The possibility that the inotropic action of epinephrine might be mediated through an effect on the excitation-contraction coupling process was explored, using techniques for measurement of isometric tension, together, in some experiments, with recording of the transmembrane potential time course from short lengths of cat papillary muscle. Four observations relevant to this question, have been made: (1) Extracellular calcium concentration can be raised and extracellular sodium concentration lowered to a point at which contraction cannot be further augmented by the addition of epinephrine. (2) The early relaxation induced by epinephrine occurs well in advance of membrane repolarization. This effect is antagonized by increasing calcium concentration, although the action of epinephrine in augmenting developed tension appears to be synergistic with that of calciumion. (3) The length-tension relationship is undiminished in the calcium-rich (8.1 mmoles /liter), sodium-poor (75 mEq/liter) medium. (4) Epinephrine, in a dose (1 to 2 µg/ml) which markedly augments twitch tension, profoundly decreases tension developed by the same preparation during a potassium chloride contracture; this is the case for both the frog ventricle strip and the cat papillary muscle. A preliminary concept of the ionic mechanism of excitation-contraction coupling, compatible with these facts and with some others, is described.

Radioiodide and creatinine clearances were measured simultaneously in dogs. Osmotic diuresis was induced by loading with mannitol, sodium salts of various anions such as chloride, bromide, iodide, nitrate and ferrocyanide, and by the administration of mercurial diuretics. Results of these experiments are compared with those obtained during water diuresis. No evidence for active tubular reabsorption of radioiodide could be observed. Renal tubular reabsorption of I131 was found to be chiefly determined by the degree of tubular water reabsorption and hence the transtubular diffusion gradient of radioiodide. Nonspecific effects of other anions in the tubular urine may modify passive tubular reabsorption: anions less readily reabsorbed displace I131 from the urine and depress its renal clearance. Indirect evidence suggests that about 95% of filtered radioiodide is reabsorbed at a tubular site proximal to that of final water reabsorption.

A method was devised which made it possible to depolarize ventricular muscle, over a short interval of length, by applying an external voltage and to record, from the same segment, the developed tension. A fiber bundle, 0.5–1.0 mm in diameter, from the right ventricular cavity of the sheep or calf, was inserted into a close-fitting hole in a plastic block, contained in a Tyrode bath. The fibers were depolarized where they exited from the block. The muscle was held, by suction, at two surface points of very small area, 0.4 mm apart. Measurements with microelectrodes showed that the depolarization was roughly uniform over the length of muscle segment from which tension was recorded. By this means, the action potential (normally lasting about 1/2 sec.) could be prolonged to a duration of 2 seconds. This caused tension to be maintained at near-peak levels; relaxation occurred only when the fibers were allowed to repolarize. Evidence was thus adduced in support of the view that the contractile mechanism is continuously responsive to depolarization.

We describe a method by which the ionic surround of an isolated frog heart cell can be changed within a small fraction of a contraction cycle while continuously measuring contraction force. With this method, we have investigated the effect on force development of changing the extracellular concentrations of Ca [( Ca]o) and Na [( Na]o) in the period between electrically driven contractions and during the rising phase of a contraction. Raising or lowering either [Ca]o or [Na]o more than 300 ms prior to a stimulus caused peak force of the next contraction to be changed 100% of the way to the steady-state value characteristic of the new ionic concentrations. Similar maneuvers at later times relative to the stimulus caused progressively smaller changes. Lowering [Ca]o from 2 to 1 mM or raising [Na]o from 78 to 110 mM 100 ms after stimulation brought twitch force 35 and 67% of the way to the new steady states, respectively. We conclude that extracellular Ca is the source of activator Ca in these cells and that extracellular Na plays a role in regulation of the intracellular Ca concentration early in the contraction cycle.