Eleven numerical methods for estimation of AUC (including 4 new methods) and 22 methods for AUMC (including 8 new methods) were tested on large simulated noisy datasets representing bolus, oral and infusion concentration-time profiles. Some methods were unacceptable because their mean error was large; these included a commonly recommended form of the linear trapezoidal rule for AUMC. Others, notably Lagrange and cubic spline methods, were unacceptable because the variance of their estimates was large. These methods should be abandoned. A simple and easily programmed new method, parabolas-through-the-origin then log-trapezoidal rule, performed especially well.

4. Indirect stimulation via the rami communicantes or the interganglionic nerves of the sympathetic chain evoked a graded synaptic response which could lead to the discharge of one or more action potentials. Hexamethonium blocked the responses to such stimulation. Occasionally an all-or-none response remained, apparently conducted antidromically along the cell's axon.5. Spontaneous synaptic potentials were observed. Their occurrence frequency was increased during indirect stimulation. If they are assumed to represent single quanta of release of transmitter, the quantal content of a threshold synaptic potential was 8-20 quanta.6. Preganglionic fibres could ascend at least three segments or descend two after entering the sympathetic chain. They had conduction velocities of 0 1-1 im/sec.7. Inexcitable cells were frequently impaled. Repetitive indirect stimulation gave rise in these cells to a large (20 mV) slow depolarizing response.

No abstract

SUMMARY1. Neurotransmitters were applied ionophoretically to spontaneously beating clusters of ventricular muscle cells cultured from neonatal rats.2. Acetylcholine or its analogue carbachol produced hyperpolarization and decreased the rate of spontaneous beating. These responses had minimum latencies of about 250 msec and total durations of 6-12 sec.3. Noradrenaline, adrenaline or isoprenaline increased the rate of spontaneous beating. The minimum latency for this effect was 3-6 sec. Following a single brief pulse the rate remained elevated for 2 min or more.4. Chronotropic responses of intact atria from adult rats to stimulation of the autonomic nerves were of similar time course to responses of the cultured muscle cells.5. Calculations based on the theory of diffusion showed that access of drugs to their receptors could not be rate-limiting for the observed responses, unless a diffusion barrier of rather special properties was postulated. A number of other explanations for the long latencies have been ruled out; these are most likely to be due to some physical or chemical process occurring in or under the cell membrane.6. Attempts to mimic responses to catecholamines by intracellular application of cyclic AMP were unsuccessful, perhaps because the release of nucleotide from the pipettes was insufficient. A theoretical treatment suggests that ionophoretic efflux of anions might be greatly diminished by the opposing electro-osmotic flux.

1. Glaucoma is a worldwide disease affecting approximately 1-2% of the population aged over 35 years in industrial countries and is a major cause of blindness. 2. Glaucoma is usually associated with an increased intraocular pressure reflecting an imbalance between the rate of production of fluid (the aqueous humor) by the ciliary epithelial cells and its drainage from the eye. Therefore, it is important to understand how this secretion is produced. This requires a knowledge of ciliary epithelial cell composition, which has, in the past, proved difficult to obtain in mammalian preparations. 3. We have recently used the technique of electron-probe X-ray microanalysis to determine this composition under a variety of in vitro conditions. 4. Our results have led to a new model for this secretion that emphasizes the potential secretory role of the Na+/K+/2Cl- cotransporter.