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In a previous series of experiments it was shown that artificial positive pressure ventilation of the lungs of foetal lambs caused an immediate fall of pulmonary and systemic arterial blood pressures (Ardran, Dawes, Prichard, Reynolds & Wyatt, 1952). In three lambs the systemic arterial pressure recovered, while the pulmonary arterial pressure continued to fall towards the level commonly found in adult animals. The observations of Reynolds, Ardran & Prichard (1953) on pulmonary circulation time in these newly delivered lambs also showed that on ventilation of the lungs pulmonary blood flow increased, on an average fourfold. These experiments led to the conclusion that ventilation of the lungs for the first time after birth leads to a decrease of pulmonary vascular resistance. This is an idea which has often been discussed during the last three hundred years but has not been tested by direct experiment. In order to obtain a direct estimate of pulmonary vascular resistance it is necessary to measure the quantity of blood flowing through a pulmonary artery per minute and also the pulmonary arterial and left atrial pressures. This paper gives an account of such measurements, from which it is concluded that positive pressure ventilation of the foetal lungs after birth causes an immediate and dramatic decrease of pulmonary vascular resistance, which must be one of the principal factors in the neonatal changes in the circulation. A brief report of some of these observations has already been given (Dawes, Mott, Widdicombe & Wyatt, 1952). METHODSTwenty Welsh ewes were used, whose duration of pregnancy was known, and three HampshireClun Forest ewes (the maternal grandam of the lamb being Clun Forest) whose date of tupping was not known, but which were in a very advanced state of pregnancy. The weight of the Welsh ewes ranged from 22-33 kg and that of the Hampshire-Clun Forest ewes from 70-85 kg. They were anaesthetized by slow injection of 'dial-urethane' (diallyl-barbituric acid 0-1 g, urethane 0-4 g/ml.) into the external jugular vein. At first a dose of 0-5 ml./kg was used, but further experience showed that 0-2-0-35 ml./kg was sufficient to keep the ewe and lamb lightly anaesthetized.

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Since the early experiments of von Bezold & Hirt (1867) the veratrum alkaloids have stimulated the interest of physiologists and pharmacologists because of the unusual nature of the cardiovascular and respiratory reflexes which they produce. These alkaloids are of complex structure and readily produce tachyphyllaxis. It was hoped that there might be simpler substances among which, therefore, the relationship between structure and action could be studied, which might be relatively free from tachyphyllaxs, and which would yet elicit the same reflex responses as the veratrum alkaloids. These criteria seemed to be met by the amidine derivatives described by Dawes & Mott (1950) and Dawes & Fastier (1950). Of the one hundred and thirty-five diguanides, guanidines, isothioureas and related compounds investigated, more than thirty possessed a considerable degree of activity of the type anticipated; that is to say, they caused a fall of blood pressure, a fall of heart rate and an inhibition of respiration in the cat, all of which were abolished by cutting the vagus nerves in the neck. These effects were attributed to three reflexes, a depressor reflex on injection into the coronary arteries, a depressor reflex from the lungs, and a reflex inhibition of respiration also coming from the lungs. In the cat, however, veratridine only causes two easily identifiable reflex responses on injection of say 5-10,ug./kg., a depressor reflex from the coronary system (the Bezold reflex), and a reflex inhibition of respiration by an action on receptors in the lungs (Dawes, 1947). In this species there is no apparent depressor reflex from the lungs with veratridine. It is true. that in the dog there is evidence of such a reflex, but it is rather feeble. There is therefore a discrepancy between the actions of veratridine and of the amidine derivatives in the cat, for the latter cause a reflex response from the lungs which the former does not.Quite apart from this discrepancy, there was another powerful incentive to a more thorough investigation of the mode of action of these amidines and of * During the tenure of a grant from the Medical Research Council.

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