J Mol Cell Cardiol 18 (Supplement 1) (1986) 79EICOSANOIDS AND SUSCEPTIBILITY TO VENIRICULAR ARRHYTHMIAS. James R. Parratt, Department of Pharmacology, University of Strathclyde, Glasgow, GI 1XW, Scotland, UK. There is increasing experimental evidence that the bsIance between the early local release of thromboxane (IxA2, mainly from platelets) andprostacyclin (PGI2, mainly from endothelium) in myocardial isehaemia is one major factor determining the incidence and severity of the life-threatening ventriculsr arrhythmias that result" both from ischaemia and subsequent reperfusion of the myocardium, ln brief, the evidence is that these eicossnoids are released within minutes of coronary blood flow reduction and that the extent of this release relates to the severity of early ischaemia-induced ventrieular arrhythmias. The evidence that TxA2 release is arrhythmogenic under these circumstances is that the~severity of these arrhythmias is reduced by (i) drugs that selectively inhibit thromboxane synthesis (e.g. dazoxiben, dazmegrel, low-dose aspirin) and (ii) drugs that block thromboxane receptors (AH.23848; BM 13,177). The evidence that PGI2 release is protective comes from (i) studies in which either PGI2 or iloprost is infused locally into the coronary circulation or (ii) the use of nafazatrom \which increases the amount of PGI2 generated during ischaemia. Both procedures reduce the severity of these srrhythmias. Evidence that prosteeyclin release is an important protective mechanism also comes from studies with cyclooxygenase inhibitors. These results draw attention to the importance of the endothelial-platelet interaction in arrhythmoqenesis.
8 0 A D E N I N E NUCLEOTIDES AND VULNERABILITY TO VENTRICULAR FIBRILLATION. W.F. Lubbe. Department of Medicine, University of Auckland and Green Lane Hospital, Auckland, NZ. An altered state of vulnerability is required for ventricular fibrillation (VF) to becc~ne established. The isolated perfused rat heart was used to study the influence of adenine nucleotides and their metabolites on vulnerability to VF. This preparation, stable even with regional ischaemia, bec(xnes vulnerable to VF on reduction of extracellular potassitln ([K+ ] o ) to 2.0nmDl/l with invariable VF after coronary ligation and following reperfusion. When [K+]o is elevated to 9.0mmol/l hearts are resistant to VF. Adenine nucleotides and metabolites were assayed in hearts vulnerable and in hearts resistant to VF. High energy phosphates, adenosine, inosine and hypoxanthine did not discriminate between hearts vulnerable and resistant to VF whereas levels of cyclic AMP in ischaemic and non-ischaemic myocardit~n did. Tissue cyclic AMP levels were elevated in vulnerable hearts and depressed in hearts resistant to VF. Cyclic AMP when administered to the isolated rat heart in dibutyryl form reduces the VF threshold, prolongs the vulnerable period and increases QT/RR ratio. These actions are opposed by adenosine and some of its analogues. Erythro9-(2-hydroxy-3-nonyl) adenosine, EHNA, reduces QT/RR. Adenosine, 2-chloroadenosine, 5'-N-ethylcerboxarnido-, N6-phenylisopropyl - and N6-cyclohexyl-adenosine have antiarrhythmic activity. The levels of cyclic AMP in the cardiac cell and the adenosine concentration it is exposed to are determinants of the state of vulnerability to VF.
8 1 CHRONOTROPIC, DROMOTROPIC AND INOTROPIC ACTIONS OF ADENOSINE. L. Belardinelli, H.F. Clemo, G.A. West. Univ. of Virginia Medical School, Charlottesville, Virginia, USA Adenosine (ADO) can affect many physiological functions and in the heart most of the interest has focused on its ability to regulate coronary blood flow. However, ADO appears to play a far more important role as modulator of other important cardiac functions than previously recognized. Present evidence suggests that ADO may modulate pacemaker activity, atrioventricular (AV) transmission, atrial contractility, and some of the myocardial actions of catecholamines. ADO causes a dose-dependent sinus slowing and pacemaker shift, slows AV node conduction that leads to variable degrees of AV block, depresses atrial contractility and in ventricular muscle antagonizes the electrophysiological and inotropic effect of agents that stimulate adenylate cyclase (e.g. 8-agonists, forskolin). The above actions of ADO are receptor mediated and are potentiated by nucleoside transport blockers (dipyridemole) and antagonized by adenosine deaminase and alkylxanthines. Bradyarrhythmias (sinus slewing and AV block) caused by hypoxia or isohemia, conditions which increase release of ADO from myocardial cells, are similar to those caused by exogenous ADO. Furthermore, the fact that the bradyarrhythmias seen during hypoxia or ischemia can be modified in a predictable manner by antagonists and potentiators of the actions of ADO supports the role of ADO in AV conduction and rhythm disturbances associated with hypoxia and ischemia. Thus, ADO may be an important regulator of the function of both SA and AV nodes under normal and pathologic conditions.