I. de Burgh Daly

The action of ions upon the frog's heart

THE following experiments were undertaken to analyse the effect upon the mechanical and electrical responses of the frogs heart of changes in the concentration of the kations, which are normally present in Ringers fluid. The effect of such changes upon the mechanical response of the frogs heart was analysed by one of us (A. J. C.) in a previous paper(l), and the effect of certain of these changes upon both the mechanical and electrical responses of the frogs heart was studied by Mines(5). Description of experiments. The experiments were commenced in the summer using R. esculenta but were repeated in the autumn on R. temporaria. The hearts were perfused, and the records of the mechanical and electrical responses were obtained, in the manner described by Mines(5). The string tension of the galvanometer was kept constant during each experiment. The Ringers fluid used had a composition of NaCl *65 p.c., CaCl2 (anhyd.) *012 p.c., KCI *016 p.c., NaHCO3 *016 p.c.: the p.H (PH) was 7-6. When R. esc. were used in summer the CaCl2 content was raised to *018 p.c. or *024 p.c. Except for the fact that R. esc. required this additional calcium in summer to produce an optimal response, the hearts of the two species of frogs responded to changes in the ionic content of the Ringers fluid in exactly the same manner. The hearts were allowed to beat at their natural rhythm in the earlier experiments, but since alteration of frequency was found to produce alterations in all of the factors measured, we maintained a constant frequency in the later experiments by arresting the heart with a Stannius ligature, and stimulating the auricle with break induction shocks. The following factors were measured: (1) frequency (length of cycle), (2) P-R interval, (3) duration of electrical response (DER), (4) duration of mechanical response (DMR), (5) height of R wave (HER), (6) height

The localisation of receptors involved in the reflex regulation of the heart rate

IN 1859 Marey() showed that a rise in the arterial blood-pressure was accompanied by a slowing of the heart rate, a fall by a quickening. Since that time numerous investigators have ,attempted to explain the law of Marey by attributing the change in cardiac rate resultant to change in arterial blood-pressure, either to a central or to a reflex mechanism. That reflex slowing of the heart is brought about by a rise of arterial blood-pressure irrespective of a concomitant change in the cerebral blood-pressure has been conclusively demonstrated by the experiments of Heymans and Ladon(2), Anrep and Segall(3), and Daly and Verney(4). The experiments recorded in this paper were undertaken to localise more exactly the receptors engaged in reflex slowing of the heart. It has been shown by Eyster and Hooker(5) that mechanical distension of the aorta causes a slowing of the heart in the dog. In their experiments the circulation was abnormal in that the superior and inferior venae cavae, the ascending and descending aortae, and the left subclavian artery were occluded. A rise in venous pressure was shown by Bainbridge(6) to be accompanied by reflex acceleration of the heart, a result which was confirmed by Sassa and Miyasaki(7), who mechanically distended the auricles and large veins by rubber balloons. As far as we have been able to determine, these experimental results of Eyster and Hooker, and Sassa and Miyasaki, are the only ones published which give direct experimental evidence on the localisation of the receptors engaged in reflex changes in cardiac rate.

The effects of stimulation of the carotid body chemoreceptors on the pulmonary vascular bed in the dog: the 'vasosensory controlled perfused living animal' preparation.

We have shown previously that stimulation of the carotid body chemoreceptors by venous blood usually caused a reflex decrease in pulmonary vascular resistance in lungs perfused at a constant blood volume inflow (Daly & Daly, 1957 b). It was stated that the method used did not enable us to establish whether this effect was a direct reflex response of the pulmonary vascular bed proper, i.e. pulmonary vasodilatation, or was passive to reflex bronchial vasomotor changes causing an alteration in the distribution of blood between the bronchial and pulmonary vascular systems (Berry & I. de B. Daly, 1931). The only way of distinguishing between these two possibilities was to repeat the tests when no blood was flowing through the bronchial circulation. This paper describes, first, the experimental procedure carried out to achieve the necessary conditions to obtain unequivocal evidence for a reflex acting on the pulmonary vascular bed proper, and secondly, the results of an investigation carried out to determine whether the carotid body chemoreceptors exert any reflex control over this vascular bed. The perfused living animal preparation in which the blood flow through the greater and lesser circulations was under independent control went some way to meet the necessary requirements (I. de B. Daly, Elsden, Hebb, von Ludiny & Petrovskaia, 1942; I. de B. Daly, Eggleton, Hebb, Linzell & Trowell, 1954). It was necessary, however, to modify the perfusion of the systemic circulation in this preparation for the following reasons. (1) When making tests of chemoreceptor stimulation in the absence of the bronchial circulation, i.e. at zero bronchial arterial pressure, the blood pressure in other parts of the

Conditions governing the pulmonary vascular response to ventilation hypoxia and hypoxaemia in the dog

1. Isolated lung lobes of the dog perfused through the pulmonary circulation only with atropinized autologous blood obtained by bleeding out the animal under general anaesthesia or following premedication with morphine hydrochloride were subjected to repetitive tests of ventilation hypoxia, the control and test gas mixtures containing similar concentrations of CO2.

Bronchial circulation and pulmonary vasomotor nerve responses in isolated perfused lungs

It is well known that pulmonary vasomotor responses to nerve stimulations in isolated lungs of the dog perfused through the pulmonary circulation alone are ephemeral or absent (for literature see Daly, 1958). It was pointed out by Berry, Brailsford & Daly (1931) that failure to obtain clear evidence of pulmonary vasomotor nerve activity in such perfused preparations might be due to an insufficient blood supply to the nerves, which Reisseisen (1822) had shown were supplied by the bronchial arterial system. For this reason they advocated additional perfusion of the bronchial vascular system. This method of perfusion was used by Daly & von Euler (1932), who obtained well marked pulmonary vasomotor responses to nerve stimulations over a period of several hours. Since that time it has been repeatedly observed that such responses are only obtained during bronchial circulation perfusion and are extinguished if this perfusion is interrupted. These observations, however, provided little evidence of the underlying mechanism reponsible for the maintenance of pulmonary vasomotor nerve function by bronchial circulation perfusion. The investigation here described on the lungs of the dog relates to (1) the survival of pulmonary vasomotor nerves during bronchial circulation ischaemia, (2) the bronchial circulation perfusion time required to recover pulmonary vasomotor nerve function after varying periods of ischaemia, (3) the duration of bronchial circulation ischaemia which extinguishes pulmonary vasomotor nerve responses, (4) the effect of reducing the partial pressure of oxygen (PO2) in the blood perfusate on the responses to pulmonary vasomotor nerve stimulation, and (5) the minimal bronchial arterial pressure required to maintain pulmonary vasomotor nerve responses.

The site of action of nerves in the pulmonary vascular bed in the dog

1. The effects of stimulation of the thoracic vagosympathetic nerve or upper thoracic sympathetic chain on the pulmonary vascular resistance have been studied in atropinized, isolated, ventilated lung lobes under various conditions of pulmonary circulation perfusion. Throughout the nerve‐stimulation tests bronchial circulation perfusion was maintained or temporarily interrupted.

An isolated mammalian heart preparation capable of performing work for prolonged periods

IN experiments performed to determine how far the lungs influence the increased diastolic filling of the heart as a result of a reduction in respiratory (intrathoracic) pressure, it was found necessary to replace the lungs of a heart-lung preparation by a blood oxygenation apparatus [Daly, 1927]; for the oxygenator a modified form of the apparatus designed by Hooker [1915] and Drinker [1922] was used. In such an isolated heart preparation performing work, it was found that the heart quickly became hypodynamic in spite of good oxygenation of the blood, the average duration of five experiments being only 36 min. (limits 25-60 min.). This rapid onset of cardiac failure, as compared with the heart-lung preparation which lasts at least five hours if not overworked, was also observed independently by Verney [1927], and has since been observed by others. At that time no attempt was made to investigate the cause of the heart failure in the isolated heart preparation, but recently we have carried out a number of experiments which have enabled us to maintain the isolated heart in good condition for a period of time at least equal to that generally obtained with the heart-lung preparation and also have disclosed conditions which may be of interest relative to all perfusion experiments performed with defibrinated blood. We do not propose to describe in detail the various forms of apparatus used in some twenty-four experiments before final success was obtained, but will merely mention briefly the cause of our early failures and particularize those experiments which are relevant to the points we wish to discuss. METHODS.

The Second Bayliss‐Starling Memorial Lecture. Some aspects of their separate and combined research interests.

The invitation extended to me by the Physiological Society to deliver the second Bayliss-Starling Memorial Lecture is a singular honour and one I greatly appreciate. But my appreciation is tinged with misgivings for I am deeply conscious that to do justice to the memories of two such remarkable personalities is beyond my powers. I hope, however, to present certain aspects of their lives and works that may interest you. My early memories of Bayliss and Starling cover the years 1919 to 1923 when Starling was replenishing his staff after the First World War, and when physiologists from abroad were once more able to visit his laboratory. In 1919 Bayliss was 59 and Starling 53 years old, and this year is the centenary of Starlings birth. I came to work under Starling purely by chance. I had written to the Professor of Physiology at St Bartholomews Hospital applying for the vacant post of Assistant in his Department. The Professor at that time was Professor Bainbridge. He replied, in addition to rejecting my application, on not unreasonable grounds, that he had mentioned my interest in clinical electrocardiography to Professor Starling who wished to carry out work on the electrical activity of the heart in the heart-lung preparation. Professor Starling was prepared to offer me the post of Sharpey Scholar; would I write to him and give him an answer? This indeed was manna in the wilderness. I wrote immediately, accepting. Meeting Starling for the first time was an exciting experience. His enthusiasm readily put young people at their ease. At the interview he ranged over a wide field of cardiovascular problems, both physiological and clinical, and said he wanted me amongst other things to join him once a week in attending Sir John Rose Bradfords ward round at University College Hospital, so that we could keep our knowledge of clinical medicine up-to-date. Rose Bradford at that time was the senior Physician. Thirtyfive years previously he had worked with Bayliss at University College on the electrical changes accompanying secretion. We attended Rose Brad-

Pulmonary vasomotor nerve responses in isolated perfused lungs of Macaca mulatta and Papio species.

1. Lung lobes of Macaca mulatta and Papio species were isolated from the body and perfused by a pump delivering a constant volume inflow. The left atrial pressure was kept constant and therefore any recorded change in pulmonary arterial pressure reflected a change in pulmonary vascular resistance. 2. In five Macaca mulatta preparations stimulation of the upper thoracic sympathetic chain, the stellate ganglion, the middle cervical ganglion and the thoracic vagosympathetic nerve caused a small increase in calculated pulmonary vascular resistance usually followed by a larger decrease. Evidence is produced which suggests that the depressor response is mediated by adrenergic beta‐receptors. In three preparations no change in pulmonary vascular resistance occurred. 3. In four Papio preparations stimulation of similar nerves invariably caused an increase in calculated pulmonary vascular resistance. In one animal no change in vascular resistance occurred. 4. A regression analysis of the results showed an inverse relationship between the magnitude of the pulmonary vascular response to nerve stimulation and the degree of excitement of the animals during capture, restraint and anaesthesia (P less than 0.01).

Negative pressure pulmonary ventilation in the heart lung preparation

M6LLGAARD(1) has shown that the minute volume of the heart is increased when the thorax, head, neck, and fore limbs of the dog are placed in a chamber in which the pressure is gradually reduced. In his experiments, the effective pulmonary arterial pressure was raised, and there was an initial rise followed by a fall in systemic arterial tension as the chamber pressure was gradually reduced to 12 mm. Hg. Mollgaards technique, although being of great value in determining the effect of lowering the intrathoracic pressure upon the vascular system in the intact animal, renders an analysis of the mechanism which brings about the vascular changes a difficult problem. A few experiments of a somewhat similar nature have been performed by the author, in which the heart and lungs were subjected to a progressively reduced pressure and the blood-flow taken through one lung lobe. Dogs were used under complete aneesthesia and the thorax closed after all operative procedure had been completed. Ventilation of the lungs was carried out by rhythmically varying the intrathoracic pressure, the mean pressure being kept negative. It was desired to investigate the effect upon the heart output of lowering the intrathoracic pressure in the absence of nervous influences. This was not possible even when the heart was completely denervated and the phrenic nerves cut, because variations in the pulmonary ventilation alter the composition of the blood and produce effects upon the medulla. For this reason, further experiments were carried out with Starlings(2) heart-lung preparation, the heart and lungs being subjected to a reduced pressure which was of an oscillatory nature in order to produce expansion and collapse of the lungs. The oxygen and carbon dioxide con,tent of the blood in the heart-lung preparation remains tolerably constant over short periods, provided the pulmonary ventilation is adequate. In addition, nervous influences are absent and the initial output of the heart may be varied at will. Method. In all experiments dogs are used, fully aneesthetised with