Reduction of mortality by sulphinpyrazone after experimental myocardial infarction in the rat

Abstract

In the Anturan Reinfarction Trial (ART 1978). reinfarctions and, expecially, sudden cardiac deaths were less frequent among patients treated with sulphinpyrazone than among those receiving placebo medication. There is wide, general interest in elucidating the mechanism by which sulphinpyrazone brings about these protective effects. Although they are presumed to be in some way related to its platelet-stabilizing action, conclusive evidence is lacking and exactly how the two phenomena are linked is still very much a matter of conjecture. Various research groups have therefore investigated the effects of sulphinpyrazone on the course of events following acute experimental myocardial infarction in animals. In their initial studies, Kelliher et al and Povalski et al (in press) and Moschos et al (1979) found that the early arrhythmias (ventricular fibrillation, ventricular tachycardia and ventricular extrasystoles) occurring subsequent to coronary occlusions in cats and dogs were less frequent if the animals had been pretreated with sulphinpyrazone. We have studied the effects of the drug on mortality after ligation of the left anterior descending coronary artery (LAD) in the rat.The operation was performed according to Selye et al (1960) in male rats (Tierfarm Sisseln), 222 f 2 g, anaesthetized with ether. Essentially, this technique consists in ligating the LAD between the left auricle and the pulmonary cone. If the operation is completed within 30 s, spontaneous respiration recommences after air has been expelled from the thorax by gentle lateral pressure and the wound closed.A few animals died as a result of haemorrhage during or short!y after the operation. In the present series of experiments, there were four deaths in the sulphinpyrazone group and two among the controls. These animals were not included in the evaluation of the results.* Correspondence.Sulphinpyrazone was administered for three days in a dose of 30 mg kg-' S.C. twice daily, mornings and evenings. The controls received 0.90,; NaCl (saline). LAD ligature was performed on the second day of treatment, that is between 1-6 h after the third sulphin. pyrazone dose. N o attempt was made to relate subsequent mortality with the exact time, after the last dose, of coronary artery ligation. After surgery, i.e. excluding the animals that died during the operation, the sulphin. pyrazone group numbered 91 rats and the control group 103. These were composed of 12 separate control and sulphinpyrazone-treated groups with 5-1 1 rats in each.The post operative mortality was followed up in both groups over a period of 21 days. In computing the mortality rates, a distinction was drawn between deaths within 30 min of the operation and later deaths. This was done because, according to previous findings (Kane et a1 1979;Kenedi & Losonci 1973), deaths occurring in the first half hour are predominantly due to arrhythmias, whereas, in our own experience, the main causes of subsequent deaths are pulmonary oedema, hydrothorax or massive infarctions with dilatation of the he...

A protective effect of sulphinpyrazone against coronary occlusion‐induced shortening of myocardial refractory periods in the rat

“…This has been shown in the dog (Povalski et al, 1980;Moschos et al, 1981), in the cat (Kelliher et al, 1980), and in the rat (Brunner et al, 1980;Lepran et al, 1981), although the drug was reported to be inactive in the pig (Staubli et al, 1984). Sulphinpyrazone has also been shown to protect animal hearts against some but not all of the biochemical and histological consequences of coronary artery occlusion (Kelliher et al, 1980;Povalski et al, 1980;Bolli et al, 1981;Innes & Wiseman, 1981;Moschos et al, 1981;Karmazyn, 1984).…”

Cardioprotective Effects of Defibrotide in Acute Lethal and Nonlethal Myocardial Ischemia in the Cat

“…However, other investiga tors found that lidocaine and verapamil were active in inhibiting ventricular arrhythmias in both man [21] and dog [22]. When admin istered for 3 days to rats in a myocardial infarction model, sulfinpyrazone reduced the mortality rate of the animals, though the un derlying mechanism of action was unknown [23], Atenolol has been suggested to have value for preserving the ischemic myocar dium [24], We were not able to demonstrate any pro tective effect with urokinase at a dosage which did cause considerable lysis of venous thrombi in the rabbit (data not shown); de spite similar fibrinolytic and plasminogen activating actions of D and urokinase [25] the underlying mechanisms may be different.…”

A direct protective effect of sulphinpyrazone on ischaemic and reperfused rat hearts

“…The mechanism of its beneficial effect is uncertain although it may be related to its ability to reduce platelet aggregation (Smythe et al, 1965), a phenomenon seemingly dependent on platelet cyclooxygenase inhibition which would reduce thromboxane A2 production (Ali & McDonald, 1977). Studies using experimental animal models have demonstrated that sulphinpyrazone protects the heart from various pathological insults including catecholamine administration (Karmazyn et al, 1981a;Innes & Weisman, 1981) as well as coronary artery ligation (Brunner et al, 1980;Innes & Weisman, 1981;Davenport et al, 1981) in vivo, although the mechanistic basis for this protection still remains obscure. Few studies have been done on in vitro preparations in which blood-borne agents such as platelets would not be contributing factors.…”

“…The mechanism of this beneficial effect is uncertain although these trials were carried out because sulphinpyrazone is a potent inhibitor of platelet aggregation. In experimental animals sulphinpyrazone has been shown to protect against cardiac injury produced by coronary artery ligation by increasing collateral blood flow , reducing mortality (Brunner et al, 1980) and preserving histological integrity (Innes & Weismann, 1981). Sulphinpyrazone also protects against catecholamine-induced cardiac injury as manifested by a lower mortality, reduced cardiac enzyme release, maintenance of histological integrity and prevention of coronary vasoconstriction (Karmazyn et al, 1981a,b).…”