Role of calcium in caffeine-norepinephrine interactions in cardiac Purkinje fibers.

Caffeine-norepinephrine interactions were studied in canine cardiac Purkinje fibers perfused in vitro. Caffeine (0.5-1 mM) or theophylline (0.5-1 mM) increased and then decreased contractile force in the absence and presence of 0.5-10 microM norepinephrine (NE) [in high extracellular calcium concentration ([Ca]o) caffeine only decreases force]. Occasionally, caffeine only decreased force in the presence of NE. In the presence of NE and 12 mM (sometimes even 4 mM) extracellular potassium concentration, caffeine did not decrease force below the precaffeine level. Reciprocally, in 0.5-2 mM caffeine NE increased force, although less than in the absence of caffeine. Even in 9 mM caffeine, NE increased force but slowed the final phase three repolarization of the action potential. Both NE and 8.1 mM [Ca]o increased force, but NE decreased force in the presence of high [Ca]o. In NE and propranolol (or propranolol alone), caffeine only increased force, whereas it had the usual effects in the presence of methoxamine or phenotolamine. In the presence of iodoacetic acid and 2-deoxy-D-glucose, NE caused contracture and caffeine exaggerated it. In contrast, in NE and 2 mM Mn, caffeine only increased force. It is concluded that initially NE diminishes the cytoplasmic calcium overload induced by caffeine (by promoting Ca uptake into the sarcoplasmic reticulum) and subsequently enhances it (by increasing the slow inward current).