Hypoxia Enhances Isoproterenol-Induced Increase in Heart Interstitial Adenosine, Depressing f3-Adrenergic Contractile Responses

Endogenous interstitial adenosine may protect the hypoxic heart by attenuating ,B-adrenergic-induced contractile and metabolic responses, thereby reducing energy utilization. Constant-flow perfused rat hearts were used to study 1) the effect of hypoxia on isoproterenol (ISO)-induced increase in interstitial adenosine, as estimated with epicardial surface transudates, and 2) the role of endogenous adenosine in hypoxic depression of ISO-induced contractile responses. ISO (1 nM for 10 minutes) in the normoxic heart increased transudate adenosine 114% from a pre-ISO normoxic value of 343 pmol/ml. ISO administered to the hypoxic heart increased transudate adenosine 357% from a pre-ISO hypoxic value of 797 pmol/ml. The absolute magnitude of the ISO-induced increase in transudate adenosine was 625% greater during hypoxia than during normoxia. This was associated with a reduction in the ISO-induced contractile response during hypoxia. In other experiments, with normoxia ISO (10 nM for 10 seconds) increased developed left ventricular pressure by 140 mm Hg, and the maximum rates of left ventricular pressure development and relaxation by 5,860 and 2,771 mm Hg/sec, respectively, above control values of 90 mm Hg, 2,250 mm Hg/sec, and 1,875 mm Hg/sec. Hypoxia reduced the three ISO-induced contractile responses by 50%, 56%, and 36%. However, 1,3-dipropyl-8-cyclopentylxanthine (5x10-7 M), an adenosine A,-receptor antagonist, added to the hypoxic hearts resulted in only a 31%, 39o, and 9%o reduction in the ISO-induced responses in developed left ventricular pressure and the maximum rates of left ventricular pressure development and relaxation, respectively. These findings indicate that the effectiveness of ISO as a stimulus for augmenting interstitial adenosine is increased with hypoxia. The resulting enhanced expression of the antiadrenergic action of adenosine attenuates the ISO-induced contractile response during hypoxia. (Circulation Research 1993;72:571-578)