Robert Gesell

Peripheral and Central Chemical Control of Pulmonary Ventilation.

Until the recent work of Heymans there has been little evidence for reflex chemical control of pulmonary ventilation. The demonstration of increased respiratory movements from perfusion of the carotid sinus with carbonated and deoxygenated blood calls for a study of the relative values of peripheral and central chemical control. 1 Several procedures were used. The effects of injection of sodium cyanide, sodium sulphide, sodium carbonate and sodium bicarbonate into the carotid arteries after occlusion of the vertebral and external carotid arteries and denervation of one carotid sinus were noted. Injection of sodium cyanide on the side on which the innervation of the carotid sinus was intact invariably produced increased ventilation. Injection on the denervated side produced relatively small or no increase in ventilation followed by depression. In general the effects of intraarterial injection of sodium sulphide were similar to those produced by cyanide. Painting the innervated sinus with sodium cyanide or sulphide elicited increased ventilation. This response was demonstrated to be due to local action. Intravenous injection of sodium cyanide or sulphide after double vagotomy and double sinus denervation was relatively ineffective or entirely ineffective in augmenting ventilation. Late depression of ventilation was not uncommon. Similar results were obtained if the common carotid arteries and the internal occipital arteries were occluded as a substitute for denervation. Injection of cyanide into the 4th ventricle was found to produce immediate excitation or depression without initial excitation. It was concluded that this action was local. In several experiments in which sodium sulphide was injected into the fourth ventricle, immediate, well sustained and marked augmentation of ventilation invariably occurred.

Hemorrhage and Ventilation.

Effects of hemorrhage and reinjection on the acidity of the arterial and venous blood were studied with the manganese dioxide, quinhydrone and hydrogen electrodes. Room air was administered by normal and artificial ventilation, by the closed circuit method. Pulmonary ventilation and changes in oxygen consumption were recorded. Hemorrhage elicited an increased alkalinity of the arterial blood, and an increased acidity of the venous blood. The increased alkalinity of the arterial blood was greater than the increased acidity of the venous blood. Subsequent injection of the blood decreased the alkalinity of the arterial blood, and the acidity of the venous blood. The extent of these changes varied with the animal and with the amount of hemorrhage. The decrease in acidity of the venous blood on reinjection may be preceded by a temporary increase in acidity. The acidity may not return to normal. On reinjection, the arterial blood may turn more acid than normal, and fail to reach the normal acid value during recovery. The acidity changes occurring during hemorrhage were accompanied by decreased oxygen consumption and increased pulmonary ventilation, and re-injection was accompanied by reverse changes. Granting an increased oxidation of hemoglobin during hemorrhage, the increased alkalinity of the arterial blood seems related to increased pulmonary ventilation. and an increased blowing off of carbon dioxide. Hemorrhage during constant artificial ventilation elicited similar directional changes in acidity of the arterial and venous blood. These arterial changes in acidity might conceivably be explained by the improved ventilation, due to a decreased flow of blood through the lungs. This being true, the significance of volume-flow of blood through the respiratory center is supported.

Complementing Action of Eserine and Acid in Neurohumoral Activation

Since eserine permits a greater accumulation of acetylcholine at junctional points of activated ganglion cells, muscle fibers and other end organs, and granting the same for increased acidity, it is to be anticipated that eserine and carbon dioxide would complement each other in their effects upon the body. 1-6 This preconceived idea was put to a simple test in anesthetized dogs connected with rebreathing tanks for alternate administration of room air and carbon dioxide mixtures. The cardio-inhibitory reflex initiated by faradic stimulation of the superior laryngeal nerve served as the physiological indicator. The superior laryngeal nerve was stimulated for a period of 5 seconds at intervals of 2 minutes with faradic shocks of uniform intensity. It was demonstrated, by the administration of a 10% mixture of carbon dioxide in 40% oxygen, that hypercapnia increased the reflexogenic inhibition of the heart. Intravenous injection of eserine superimposed upon a continuing hypercapnia increased and prolonged the reflexogenic cardio-inhibition still more. Return to room air while the effects of eserine were still evident produced an abrupt diminution in the degree of cardio-inhibition. These results permit 4 conclusions. 1. Hypercapnia potentiates the cardio-inhibitory reflex initiated by stimulation of the superior laryngeal nerve. 2. Eserine produces a comparable potentiation. 3. The potentiation produced by eserine is addible to that of hypercapnia. 4. The potentiating action of hypercapnia is subtractible from that of eserine. Because the frequency of the heart beat is probably the end effect of the influences of many junctional stations, parasympathetic, sympathetic and central, a quantitative allocation of the acid-neurohumoral effects at the several stations is at present impossible.

Continuous recording changes in hydrogen ion concentration of circulating blood: The relation to respiration.

In the study of the chemical regulation of respiration a need for a continuous method of recording changes in the hydrogen ion concentration of the circulating arterial and venous blood was felt. Such a method has been developed. By means of a specially devised electrode vessel, a manganese dioxide electrode was placed in the circulating blood. The chain was closed with a non-polarizable electrode, and the E. M. F. recorded potentiometrically on smoked paper by means of a writing point attached to the hard rubber drum of a Leeds and Nor-thrup type K potentiometer. The continuity of the method, the facility of recording changes in CH+, the amount of data obtainable from single animals, and the possibility of recording synchronous changes in CH+ in the arterial and venous blood along with changes in pulmonary ventilation, oxygen consumption, blood pressure, etc., are advantages which make the method extremely valuable. In experiments so far performed the method has shown characteristic changes in the CH+ of the blood with various procedures. The administration of CO2 eliciting increased pulmonary ventilation was accompanied by a sharp rise in the CH+ of the arterial blood, followed by a slower fall in CH+ during recovery. The intravenous injection of NaHCO3, produced a sudden fall in the CH+ of the arterial blood, followed by a slow return to normal. Though the changes in CH+ were large they were unaccompanied by changes in pulmonary ventilation. See Figure 1. Occlusion and de-occlusion of the trachea produced typical changes in blood pressure and respiration. The CH+ record resembled in detail the form of the blood pressure record. A record of such an experiment is shown in Figure 2. The administration of rarefied air eliciting increased pulmonary ventilation was accompanied by a decrease in the CH+ of the arterial blood. Subsequent administration of room air was followed by a further short but sudden decrease in CH+, giving way to an increased CH+.

Effects of Low Oxygen Pressure on Respiratory Phenomena.

Eight per cent oxygen mixtures were administered for a period of approximately 30 minutes to 3 dogs anesthetized with morphine and urethane. Such administration produced an initial decrease in oxygen consumption which was followed by an increase slightly in excess of normal. This excess oxygen consumption was ascribed to the increased muscular effort of augmented ventilation. The augmented ventilation increased the elimination of carbon dioxide considerably above normal. On readministration of room air there was a decrease in pulmonary ventilation, a relative retention of carbon dioxide and an oxygen consumption above normal. In one experiment the expiratory quotient rose to 2.86 during the period of oxygen lack and fell on readministration of room air to 0.24. During oxygen lack there was a substantial decrease in the carbon dioxide capacity of the blood which was promptly followed by an increase approaching or exceeding the initial carbon dioxide capacity. There was a similar increase and decrease in blood lactic acid. The blood lactic acid content at the end of the period of oxygen lack was only moderately increased. The lactic acid changes occurred earlier than and were smaller than the changes in blood carbon dioxide capacity. The lactic acid content of the testicle and the rectus femoris muscle before and after the period of oxygen lack was determined. The tissue was dropped in liquid air and a satisfactory suspension was obtained by sectioning in the frozen state with a rotary microtome. The lactic acid content of the testicle and of the muscle was increased during the period of oxygen lack. The amount of lactic acid in the muscle was greater than in the blood. In the testicle it was less than in the blood.

Action Potentials of the “Respiratory Center.”

A systematic study of localized potentials lends itself well to the localization of the respiratory center and to an analysis of its still unknown mode of function. After removing the skull cap and the cerebral and cerebellar hemispheres in the dog, we explored the depths of the brain stem from the thalamus through the upper portion of the cervical cord with needle electrodes. A variety of potentials were encountered but in the medulla and upper cervical cord discrete potentials, of orderly sequence, associated with the respiratory act, have been definitely established. These potentials are readily counted and appear to arise from individual nerve cells or neuraxones. Inspiratory potentials commonly accelerate and deaccelerate with the waxing and waning of inspiration. These potentials cease during the phase of expiration, or continue at a lowered rate during this period. As a rule, the amplitude of discrete potentials remains moderately constant, but instances of gross change of intensity associated with little change in rate have been encountered. Expiratory potentials during active expiration may accelerate and deaccelerate with waxing and waning of the expiratory act. Usually discrete potentials progress at a uniform rate throughout expiration regardless of its duration indicating a tonic nature of discharge. They are inhibited in rate or number, only during the phase of inspiration. These results fit in with classification of types of breathing previously recorded by the potential method in respiratory muscles of the dog (Gesell). Central expiratory potentials, of the tonic type, were commonly of a much higher frequency than those previously recorded in respiratory muscles (Gesell), suggesting the existence of a step-down mechanism. There is also some evidence that certain potential frequencies may be a multiple of a lower rate of discharge.

Some Effects of Alveolar Carbon Dioxide Tension on the Carotid and Femoral Flow of Blood.

The importance of volume-flow, as well as composition of the blood, to the transport of oxygen and carbon dioxide and to respiratory control, led to the development of the electrometric method of recording volume-flow of blood, and its use in the study of disturbances in respiratory equilibrium. This report deals briefly with the effects of artificially produced changes in the alveolar concentration of carbon dioxide. The volume-flow in the carotid and femoral arteries was continuously recorded, along with mean blood pressure and pulmonary ventilation. Room air and carbon dioxide (4 to 12 per cent) in room air were administered with re-breathing tanks. In some experiments the gases were administered by natural respiration, and in others pneumothorax was established, and the gases administered by closed circuit artificial ventilation. The administration of carbon dioxide by either method elicited, in general, an increased flow of blood through the carotid artery, followed by a decreased flow on re-administration of room air. The same administration elicited a decreased femoral flow of blood, which increased on re-administration of room air. Changes in artificial pulmonary ventilation with room air were accompanied by corresponding changes in volume-flow of blood. Increasing pulmonary ventilation above normal resulted in decreased carotid flow, and increased femoral flow. Decreasing ventilation produced reverse effects. Artificial control of blood pressure showed the same directional changes in volume-flow of blood in the absence of changes in the driving head of pressure, The results suggest that the circulatory adjustments occurred in favor of the brain. They illustrate the importance of the factor of acidity in the control of circulation, as well as respiration. The fact that the respiratory and circulatory centers are both highly sensitive to changes in acidity agrees with the common and coördinated function of both

Low Alveolar Oxygen Pressure, Sodium Cyanide and the Carotid and Femoral Flow of Blood.

Methods of study similar to those described in the preceding paper on the effects of variations in alveolar carbon dioxide were used. The administration of low oxygen by either natural or artificial ventilation elicited an increased carotid flow of blood, followed by a decrease on re-administration of room air, and a decreased femoral flow, which increased on subsequent administration of room air. Variations from this response were slightly more common than variations with the administration of carbon dioxide. An initial decrease in carotid flow, preceding the increase, and a subsequent decrease in flow below normal, on re-administration of room air, were not infrequent. Changes in flow were more abrupt, and more fluctuating, than those produced by carbon dioxide. This peculiarity, however, was frequently missing. A response to low oxygen may be identical to a response to high carbon dioxide. Intravenous injection of sodium cyanide produced a general increase in carotid flow of blood, and a decrease in femoral flow. An initial decrease in carotid flow preceded the increase. When the mean blood pressure was maintained approximately constant by artificial regulation, the same directional changes in flow obtained. The similarity of circulatory response to low oxygen and sodium cyanide suggests like chemical disturbances in and on the opposite sides of the neurone membranes of the circulatory centers involved in the regulation of circulation. The inverse relation of carotid and femoral flows suggest again that circulatory adjustments occurred in favor of the brain. Likewise, the similarity of the circulatory response to the administration of carbon dioxide on the one hand, and to the administration of low oxygen and sodium cyanide on the other, suggests common factors of control.

Carbon dioxide and the HCO3 ion as specific respiratory stimulants

It has been noted by Howell, Collip, Dale and Evans, the author and others that the intravenous injection of sodium bicarbonate may act as either a respiratory or circulatory stimulant, eliciting hypernea or a marked rise in the blood pressure. Such injection obviously increases the hydrogen ion concentration of the blood and inasmuch as it produces a slight dilution, it decreases the amount of carbon dioxide in the blood eliciting the stimulation. The increased respiration is, therefore contrary to the usually accepted laws of respiration. The only apparent change in the blood which might elicit stimulation is the greatly increased number of HCO3 ions. Collip, therefore, suggests that the HCO3 ion exerts a specific stimulating action on the respiratory center. We believe, however, that this anomalous result may be otherwise explained. When the carbon dioxide is dissolved in water it exists primarily in three forms—dissolved CO2 molecules, dissolved undissociated H2CO3—molecules and dissociated H2CO3—thus . Addition of sodium bicarbonate to the solution pushes the reaction to the left increasing both the dissolved CO2 and the undissociated H2CO3. If we accept the view that the dissolved CO2, and the undissociated H2CO3, diffuse freely into cells while the ions as such do not penetrate to any appreciable extent it is apparent that the injection of sodium bicarbonate increases the freely diffusable forms of carbon dioxide at the expense of the poorly diffusible ions and in that way increases the acid effects of the blood, at least on the interior of the cells (and possibly in the lymph bathing the cells as will be discussed in a later paper) even though the actual sum total of the original dissolved carbon dioxide in its various forms is not increased and the hydrogen ion concentrate of the blood is actually decreased.

Comparison of the Acid Humoral Intermediation of Stimulation in Respiratory and Non-Respiratory Muscles.

The strength of contraction of the rectus abdominus muscle of the frog immersed for varying periods (15-60 seconds) in weak acetylcholine solution (about 1 part in 500,000 parts of Ringers solution, depending on the sensitivity of the preparation) was found to increase with the hydrogen ion concentration of the environment. Such effects occurred within a range of pH 7.5 to pH 5.0. Lactic, phosphoric, and carbonic acids produced comparable effects. These results agree with those previously reported in the rectus abdominus. 1 , 2 However, when the sartorius muscle was used it was found to respond with a weaker contraction under increasing hydrogen ion concentration of the environment. This unexpected finding led us to make comparative observations on a number of muscles of the frog, turtle and alligator. The rectus abdominus, mylohyoid and geniohyoid of the frog, mylohyoid of the turtle, and diaphragm of the alligator, muscles which contribute to the respiratory act, were found to show a progressively increasing strength of contraction with an increasing cH of the acetylcholine-containing environment, while the sartorius, peroneus longus andgracilis minor of the frog, muscles possessing primarily a locomotor function, showed either a consistent depression or an initial augmentation followed by an early depression. This differential effect of acid on these two groups of muscles is of interest in suggesting, for the lower forms at least, that the control of breathing is not strictly a central reflex phenomenon but is supported by a peripheral motor adjustment as well. The chemical (acid) control of respiration may thus be extended to the respiratory muscles as well as 5 to the carotid body and the intra-cranial portions of chemically sensitive control centers.