Time-dependent effects of theophylline on myocardial reactive hyperaemias in the anaesthetized dog

1. The effects of a loading dose of theophylline (5 mg kg^-1 i.v.) on the hyperaemias resulting from short-term (15 and 30s) interruptions in coronary blood flow and intracoronary adenosine were studied at given intervals over a 2h period in the anaesthetized dog. 2. These hyperaemic responses were affected differently by theophylline and each effect was time-dependent. The reactive hyperaemic response progressively decreased after drug delivery, reaching 46% of control at 2h. In contrast, after a maximal attenuation to 23% of control 5 min after theophylline, the hyperaemia resulting from intracoronary adenosine progressively increased over the same period, reaching 64% of control 2h after the loading dose. 3. Two-compartment model results based on plasma theophylline measurements and the time course of theophylline accumulation in pericardial infusates, suggested that complete drug distribution throughout the heart may require at least 20 min following a single intravenous dose. 4. If it is assumed that theophylline blocks coronary vascular adenosine receptors, these pharmacokinetics are consistent with the time-dependent pattern of response attenuation we observed for the adenosine-induced hyperaemias, but they cannot entirely explain the pattern of response attenuation observed for the occlusion-induced hyperaemias. The continued increase in attenuation of this response after complete drug distribution suggests an additional pharmacodynamic action of theophylline. 5. We conclude that a single therapeutic dose of theophylline results in distinct time-dependent pharmacological effects with respect to the ability of the coronary vasculature to dilate in response to temporary interruptions in oxygen supply and in response to exogenously administered adenosine. These effects deserve consideration in both experimental studies in which adenosine antagonists are used to assess adenosine action in vivo, and in clinical practice where theophylline pharmacotherapy for pulmonary disorders is commonplace.