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52 RELATIONSHIP BETWEEN REPERFUSION-INDUCED VF,! ISCHAEMIA-INDUCED ARRHYTHMIAS AND TIME OF DRUG INTERVENTION IN ANAESTHETISED DOGS. S.J. Coker & J.R. PaFra t t . Department of Physio logy & Pharmacology, U n i v e r s i t y of St ra theLyde, Glasgow, Scot land.

The a n f i a r r h y t h m i c a c t i v i t y of the thromboxane synthetase i n h i b i t o r Dazmegrel (3mg/kg) and n t f e d i p t n e (5#g/kg + lpg kg -1 mtn -1) were examined tn c h l o r a l o s e - anaes the t i sed open-chest greyhounds sub jec t to occ lus ion of the LAD wi th subsequent repe r fus ion a f t e r 40 min of ischaemia. Pret reatment wi th e i t h e r drug markedly reduced the inc idence of VF f o l l o w i n g repe r f us i on whereas drug admin is t ra tLon 25 min a f t e r occ lus ion of the LAD f a i l e d to reduce repe r fus ion - i nduced VF. The e f f e c t s of both drugs on the number of ischaem[a- induced ec top[c beats (VEBs) and the inc idence of repe r fus ion - i nduced VF are d e t a i l e d below,

Pre-ischaemLa 25 min Post-tschaemia Cont ro l Dazmegrel N [ f ed ip ine Cont ro l Dazmegrel N i f ed tp ine

n=9 n=7 n=9 n=lO n=/O n=lO

VEBs 720• 193• 119• 702• 655• 677•

% VF 88% 29% t 22% t 70% 50% 70%

These r e s u l t s suggest tha t the inc idence of repe r fus ion - i nduced VF depends on events occur r ing dur ing ischaemia, such as the number of a r rhy thmias .

53 ROLE OF Ca 2+ IN ABNORMAL PACEMAKER ACTIVITY OF GUINEA-PIG PAPILLARY MUSCLE. S. Saman, W. Coetzee, L.H. Opie. MRC Ischaemic Heart Research Unit, Medicine Dept and Groote Schuur Hospital, University of Cape Town, Observatory, 7925, South Africa.

Abnormal pacemaker activity (APA) of ventricular myocardium might underlie malignant arrhythmias. We observed APA under procedures that increased internal Ca 2+ in the guinea-pig papillary muscle. APA was preceded by the appearance of delayed afterdepolarizations (DAD) . Isoproterenol (10-7M to 10-5M) produced DAD's and APA when the external K + was 5,9 mM, PO 2 was over 450 mmHg and glucose was ii mM. Decreasing K + to 1.2 mM or added ouabain (7 x 10-7M) increased the

incidence of the isoproterenol induced APA. Higher stimulation rates and increased external Ca 2+ increased the DAD amplitude. Reperfusion after 40 min of simulated

ischaemia (PO 2 = 30 mmHg; substrate free) caused a high incidence of APA that could be blocked by lidocaine (2,5 x 10-4M) or verapamil (5 x 10-6M) added in

the "ischaemic" period. Our results support the hypothesis that increased internal Ca 2+ triggers APA. Isoproterenol might directly enhance Ca 2+ channel activity whereas "ischaemia", low K + or ouabain by increasing internal Na + (by Na+/K + pump inhibition) might indirectly increase internal Ca 2+ (by reducing Na+/Ca 2+ exchange). Lidocaine or verapamil may have protected by respectively blocking Na + or Ca 2+ channel activity. We propose that APA plays a major role in ventricular fibrillation and tachycardia during regional ischaemia and reperfusion.

54 VOLUME LOADING INCREASES ARRHYTHMIAS AND MORTALITY IN BEAGLES DURING CORONARY LIGATION AND REPERFUSION. A.J. Higgins and R.C. Williams. Pfizer Central Research, Sandwich, Kent CTI3 9NJ, U.K.

Coronary ligation and reperfusion in Beagles often produces low and variable mortality due to an extensive collateral network. In an attempt to overcome this problem, we exploited the observation that heart failure in post-infarction patients is a major risk factor for VF. Under chloralose anaesthesia, a nylon suture was placed around the left anterior descending coronary artery proximal to the first major branch but distal to the septal artery. 10-20 rains before occlusion, dextran iiO (6% w/v) was infused to increase plasma volume by up to 50%. 30 rains coronary occlusion was then followed by IO rains reperfusion, at which time survivors were invariably in sinus rhythm. Overall severity was assessed on a continuous scale, ranging from death soon after occlusion, to survival with only few extrasystoles. D e . r a n (ml/kg) 0 15 17.5 20 25 Occlusion mortality O/IO(0%) 0/7(0%) 0/7(0%) 4/10(40%) 2/7(29%) Total mortality 4/10(40%) 4/7(57%) 5/7(71%) 9/10(90%) 5/7(71%) Dextran (15-25 ml/kg) significantly increased (a) occlusion mortality, (b) total mort- ality, and (c) overall severity, the latter in a dose-related manner. Severity was positively correlated with left ventricular end-diastolic pressure. We conclude that this procedure may serve as a useful model of the high-risk MI patient.