Analysis of catecholamine effects in single atrial trabeculae of the frog heart

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Abstract
The time course of the effects of adrenaline [epinephrine] and isoprenaline on twitch tension and the intracellular action potential of single atrial trabeculae from frog heart was examined under a variety of experimental conditions. Twitch tension and overshoot of action potentials rose and subsided in a parallel fashion during build-up and decline of catecholamine action. Cessation of stimulation during drug application had little effect on the tension responses to the drugs. These actions, along with results obtained with step changes of external Ca concentration during drug exposure suggest that tension enhancement is a direct consequence of the increased Ca inward current produced by the catecholamines. Exceptional results from trabeculae of hypodynamic hearts are described and interpreted on the basis of previous findings obtained in the hypodynamic condition. Under suitable conditions, including the use of brief periods of drug exposure (.ltoreq. 20 s), 3 phases of .beta.-catecholamine action were discernible: a latency period of up to 15 s which preceded tension and potential rise after drug application. This latency appears to mainly reflects the time which it takes for drug-combined receptors to activate adenylate cyclase in the cell membrane. A subsequent phase was critically dependent in both its magnitude and time course on phosphodiesterase activity as was shown by the application of the specific inhibitors papaverine, ICI 63 197 [6-methyl-8-propyl-1,2,4-triazolo[4,3-a]pyrazin-2(3H)-amine-7-oxide] and Ro 20-1724 [d l-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone]. This phase is probably controlled by the build-up and decline of c[cyclic]AMP within the cells and the subsequent activation and deactivation of a protein kinase. A 3rd phase associated with the final portion of the decline of catecholamine action was relatively insensitive to moderate inhibition of phosphodiesterase activity. It is attributed to a change of phosphorylation of sites at the internal surface of the cell membrane, the process which probably determines the size of Ca inward current during an action potential. Tension decline after a short staircase occurred with a time course closely similar to that of the final phase of the declining catecholamine response. A common final step in the sequential cellular processes underlying the 2 responses is proposed. In some 40% of the trabeculae examined, adrenaline responses were of mixed origin: in addition to the relatively slow .beta.-adrenergic action an initial rapid tension change was present which appears to be mediated by .alpha.-type receptors.