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The purpose of this study was to compare the responses of isolated hearts of the diving muskrat with the nondividing guinea pig (GP) to determine the contribution of adenosine (ADO) to the profound bradycardia that was seen in isolated muskrat hearts during exposure to hypoxia. Muskrat hearts were more sensitive than GP hearts to the heart rate-lowering effects of exogenously applied ADO or a stable ADO analogue, (R)-N6-(phenylisopropyl)adenosine. The hearts of both species were unpaced, and the bradycardia appeared to be due to high degree of atrioventricular block. Radioligand binding with 8-cyclopentyl-1,3-[3H]dipropylxanthine to A1-ADO receptors was greater in cardiac membranes prepared from GP hearts than from muskrat hearts. Nucleoside transporter antagonist binding was also greater in GP hearts compared with muskrats. This was determined by membrane binding of [3H]-nitrobenzylthioinosine, an antagonist of nucleoside transport. Both muskrat and GP hearts responded to 30 min of hypoxic perfusion by releasing ADO into the coronary effluent; however, the muskrat hearts released approximately five times more than the GP hearts. When hearts were subjected to hypoxia in the presence of ADO deaminase, theophylline, or 8-(p-sulfophenyl)theophylline, the hypoxia-induced bradycardia was blocked in the GP hearts and either slightly reduced or not affected in muskrat hearts. In contrast to GP hearts, muskrat hearts release larger amounts of ADO during hypoxia and are more sensitive to the negative chronotropic effects of exogenously administered ADO; yet the hypoxia-induced bradycardia does not appear to be exclusively mediated by ADO in the muskrat as it is in the isolated GP heart.