Route dependent effects of 2-chloroadenosine and theophylline in isolated perfused guinea pig hearts

The adenosine hypothesis for the metabolic regulation of coronary blood flow remains controversial, in part because of differences in results obtained between intravascular and endogenously released adenosine. The main objective of this study was to compare the responses of coronary perfusate flow to intravascular and pericardial 2-chloroadenosine and theophylline. The periocardial route was used to simulate physiological conditions.

An isolated, perfused guinea pig heart preparation was used. Hearts were submerged in 10 ml Krebs-Ringer bicarbonate solution having the same chemical composition as that used to perfuse the coronary vasculature. The submersion fluid was assumed to simulate myocardial interstitial fluid. Hearts were divided into four experimental groups. The first group (n = 6) was used to check that the submerged hearts functioned normally. The second group (n = 12) was used to compare differences between intravascular and pericardial 2-chloroadenosine. The third group (n = 16) was used to evaluate the two routes of administration of 2-chloroadenosine on transmural distribution of coronary flow. The fourth group (n = 24) was used to test the effects of hypoxia in the absence and presence of pericardial theophylline.

Hearts were obtained from adult guinea pigs of either sex weighing 300-400 g.

All submerged hearts were functionally stable for at least 30 min. Pericardial 2-chloroadenosine was about 1000 times less potent than intravascular 2-chloroadenosine in relaxing the coronary vasculature. Venous concentrations of pericardial 2-chloroadenosine were significantly greater than those of intravascular 2-chloroadenosine, at 0.72(SEM 0.17) v 0.18(0.02) mumol.litre-1. Pericardial 2-chloroadenosine caused more uniform distribution of radiotracer microspheres than intravascular 2-chloroadenosine. Finally, pericardial theophylline significantly attentuated the vasodilator response to hypoxia but not to exogenous adenosine.

The isolated submerged heart is a viable preparation for investigating the adenosine hypothesis. Our results suggest that intravascular adenosine does not simulate physiological conditions of interstitial adenosine release and action.