Mediation by adenosine of bradycardia in rat heart during graded global ischaemia.

The role of adenosine as a mediator of the bradycardia associated with graded global ischaemia in rat heart was examined. Hearts were perfused at 37 degrees C in the isovolumic mode with Krebs-bicarbonate medium at 12.0 ml/min/g. After equilibration, the coronary flow was reduced to 0.5, 2.5, or 5.0 ml/min/g for 20 min. Effluent was collected and assayed for adenosine and inosine by HPLC. Heart rate was measured and bipolar electrograms were obtained in severely ischaemic hearts. Basal adenosine release was 124 +/- 15 pmol/min/g. Adenosine release increased by approximately 50% in hearts perfused at 5.0 ml/min/g. In hearts perfused at 2.5 and 0.5 ml/min/g, adenosine release increased by approximately 1300 and 2300% respectively. The pattern of adenosine release at 0.5 and 2.5 ml/min/g was phasic, with adenosine release rate increasing to a maximum after about 10 min then dropping to values slightly higher than initial values. Ischaemia produced significant bradycardia and first degree AV block. Adenosine antagonism with 5 micron 8-phenyltheophylline blocked up to 25% of this bradycardia and significantly reduced the conduction delay. Adenosine release rate correlated closely with that component of heart rate slowing which was inhibited by 8-phenyltheophylline. It is concluded that adenosine released during graded global ischaemia mediates up to a quarter of the associated bradycardia. The effect of adenosine is phasic. Adenosine acts primarily to depress the sinus pacemaker. First degree AV block also occurs. These effects were only apparent at coronary flow rates below 5.0 ml/min/g.