Studies on the Pituitary.—iv. Quantitative Comparison of Pressor Activity

Abstract

1. A method of standardising pressor activity of pituitary extracts with an order of precision not significantly inferior to that obtained with the virgin uterus of the guinea‐pig is described. 2. For quantitative or clinical purposes involving action on the circulatory system, pituitary extracts free of depressor substances can be prepared, as SCHAFER and VINCENT indicated, by alcoholic extraction. 3. For depressor‐free extracts tolerance is a function of the dosage and time interval between successive injections. 4. With appropriate time intervals a remarkable constancy of response of the same character and order of magnitude as the initial rise in blood‐pressure may be obtained with the spinal cat for periods up to twenty hours. 5. With sub maximal doses the period of recovery for response of the same order as that obtained on initial injection is rather less than an hour. 6. Consistent discrimination tending to increase as the experiment proceeds may be obtained for ten or twelve hours between hourly doses differing by 10 per cent. 7. The curve obtained by plotting increase of pressure against dose shows the steepest gradient near a point corresponding to half the dose requisite to produce maximal response; and the best discrimination is obtained by working with a standard in the neighbourhood of this value. 8. It is therefore suggested that the match should be made against a standard for which a curve of reference is kept in use: the limit of accuracy can be defined in any instance by interpolating a known dilution between two injections of the standard.

The action and fate of injected posterior pituitary extracts in the decapitated cat

“…The pressor assays were made by the method of Hogben, Schlapp and Macdonald [1924] approximately the same in all cases, mixing being assumed to be complete in the 30 sec. The withdrawal of the 20 c.c.…”

“…Hogben, Schlapp and Macdonald [1924], in elaborating their method of pressor assay on the spinal cat, were able to show that for small doses up to 2 mg. of dried posterior pituitary substance, the period of tolerance did not exceed 1 hour.Little is known concerning the factors responsible for the tolerance, but Dale and Laidlaw [1912] surmized that it might be the consequence of a slow disappearance of the active principles from the blood. On the other hand, it seemed possible that an effect on the blood volume was to some extent concerned.…”

“…Thus Dale and Laidlaw [1912] were induced by its existence to turn their attention to the oxytocic activity, and they devised the method of assay with the isolated uterus of the virgin guinea-pig, and this is now probably the method most extensively employed. Hogben, Schlapp and Macdonald [1924], in elaborating their method of pressor assay on the spinal cat, were able to show that for small doses up to 2 mg. of dried posterior pituitary substance, the period of tolerance did not exceed 1 hour.…”

Attenuation of Response to Repeated Drug Administration: A Proposal for Differentiating Tachyphylaxis and Tolerance

“…Barger and Dale (Barger and Dale, 1910), who proposed the term sympathomimetic, appear to have been the first to have noted an attenuation of response to repeated doses of pharmacologic agents through their studies of a series of basic amines. Subsequent investigations examining the pressor effect of pituitary extracts found that sequential doses of these extracts exhibited a reduced in vivo pressor response in comparison to the first dose, a phenomenon that was both dose and time-interval dependent (Dudley, 1923;Hogben et al, 1924). This diminution in effect was termed acquired tolerance and found to be overcome through an adequate lapse of time between doses.…”

The Action of Extracts of the Posterior Lobe of the Pituitary Body on the Pulmonary Circulation

“…And since pituitary extract is used to counteract the effects of " shock "-and this condition is believed to be due, in large measure, to capillary dilatation-the extract would be more efficient if freed from histamine, which itself tends to produce " shock." This consideration has been already urged by HOGBEN, SCHLAPE, and MACDONALD (8).…”