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1. Membrane potential changes produced by adenosine and adenine nucleotides, acetylcholine, and vagus nerve stimulation were studied by intracellular recording in the sinus venosus of the frog, Rana pipiens. 2. Acetylcholine (ACh) released from the vagus nerve terminals evoked a slow hyperpolarization lasting several seconds in the cells of the sinus. Ionophoretic application of ACh from a micropipette produced a response which is similar in time course and amplitude to that evoked by vagus nerve stimulation. Bath application of ACh caused a steady hyperpolarization in quiescent preparations, or cessation of action potential generation in spontaneously active preparations. 3. Adenosine and adenine nucleotides produced hyperpolarizations when applied by addition to the bath or by ionophoresis from micropipettes. The hyperpolarization produced by ionophoresis of adenine compounds was somewhat slower than that produced by ACh. 4. Adenosine and the adenine nucleotides, 5'-AMP, 3'-AMP, 2'-AMP, and 5'-atp were virtually equipotent in their action. Adenosine was at least 1000-fold more potent than other purine and pyrimidine nucleosides or adenine. Both the ribose and adenine groups were important for agonist activity. 5. The concentrations of agonist required to produce half-maximal responses were estimated from dose--response curves as 3 x 10(-7) M for ACh and 2 x 10(-6) M for ATP. ACh is about 7 times more potent than ATP in producing a hyperpolarization. 6. Adenine compounds act directly upon the cardiac muscle fibres: bath or ionophoretically applied adenine compounds act even when transmitter release from nerve terminals is blocked with high (Mn2+) or when ACh receptors are blocked with atropine. 7. Adenine compounds act on the surface of the muscle fibre membrane. Analogues of adenosine which do not enter the cell are potent agonists of the receptor. An adenyl oligonucleotide too large to enter the cell was 2.6 times more potent per mole than adenosine in producing a hyperpolarization. Drugs such as dipyridamole and 6-(2-hydroxy 5-nitrobenzyl) thioguanosine, which are potent blockers of adenosine transport, potentiate the response of the sinus cells to adenosine. 8. Aminophylline and theophylline are competitive antagonists of adenosine action. The apparent Ki for aminophylline inhibition was 5 microM. 9. The response produced by adenine compounds is partly caused by an increase in the permeability of the membrane to K+. The maximum response to both ACh and adenine nucleotides approached the estimated level of EK or ECl. Replacing extracellular chloride with impermeant isethionate had no effect on responses to ACh or adenine nucleotides. The hyperpolarization was not produced by an activation of an ouabain-sensitive pump since 20 microM-ouabain had little effect on the response to adenosine. 10. The response to vagus nerve stimulation is completely blocked by 50 nM-atropine...