmogenic properties and these are largely due to elicitation of two opposing neural reflexes - one being protective and another being deleterious to ouabain-induced arrhythmias.

Neurally induced digitalis arrhythmias and the adrenoceptors

Abstract Intracerebroventricular (i.c.v.) administration of ouabain to chloralose-anesthetized, vagotomized cats elicited a dose-related increase in blood pressure and heart rate followed by ventricular arrhythmias; these effects were attributable to a sympathoadrenal discharge triggered fromthe centeral nerouv system. In presence of an effective vascular α-blockade with an i.v. α-blocker, the vasopressor response to i.c.v. ouabain was reverse toa vasodepressor one; this is reminiscent of the ‘vasomotor reversal phenomenon of Dale’. On the other hand, in the presence of an effective β-blockade with an i.v. β-blocker the vasopressor response was augmented. The vascular response to i.lc.v. oubain is thus the net effect mediated by both α- and β-2-receptors and the blockade of one unmasks the other. The pre-existing α-blockade prevented the appearance of arrhythmias after i.c.v. auabain. This may have been due to the ability of the α-blocker to prevent the rise in BP, however, a direct antiarrhythmic effect on the heart may also have been involved. The pre-existing β-blockade failed to significantly affect the tachycardia and the incidence of arrhythmias. This suggests that adrenergic neurogenic arrhythmias differ from the arrhythmias induced by exogenously administered catecholamines, since the latter are completely antagonized by β-blockers wehreas the former and less readily antagonized. Further, the ability of a β-blocker to inhibit the isoprenaline-induced tachycardia (as a test of β-blockade) may not accurately reflect the ability to antagonized the cardiac effects evoked by a strong and diffused sympathetic stimulation. Futhermore, it appears that the blockade of cardiac β-receptors is not equivalent to surgical sympathetic denervation of the heart and that the arrhythmogenic stimuli originating in the central nervous system may travel to the heart through pathways resistant to conventionally employed antagonists such as β-blockers.

The lack of involvement of central nervous system in the antiarrhythmic effects of prostaglandins E2, F2α, and I2 in cat

The role of the central nervous system (CNS) in the antiarrhythmic effects of prostaglandins (PGs) E2, F2 alpha, and I2 was studied by administering each agent into the left lateral cerebral ventricle (i.c.v. administration) of chloralose-anaesthetized cats. The cardiac arrhythmias were produced by intravenous (i.v.) infusion of ouabain (1 microgram/kg/min). The PGs E2, F2 alpha and I2 on i.c.v. administration in the dose range of 1 ng to 10 micrograms failed to inhibit ouabain-induced cardiac arrhythmias. However, when infused i.v., PGE2 (1 microgram/kg/min), PGF2 alpha (5 micrograms/kg/min), and PGI2 (2 micrograms/kg/min) effectively suppressed these arrhythmias. The standard antiarrhythmic drug propranolol (0.5-8.0 mg) on i.c.v. administration also significantly reduced the ouabain-induced cardiac arrhythmias. It is suggested that the CNS is not the site of action of PGs E2, F2 alpha, and I2 in antagonising the ouabain-induced cardiotoxicity in cats.

Effect of Nifedipine and Hyaluronidase Alone and in Combination on Myocardial Preservation in Experimental Myocardial Infarction — A Morphological and Biochemical Profile

The extent of myocardial necrosis subsequent to coronary artery occlusion is of utmost significance, because the patient’s survival depends largely on the extent of damage and the reversibility of ischemic tissue. Though various pharmacological interventions have been found to have some salutory effects on the ischemic myocardium, nevertheless, no drug administered singly has been shown to be totally effective in preventing further damage or to retrieve the ischemic tissue. Hence the combinations of various cardioprotective drugs, eg; calcium channel blockers, beta-blockers, nitroglycerine etc. are being investigated for their synergistic effects (1–6).

Modified method for the production of cardiac arrhythmias by ouabain in anesthetized cats

A modified method of producing ouabain-induced cardiac arrhythmias in chloralose-anesthetized cats has been developed, whereby prolonged arrhythmias with low incidence of mortality (12%) are observed. Furthermore, the employment of a modified arrhythmia scale in the present model allowed a quantitative estimation of antiarrhythmic efficacy of test drugs and also made it possible to unravel the arrhythmogenic nature of these substances. This improved method could be conveniently used for the quantitative screening of both the antiarrhythmic or the arrhythmogenic nature of test drugs.

Comparison between serum isonicotinic acid hydrazide (INH) levels and urinary sulfadimidine (sulfamethazine) acetylation as predictors of INH acetylator status

The acetylator status of 40 children with pulmonary tuberculosis was investigated by (1) sulfadimidine (SDM; sulfamethazine) acetylation test in urine and (2) estimation of isonicotinic acid hydrazide (INH) levels. The antimode was at 70% based on the frequency distribution of SDM acetylation. Children acetylating less than 70% of administered SDM were taken as slow acetylators while those with more than 70% as rapid acetylators. The serum INH antimode was at 0.85 micrograms/ml. Thus serum values less than 0.85 micrograms/ml categorised a child as rapid and those with more than 0.85 micrograms/ml as slow acetylators. The sensitivity of these two methods was similar with a correlation coefficient r = 0.64. Thus the determination of the type of acetylator by SDM acetylation test is equally reliable and technically simpler and is recommended instead of INH serum concentration.