The purpose of this experiment was to study whether the unusual findings on venous return and its regional distribution in essential hypertension previously reported by Ninomiya, could be produced in experimental hypertension, and if it could be realized, how would it be possible. Further, the author wishes to discuss the pathogenesis of essential hypertension. To make experimental hypertension, three methods, that is, continuous drip infusion of noradrenalin, ablation of both carotid sinus nerves and obliteration of unilateral renal artery, were adopted. In each experiment, venous return and its regional distribution were measured and the comparison was made with that of essential hypertension. Experimental animals and method Normal adult dogs were used for the experiment under morphine and urethane anesthesia. Venous return was measured by already published Electric Conductivity Method which is based on Stewart-Hamilton's principle and the return flows of the superior and inferior caval, hepatic and renal vein, and of the upper and lower extremities, were measured respectively. Taking the total venous return as 100, ratio of respective regional venous return to it, i.e., return ratio, was calculated. Peripheral blood pressure and E.C.G. were also recorded simultaneously. Moreover, regional vascular resistances were calculated from the above obtained data, and renal function was studied by renal clearance method. The following three procedures were adopted to produce the experimental hypertension.A. Hypertension due to noradrenalin drip infusion.The noradrenalin saline solution was infused during 20 to 30 minutes at the rate of 0.5, 2.0 and 6.0 μ g/min/kg (small, middle and large doses). Before and during this procedure circulatory hemodynamic changes were measured.B. Hypertension following the denervation of both carotid sinus nerves. The bifurcated region of the internal and external carotid artery in the common carotid artery was destroyed by concentrated carbolic solution and then change in blood pressure and pulse rate were observed during the period of 30 to 90 days.C. Hypertension caused by an unilateral obliteration of the renal artery. An unilateral renal artery was ligated in such a way that it narrowed down to 1 mm in diameter. Blood pressure and pulse rate were measured for a period of 30 to 75 days following the arterial occlusion.Results A. The noradrenalin hypertension : Elevation of both systolic and diastolic blood pressures was observed after the infusion of noradrenalin ; the more graded noradrenalin was infused, the more marked elevation of blood pressure was seen. The cardiac rate was unchanged with the small dose, but the brady-cardia appeared with increasing dose of infused noradrenalin. The cardiac output and the total venous return were unchanged with the small dose, but decreased with the moderate or the larger dose. Speaking of the venous return and its distribution, the cranial venous flow (C.V.F.) decreased with the small dose infusion, in spite of the fact that the hepatic venous flow (H.V.F.) and the renal venous flow (R.V.F.) increased. With the a larger dose of noradrenalin the C.V.F. and the R.V.F. markedly decreased, but the H.V.F. decreased slightly. The peripheral vascular resistance showed marked increase in the cranial and the renal region and slight increase in the abdominal visceral region. With respect to the renal function, RBF, RPF and GFR showed a little increase with the noradrenalin infusion of small dose but the notably decreased as the noradrenalin dose was increased. The increase of the renal vascular resistance was observed in afferent vessels rather than in efferent ones.B. The neurogenic hypertension due to the carotid sinus denervation. : An immediate rise of the blood pressure after the carotid sinus denervation was followed by the prolonged fluctuation, resulting in a sustained elevation. [the rest omitted]

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It is well known that various pulmonary diseases result in circulatory failure, particulary in right heart overload or failure. Since the concept of cor pulmonale was proposed by MeGinn and White in 1935 from a monogenetic standpoint of cardiopulmonary physiology, there have been many works on the right heart function in the disturbance of the pulmonary circulation resulted from decrease in pulmonary vascular bed. As a part of our serial works on the genesis of chronic cor pulmonale, the measurement of the right ventricular residual blood volume was done in chronic pulmonary diseases, since it was our understanding that to know the right heart function the residual blood volume and end-diastolic volume of the right ventricle and the residual fraction or the ration of the residual blood volume to end-diastolic volume are as important as cardiac output, pulse rate, circulation time, circulating plasma volume and intra-cardiac and intra-vascular pressure.Method The dye dilution method of Bing and the formula of Holt were utilized. Two cardiac catheters were inserted, the one into the main pulmonary artery and the another into the right ventricle. The evans blue was instantly injected into the right ventricle, and the blood was continuously aspirated from the main pulmonay artery by the specially made apparatus which is, under the negative pressure of more than 500 mmHg, capable of aspirating four or more fractional blood samples a minute. The concentration of the evans blue in the plasma of each blood sample was measured and plotted against time. From the thus obtained dye dilution curve, the residual volume was calculated according to the formula of Holt.Results and Discussion a) The right ventricular end-diastolic volume showed a direct linear correlation with the residual volume and the stroke volume. That is, the residual volume was increased as the right ventricular end-diastolic volume was increased.b) The residual fraction was increased and the mean pulmonary circulation time was prolonged in chronic pulmonary diseases. An increase in the residual fraction was marked in cor pulmonale. The residual fraction was 53.5% in chronic pulmonary emphysema, 52.8% in bronchiectasis, 55.5% in bronchial asthma and 51.1% in pulmonary tuberculosis. When compared with means of healthy subjects (48 to 55%), these values were within normal limits or around the upper border of the normal. In 6 cases of cor pulmonale, however, which had elavated pulmonary artery pressure and was in right heart failure, the residual fraction was markedly increased showing the mean of 64.5%.c) There was a significant difference between a group with the electrocardiographic finding of right ventricular hypertrophy and a group without right ventricular hypertrophy. In the former group, the residual volume and the residual fraction were increased.d) Both the residual volume and the residual fraction were directly correlated with the mean pulmonary artery pressure. The residual fraction was increased in those with the total pulmonary vascular resistance above 400 dyne·sec·cm^-5.e) The residual volume and the residual fraction were not correlated with the finding of cardiac enlargement by chest roentgenogram.f) The residual fraction was increased in many cases of tachycardia which showed the resting pulse rate of more than 100 per minute.g) The mean pulmonary circulation time was not at all correlated with the residual fraction.h) Inhalation of air of low O₂ or high CO₂ content and exercise were done in 13 cases. From the change in circulatory hemodynamics in these cases, it is clear that the cardiac output was increased to maintain the enough blood flow to meet the increased demand of each living tissue. An decrease in the residual blood volume and a marked decrease in the residual fraction were observed at the same time and with an increase in pulse rate the cardiac output was increased as well. [the rest omitted]

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The pulmonary circulation time measured by the right heart catheterization actually includes the circulation time from the left ventricle to an arm where the blood sample is taken. Therefore, it does not represent the accurate pulmonary circulation time. It is not accurate as well to measure the pulmonary blood volume by the right heart catheterization.The radio-cardiogram obtained by the use of radio-isotope records two peaks on its curve, the one representing the time when the isotope used is passing through the right heart, and the another representing the time when it passing through the left heart. Thus obtained pulmonary circulation represents the circulation time from right to left heart and is much more accurate. It is called ""R-L time"".To avoid the inaccuracy of the traditional dye dilution method, the pulmonary circulation time was measured from the radio-cardiogram obtained by the use of ¹³¹I. Method Total of 44 cases were studied, including 7 normal subjects, 20 cases of pulmonary diseases and 17 cases of cardiac diseases.On the chest of a patient in supine position, a scintilation detector was placed at the center of the cardiac siluette under fluoroscopy or at the center of the absolute cardiac dullness. 20 to 60 μc of ¹³¹I diluted with 0.3 to 1.1 cc of normal saline was instantly injected into cubital vein and radiocardiogram was obtained by the use of scintilation counter and scintilation ratemeter, from which R-L time was measured. Immediately afterward cardiac output was measured by the dye dilution method and the pulmonary blood volume was calculated according to the formula of Stewart-Hamilton. Hemodynamic changes by exercise were also observed in these patients.Result and Conclusion 1) Means of resting R-L time were 3.9 sec. in normal subject, 7.7 sec. in mitral stenosis, 5.2 sec. in hypertension, 5.7 sec. in coronary disease, 4.3 sec. in pulmonary tuberculosis, 4.7 sec. in bronchial asthma, 5.1 sec. in bronchiectasis and 5.3 sec. in pulmonary emphysema. This shows that the pulmonary circulation time was markedly prolonged in cardiac disease even at rest.2) Pulmonary blood volume calculated from the R-L time was much lower than that from the dye dilution method.3) By exercise, R-L time was altered along with changes in mean circulation time measured by the dye dilution method. In most of the cases, R-L time was shorted when mean circulation time was shortened, and R-L time was prolonged when mean circulation time was prolonged.4) By exercise, R-L time was shortened, cardiac output was increases and pulmonary blood volume was slightly decreased in healthy subjects and in pulmonary diseases. On the contrary, in many cases of cardiac diseases, especially in coronary disease, R-L time was prolonged, cardiac output was decreased and pulmonary blood volume was slightly increased. In cardiac disease, already increased pulmonary blood volume at rest was more increased by exercise and pulmonary congestion developed consequently.5) The prolongation of the R-L time by exercise suggests decreased reserve capacity of the heart. To know the cardiac reserve capacity, the method is recommendable as a non-operative procedure which can be done easily and repeatedly.

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The adrenalin pulmonary edema induced by the intravenous injection of adrenalin presents resemblance, in its marked clinical and pathological findings, with the acute pulmonary edema of man. Buffer nerve reflex has been thought to play an important role on the development of adrenalin pulmonary edema by various investigators. To elucidate this process more precisely, the author has investigated the pathogenesis of the adrenalin pulmonary edema with special reference to the buffer nerve mechanism by means of modifying the effect of the carotid sinus reflex.Methods : Lung body index, pathological findings, and mortality rate were examined in the rats weighing 100∼200 gm. in the experimental conditions described below. Four kinds of procedure were used for the modification of the buffer nerve reflex.(1) The withdrawal of blood from the femoral artery : The with-drawal of blood was made by an ordinary syringe from the femoral artery and its volume was calculated and given in percentage to the estimated total volume of the rat. According to Everett's formula total blood volume per 100 gm. of body weight was estimated 5.65 cc. The withdrawal of blood was made respectively before and 30 seconds, 1 minute and 2 minutes, after the injection of adrenalin.(2) Application of the blood reservoir was tried to be applied to the femoral artery, for the purpose of protecting the hemorrhagic shock. When a blood reservoir was connected by a rubber tube to the femoral artery, not only hardly any blood was lost, but also could the systemic blood pressure be controlled by regulating the intra-reservoir pressure.(3) The ligation of the carotid artery : In order to prevent the carotid sinus reflex from eliciting its effect the bilateral common carotid arteries were ligated. The unilateral ligation of the common carotid artery and the bilateral ligation of both the internal and the external carotid arteries were needed for comparison.(4) The influence of the various doses of adrenalin on the lung body index was investigated in the normal rats and the rats wich received bilateral sinus denervation or the bilateral ligation of the common carotid arteries.Discussion and Result : 1) Withdrawal of blood : The volume of the blood withdrawn amounted 10∼80 percent of the estimated total blood volume. When the blood was withdrawn before and 30 seconds after the injection of adrenalin, lung body index was within normal range, but when the withdrawal of blood was carried out 1 or 2 minutes following the injection, lung body reached higher level and the pulmonary edema was seen either macroscopically or microscopically. Regardless of the development of the pulmonary edema, mortality was significantly high, presumably due not only to the pulmonary edema, but also to the hemorrhagic shock.2) Application of the blood reservoir : When blood reservoir was applied before the injection of adrenalin, the lung body index remained in normal range ; when applied 1 or 2 minutes after the injection, lung body index was elevated and the pulmonary edema was found, but mortality rate was lower than those in the former experiment. In the animal to which the blood reservoir was applied prior to adrenalin, the adrenalin bradycardia lasted only for 1 minute in spite of the fact that in the latter cases the bradycardia continued for about 5 minutes.From these experiments described above, the adrenalin pulmonary edema was thought to devolop in the early period after the injection of adrenalin, because letting out the blood within 1 minute after injection was able to protect the occurence of the pulmonary edema. [the rest omitted]

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The author investigated the application of extracorporeal circulation as treatment for the circulatory failure in the experimentally induced acute pulmonary edema.Method : 33 dogs were used for the present study. After pneumonectomy, the dogs were made to breath room air and were given plasma expander (50 cc/kg) intravenously to induce acute pulmonary edema, Jordan's grade IV. Then one of the 4 types of extracorporeal circulasion, i.e. 1) cardiopulmonary by-pass method (Fig. 1), 2) pulmonary by-pass method (Fig. 2), 3) simple oxygenation of the venous blood (Fig. 3), and 4) oxygenation of the venous blood of the inferior vena cave (Fig. 4) was started to treat the edema. Simultaneously positive pressure breathing with oxygen was started. Among these four methods, satisfactory result was obtained only by the cardiopulmonary by-pass method.The cardiopulmonary by-pass method was done by the following procedure. The venesection on the superior- and inferior venae cavae were performed. The venous blood was oxygenated by the bubble oxygenator of Lillehei-DeWall type, and then, the oxygenated venous blood was infused into both femoral arteries by the Sigma motor-pump.Results : In each method, results of treatment of pulmonary edema were as follows (Table I). 1) Cardiopulmonary by-pass method-Among 19 dogs treated 20-90 minutes by this method, 11 dogs recovered, 6 dogs improved and 2 dogs did not improve. 2) The pulmonary by-pass method-In this type of circulation one improved out of 5 dogs, 2 were not improved and died during the perfusion. None was cured by this method. 3) Simple oxygenation of the venous blood-Among 5 dogs, one cured, one improved, one not improved and 2 died immediately after the onset of the perfusion.4) Simple oxygenation of the venous blood of the inferior vena cava-Among 4 dogs, one improved, one not improved and 2 died during the course of the perfusion.To determine the optimum rate of perfusion in cardiopulmonary by-pass method, the clinical effectiveness of the treatment, changes in the arterial oxygen saturation and changes in the pulmonary arterial pressure were studied under various flow rates. Of the 4 dogs using the low flow rate, 35 cc/kg/min, 2 were improved and the other 2 were unchanged. In contrast, with the medium rate of perfusion, 40-65 cc/kg/min, 6 were recovered from the pulmonary edema and 2 were improved. Good results were obtained with the rate of perfusion over 70 cc/kg/min ; among 7 dogs, 5 were cured and 2 were improved.Immediate improvement of the arterial oxygen saturation was observed with any rate of perfusion (Fig. 5). Under the low perfusion rate the depressed arterial oxygen saturation showed steep elevation immediately after the beginning of the extracorporeal circulation, however, in this rate of perfusion, no significant improvement was obtained and the oxygen saturation remained below 90% even after 60 minutes' perfusion. The oxygen saturation rate in the 2 dogs not cured was 85 and 87% respectively, and it tended to decrease after 30 minutes' perfusion. Under the medium or the high rate of perfusion the arterial oxygen saturation was elevated up to the normal range (over 90%) within 5 minutes of perfusion. The maximum arterial oxygen saturation was observed 30 minutes after the onset of the extracorporeal circulation ; 91-96% in the medium rate of perfusion and 94-98% in the high rate of perfusion.The changes in the pulmonary arterial systolic pressure under various rates of perfusion were as follows (Fig. 6); During the established pulmonary edema the pulmonary arterial pressure was 40 mmHg or higher. Under the low perfusion rate 20-30 minutes elapsed before the pulmonary arterial pressure came down to the normal value (20 mmHg). It was 28 mmHg in one instance. It had also a tendency to begin to elevate after 30 minutes of perfusion. Under both the high and the medium perfusion rates the pulmonary arterial pressure fall to the normal range within 5 minutes perfusion. The de

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