title: The antiarrhythmic effects of the nucleoside transporter inhibitor, R75231, in anaesthetized pigs.
abstract: 1. The effect of R75231, an inhibitor of purine nucleoside transport, were examined on ischaemic arrhythmias in anaesthetized pigs. 2. In closed chest pigs (n = 4), R75231 exerted a moderate dose-dependent decrease in mean arterial blood pressure (from 97 +/- 4 mmHg to 95 +/- 4, 90 +/- 1 and 83 +/- 2 mmHg at 25, 50 and 100 micrograms kg-1 respectively) and produced a dose-related shift to the left of the blood pressure dose-response curve to intravenous bolus doses of adenosine. The degree of inhibition of adenosine uptake by R75231, assessed ex vivo in erythrocyte suspensions, was 43 +/- 5%, 64 +/- 13 and 114 +/- 15% at doses of 25, 50 and 100 micrograms kg-1 respectively. 3. In open chest pigs, intravenous injection of R75231 (50 micrograms kg-1; n = 6 and 100 micrograms kg-1; n = 10) induced a dose-related decrease in both systolic and diastolic arterial blood pressure which was more marked than in closed-chest pigs (mean pressure 86 +/- 4 to 70 +/- 2 mmHg and 88 +/- 6 to 60 +/- 6 mmHg with 50 and 100 micrograms kg-1 respectively), without affecting heart rate or myocardial contractility. Coronary artery occlusion in these pigs caused a secondary decrease in blood pressure. This was not observed in controls (n = 10). The lower dose of R75231 did not exert any antifibrillatory effects, whereas the higher dose significantly reduced the incidence of ventricular fibrillation, from 80% in control pigs to 30%. Neither dose modified the incidence of ventricular tachycardia (33% and 40% with 50 and 100 microg kg-1 respectively, compared to 30% in controls) or had any effect on the total number of ventricular ectopic beats (85 +/- 47 and 130 +/- 31 vs 110 +/- 19 in controls). R75231, at a dose of 100 microg kg-1, also attenuated the ischaemia-induced shortening of QRS-interval, but neither dose modified the ST-segment depression seen following occlusion.4. These results show that the nucleoside transport inhibitor, R75231, exerts an antifibrillatory effect ina model of severe myocardial ischaemia in a dose which completely inhibits adenosine uptake ex vivo.However, while this agent has minimal haemodynamic effects in closed chest animals, the reduction in blood pressure induced by R75231 in open-chest pigs cannot be excluded as a possible contributory mechanism of the antiarrhythmic effects of this drug.
authors.affiliation: Department of Physiology & Pharmacology, University of Strathclyde, Glasgow.
authors.forename: C L
authors.initials: CL
authors.lastname: Wainwright
authors.forename: J R
authors.initials: JR
authors.lastname: Parratt
authors.forename: H
authors.initials: H
authors.lastname: Van Belle
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000517:prevention & control; D001794:Blood Pressure / Q000187:drug effects; D003331:Coronary Vessels / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D017202:Myocardial Ischemia / Q000150:complications; D009705:Nucleosides / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D013552:Swine; D014693:Ventricular Fibrillation / Q000503:physiopathology / Q000517:prevention & control; D016276:Ventricular Function
chemical_list: D000889:Anti-Arrhythmia Agents; D009705:Nucleosides; D010879:Piperazines; C072040:draflazine; D000241:Adenosine