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Reflex Control of the Systemic Venous Bed EFFECTS ON VENOUS TONE OF VASOACTIVE DRUGS, AND OF BARORECEPTOR AND CHEMORECEPTOR STIMULATION By Eugene Braunwald, M.D., John Ross, Jr., M.D., Richard L. Kahler, M.D., Thomas E. Gaffney, M.D., Allan Goldblatt, M.D., and Dean T. Mason, M.D. Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 • Dr. Carl AViggers concludes the introductory chapter to the section on the circulation of the Handbook of Physiology1 in the following manner: " The present author finds it difficult to understand why so much current emphasis is given to mechanisms of blood supply that can be only temporary emergency mechanisms. My calculations indicate that the total cardiopulmonary reserve can be pumped out within five or six seconds after the onset of strenuous exercise. Thereafter, augmented cardiac output can be maintained only by a corresponding increase in venous retui'n. Despite many earnest efforts to elucidate the sources of additional venous blood and the mechanisms by which venous return is augmented, most of the conclusions are based on inference and extrapolations rather than on direct experimental evidence. Hence the study of venopressor mechanisms remains a promising field for future investigations." In order to understand the importance of the venous system in circulatory control, it has been found helpful to consider the heart as a pump which is capable, within broad limits, of expeUing blood at the same rate at which it is received from the venous bed. Since the postcapillary bed contains approximately 75% of the extrathoracic blood volume, it is clear that even slight changes in venous compliance can profoundly modify the distribution of blood between the systemic and intrathoraeic beds and can thereby alter the venous return to the heart and the cardiac output. Thus, generalized systemic venodilatation increases the volume of blood contained in the venous bed at any given venous presFrom the Cardiology Branch, National Heart Institute, Bethesda Maryland. Circulation Research. Volume XII, May 190S sure, and decreases the venous return, cardiac output, and arterial pressure in a manner analogous to hemorrhage; generalized venoconstriction has the opposite effect. For a number of years, it has been appreciated that the venous bed is not a simple series of elastic tubes, but that the veins are capable of reacting to a number of humoral or neurogenic stimuli.3"7 Thus, several investigators have demonstrated that sympathomimetic amines produce a contractile response of excised vein segments, 8 ' ° while others have shown that changes in the capacity of isolated venous segments result from activation of carotid sinus receptors.10"17 It is the objective of this report to review the results of a series of experiments in which the effects of a variety of stimuli on the entire systemic venous bed of the dog could be determined in a precise manner, and in which the effects of alterations of venous tone on venous return could be established quantitatively. In addition, the importance of effects on the venous system in the mechanism of action of some antihypertensive drugs will also be considered. In order to study the entire systemic venous bed of the dog directly, it was necessary to devise a preparation in which changes in cardiac activity and in the pulmonary vascular bed would not obscure alterations in the systemic vascular bed. The basic experimental plan employed was to remove the heart and lungs from the circulation functionally, by means of extracorporeal circulation, as shown in figure I. 18 Utilizing morphine-chloralose-urethane anesthesia, positive pressure respiration was maintained through a cuffed endotracheal tube until extracorporeal circulation was established. After right thoracotomy and isolation of the femoral ves539 540 BBAUNWALD ET AL. Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 FIGURE 1 Diagrammatic representation of the basic extracorporeal circuit employed. Blood drains by gravity from the superior vend wva (SVC) and inferior vena cava (IVG) to the oxygenator. The aorta (A0) is cross-clamped above the coronary arteries and blood accumulation in the right atrium (RA) and left atrium (LA) is prevented by means of tiuo other drainage tubes. Oxygenated blood is pumped through a rotanneter (ROT.) into the femoral artery (FA). The level of blood in the oxygenator is sensed by the detecting electrodes (DET.) which activate a reversible pump connected with the calibrated reservoir (RES.). sels, cardiopulmonary bypass was instituted. Blood was drained from the venae eavae and atria through large-bore, rigid cannulae into a rotating disc oxygenator. The blood then passed to a roller pump through a recording rotameter, and was returned to the dog through a cannula in the femoral artery. All blood entering the right atrium was diverted into the oxygenator and thus the pulmonary circuit was not perfused. Except when specifically noted, the S3rstemic perfusion rate was maintained constant at approximately 100 ml/kg/min throughout each experiment. Heparin (4 mg/kg) was used as the anticoagulant. The blood volume in the oxygenator was kept constant at all times by an electronic sensing device which actuated au auxiliary pump. In order to maintain the volume of blood in the oxygenator at a constant value, the auxiliary pump automatically exchanged blood between the oxygenator and a separate blood reservoir. By this technique, any change in the volume of this second reservoir reflected an inverse change in the intravascular blood volume of the animal. The volume of blood in the reservoir was determined at one-minute intervals throughout each experiment, providing minute-to-minute measurements of changes in the animal's intravascular blood volume. Thus, generalized venoconstriction would be accompanied by an increase in venous return to the oxygenator. a decrease in intravascular blood volume, and a reciprocal increase in the volume of blood in the second reservoir. In other experiments, in order to measure venous return more directly, alterations of the intravascular blood volume could be prevented by modifying the output of the pump. For example, when venous return to the reservoir increased, the pump output was manually increased at a rate sufficient to maintain the volume of the extracorporeal circuit constant. The alterations of systemic perfusion rate were determined and provided Circulation Research, Volume XII, May 196S 541 REFLEX CONTROL OF SYSTEMIC VENOUS BED Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 a direct measurement of the changes in venous return. In addition, changes in venous distensibility of the entire systemic venous bed could also be studied in this preparation by modifying the method utilized by Alexander 14-10 in studies on the splanchnic venous system. Pressures were measured in the superior and inferior venae cavae during sudden, brief occlusions of the venous outflow line, while arterial inflow was maintained constant. During a steady state, venous return to the oxygenator equaled the output of the pump and it is assumed that blood entered the venous segment of the circulation at an identical rate. When, under these circumstances, the venous outflow is briefly occluded, the pressure in the venous system rises abruptly. The rate of this pressure elevation is primarily a function of the initial volume of the venous bed, its distensibility, and the rate of blood flow into it; since the latter Avas held constant throughout any given experiment, the influence of flow rate, as well as of any effects due to the inertia! and viscous properties of the vessel walls, was minimized. The steady state was assured by performing the venous occlusions only after the transient alterations in venous return accompanying the intervention under study had been completed and at a time when arterial pressure was stable. intravascular blood volume. In four experiments, in which the extracorporeal blood volume was held constant during infusion of either catecholamine, it was necessary to increase the output of the pump by an average of 40% of the control perfusion rate. These changes in pump output are analogous to the alterations in cardiac output which would have occurred had the heart responded passively to the volume of blood returned to it by the venous s}rstem, and had the intervention under study produced no effect on the heart itself or on the pulmonary vascular bed. Analysis of the venous occlusion curves in five experiments also confirmed the impression that the catecholamines had produced a profound generalized sjrstemic venoconstriction. The infusion of trimethaphan (Arfonad) at an average rate of 26 ptg/kg/min into four dogs had the opposite effect. The intravascular blood volume increased by an average of 17.3 ml/kg at the expense of the volume of blood in the oxygenator. Venous occlusion curves also indicated that the trimethaphan had resulted in generalized systemic venodilatation. In experiments in which blood volume was held constant, the infusion of trimethaphan resulted in a decline in venous return by an average of 30% of the control level.20 CAROTID SINUS REFLEXES DIRECT EFFECTS OF VASOACTIVE DRUGS The infusion of norepinephrine at an average rate of 2.4 fig/kg/min, and of epinephrine at a rate of 1.5 /Ag/kg/min, into seven dogs, resulted in a prompt and profound shift of blood from the systemic venous bed into the oxygenator. The volume of blood displaced into the oxygenator averaged 19.0 ml/kg. The large magnitude of the alterations in the systemic vascular volume observed in these experiments suggested that the major changes in capacity occurred in the postcapillary or venous bed. The importance of the changes in the venous return accompanying these shifts in blood volume is indicated by the large modifications of the output of the pump which were necessarj' to obviate alterations in Circulation Research. Volume XII. May 1963 The chief purpose of studying the effects of these well-known venoconstrictor and venodilator drugs was to provide a background from which the effects of a number of circulatory reflexes on the venous bed could be evaluated. Attention was first directed to the well-known carotid sinus reflex. The basic preparation shown in figure 1 was modified in a manner so as to permit study of the effects of altering the pressure acting on the carotid sinuses on the systemic arterial and venous beds.20 The carotid artery bifurcations were completely isolated in the manner described by He j 'mans and Bouckaert.21 The common carotid arteries were cannulated proximal to their bifurcations, and the external carotid arteries were cannulated distally. Care was taken to avoid 542 BKAUNWALD ET AL. MIC FLOW Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 zooo isoo •cot H CAROTID MEAN L CAROTID MEAN A BU30C «J H FIGURE 2 Recordings, from above, of pressures in the superior vena cava (S.V.C.), inferior vena cava (I.V.C.), aorta. Systemic flow and mean pressures in the right (R.) and left (L.) isolated carotid, sinuses. Venous occlusion curves inscribed at a loto (left) and at an elevated (right) pressure. The graph at the bottom indicates the time course and the magnitude of the reflex increment in intravascular blood volume which resulted from carotid sinus hypertension. (Reproduced by permission from Ross, J., Jr., Frahm, C. J., and Braunivald, E.: Influence of carotid baroreceptors and vasoactive drugs on systemic vascular volume and venous distensibility. Circulation Research 9: 75,1961.) denervation of the carotid bodies, the carotid sinuses and their nerves. Perfusion of the sinuses was carried out by the arterial pump, and variations in perfusion pressures were achieved b}' modifying the resistance of the outflow line from the sinuses with a screwclamp. Bilateral cervical vagotomy was performed in these animals in order to minimize the buffering effects of the aortic pressure receptors. When carotid sinus pressure was suddenly elevated while the systemic perfusion rate was held constant, systemic vascular resistance fell by an average of 40%, venous return declined, and the dag's systemic blood volume increased. The increases averaged 12.9 ml/kg, and the venous occlusion curves confirmed the impression that venodilatation had taken place, in a manner similar to that which was observed during the infusion of trimethaphan (fig. 2). In contrast, when carotid sinus pressure was suddenly reduced, systemic vascular resistance increased by an average of 41% of the control values, venous return suddenly increased, and blood shifted from the dog into the extracorporeal circuit. When the pump Cirndation Research, Volume XII, May 196S KEFLEX CONTBOL OF SYSTEMIC VENOUS BED Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 output was changed in order to measure this augmented venous return, it was found to have increased by 27% of the control levels. Analysis of the venous occlusion curves also confirmed the impression that lowering of the carotid sinus pressure had resulted in generalized reflex venoconstriction, quite similar to that which occurred after norepinephrine infusion. As a result of these studies, the baroreeeptor mechanism may be considered to assume a broader integrative role in circulatory regulation. It appears that the well-known homeostatic role of these receptors may be extended to include the reflex control of the entire systemic venous bed. Thus, when hypotension activates the baroreceptor mechanism, or when a sympathoadrenal discharge is initiated by exercise, anxiety, or other stimuli, in addition to arteriolar constriction, tachycardia, and augmented myoeardial contractility, reflex venoconstriction also takes place and results in an augmentation of venous return to the heart and an increase in the cardiac output. REFLEXES ORIGINATING FROM INTRACARDIAC BARORECEPTORS The presence of baroreceptors in the walls of the cardiac chambers and the pulmonary vascular bed is now well established, and their function in the reflex control of the circulation has been the subject of a number of investigations.11' 22~27 Action potentials have been recorded from afferent fibers originating in the heart and lungs, 22 ' 23 and elevation of pressures within the ventricular chambers24"27 and pulmonary vascular bed 25 ' 2S| "" has resulted in bradycardia,24"28 a decline in systemic arterial pressure,25"27 and in changes in ventilation.25'26>28>29 In order to study the effects of stimulating the cardiac baroreceptors on the venous bed, the basic preparation shown in figure 1 was again modified.30 Blood was circulated through the heart by utilizing a separate circuit, entirely separated from the pump-oxygenator system. Oxygenated blood drained from a reservoir through a cannulated pulCirculation Research, Volume XII. Mw 1SGS 543 nionary vein and into the left side of the heart. In addition to the drainage cannula placed in the right ventricle, a tube was inserted into a segmental pulmonary artery to assure complete emptying of the right heart and pulmonary artery; the blood from these two drainage tubes was collected in an accessory reservoir. Circulation through the lungs was prevented by mass ligation of each hiluni. Alterations in pressure in the left side of the heart could be induced by varying the inflow from the reservoir while the ascending aorta was kept clamped. When the inflow of blood into the heart was increased, left heart pressures rose, since the only egress of blood was through the coronary bed. Pressure in the right side of the heart could be modified by varying the resistance in the right ventricular and pulmonary arterial drainage lines, since clamping of the lines resulted in a "damming u p " of blood in the right side of the heart. In all 10 dogs studied, elevation of intracardiac pressures resulted in a decline of the extracorporeal volume and, therefore, an augmentation of intravaseular blood volume, which averaged 120 ml (fig. 3). In six of these animals, the pressures were raised in the right side of the heart, the left atrium and the left ventricle, and in four dogs the pressure elevation was confined to the left side of the heart, while right heart pressures were not altered. The increments of intravaseular volume observed in these two groups of experiments were similar. When intraeardiac pressures were elevated in these experiments, the pump output had to be diminished by an average of 25.3% of the control values in order to maintain the intravaseular blood volume constant, i.e., an increase in the intraeardiac pressure resulted in a reflex venodilatation which diminished venous return by approximately one-fourth of the control level. In the course of these experiments, it was observed that an increase in left ventricular systolic pressure alone, or combined with an elevation of left ventricular diastolic pressure and left atrial pressure, resulted in a reflex decline of systemic vascular resistance. How- 544 BEAUNWALD ET AL. A. Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 rr.l 50 CONTROL 9MIN. 6 MIN B. A BLOOD VOLUME __, 00 i 0 0- Control 5 Minutes FIGURE 3 (A.) Recordings, from above downtoard, of "pressure in the aorta (Ao.), systemic In flow (8.F.), pressures in the left ventricle (L.V.), and right ventricle (R.V.). the panel on the left, ventricular pressure was elevated. Six minutes later, R.V. pressure ivas also elevated (center panel). In the panel on the right, ventricular pressures were lowered. (B.) The alterations in systemic vascular volume which occurred simultaneously are depicted. The vertical arrows indicate the points in time at which left and right ventricular pressures were elevated. ever, there was little change in systemic resistance when only right heart pressures were altered.30 The reflex effects of the stimulation of intracardiac baroreceptors may be of importance in a variety of physiological and pathological circumstances. It would seem likely that they operate in conjunction with the sino- aortic mechanism in the regulation of both arteriolar and venous tone and therefore of arterial pressure and cardiac output. In addition, when intracardiac pressures alone are elevated, as in the presence of congestive heart failure or valvular stenosis, the resulting arteriolar and venous dilatation could serve to decrease the hemodynamic burden Circulation rch, Volume XII. May 196S 545 KEFLEX CONTROL OF SYSTEMIC VENOUS BED imposed on the heart by diminishing systemic pressure and by decreasing venous return. EFFECTS OF HYPOXIA Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 In view of the profound circulatory changes whicli occur during hypoxia, it was of interest to determine whether this stimulus also alters venous tone. In the experiments described thus far, the gas mixture in the oxygenator consisted of 98% O2 and 2% CO2. In order to study the effects of hypoxia, this mixture was suddenly changed to 10% 0 2 , 2% CO2, and 88% N2. This resulted in a decline of arterial O2 saturation from an average value of 97.4% during the control period to an average value of 50.1% during the experimental period.31 Hypoxia resulted in an increase in venous return and a consequent decline in systemic blood volume in all 11 dogs with intact chemoreceptors studied. The decrease in blood volume averaged 16.0 ml per kg in the seven "intact" dogs (including two animals which had received succinylcholine and one animal in which the phrenic nerves had been sectioned—fig. 4). In four dogs in which bilateral adrenaleetomy and splenectomy had been performed, the blood volume decreased by an average of 10.9 ml per kg. In order to maintain the volume of the extraeorporeal circuit and therefore of the intravascular compartment constant, it was necessary to increase the output of the pump by an average of 20% of control values in dogs with intact chemoreceptors during the period of hypoxia. Hypoxia did not result in any change in venous return or in intravascular blood volume in the six dogs which had been subjected previously to denervation of the carotid and aortic chemoreceptors. These observations indicate that, in the absence of any direct effect upon the heart itself, hypoxia would increase the cardiac output as a result of venoconstriction and the resultant increase in venous return. Since the augmentation of venous return induced by hypoxia was completely eliminated by interruption of the chemoreceptor reflex arc, it is concluded that it resulted from stimulation Circulation Research. Volume XII. May 196S DECREASE IN INTRAVASCULAR BLOOD VOLUME DURING HYPOXIA ML./KG. • • NORMAL ADRENALECTOMY AND SPLENECTOMY FIGURE 4 Decrease in intravascular blood volume during systemic hypoxia. The circles represent observations carried out on dogs with adrenal glands and spleen intact, while the squares represent observations carried out following bilateral adrenaleetomy and splenectomy. The upper horizontal line represents the mean value in the "normal" dogs, while the lower horizontal line represents the mean value in the adrenalectomized-splenectomized dogs. of the carotid and/or the aortic chemoreceptors. Bilateral adrenaleetomy and splenectonvy tended to diminish the decrease in blood volume that occurred during hypoxia, although there was considerable overlap among the values observed in these animals with those obtained in the " i n t a c t " dogs. These findings suggest that the release of eatecholamines from the adrenal medulla and/or the contraction of the spleen, play a significant but not a major role in the displacement of blood from the systemic vascular bed during hypoxia. The observation that the decrease in systemic blood volume induced by hypoxia was not diminished by section of the phrenic nerves or by skeletal muscle paralysis, indicates that in these open-chest dogs increased activity of the thoracic pump induced by hy- 546 BRAUNWALD ET AL. Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 FIGURE 5 Decrease in intravascular blood volume during hypercapnia induced with 6% COS. The circles represent observations carried out on dogs with adrenal glands and spleen intact, while the squares represent observations carried out folloiving bilateral adrenalectomy and splenectomy. poxia was not responsible for the augmentation of venous return. EFFECTS OF HYPERCAPNIA Hj'percapnia was produced by changing the gas mixture in the oxygenator from 98% O2 and 2% CO2 to 94% O2 and 6% CO2. In tins manner, the pCO2 of the blood pumped into the arterial system was elevated. During the control period, the arterial blood CO2 content ranged from 17.4 to 30.2 vol % with an average value of 23.6 vol %. At the termination of the period during which 6 % CO2 was employed in the gas mixture, the CO2 content ranged from 24.0 to 37.0, with an average value of 31.8 vol %. Although pCO r was not determined directly in these experiments, the elevation in arterial CO2 content substantiates the view that PCO2 actually rose. An increase in venous return, and consequently a decline in intravascular blood volume, occurred in all of the dogs studied. This decrease ranged from 5.0 to 12.6 ml/kg, with an average value of 9.5 ml/kg in nine dogs (including one animal which had received succinylcholine—fig. 5). In order to maintain the volume of the extracorporeal circuit and therefore of the intravascular compartment constant during the period of C0 2 administration, it was necessary to increase the output of the pump by 22% and 28% of the control values in the two dogs with intact cliemoreceptors studied in this manner. In two additional dogs, which had undergone adrenalectomy and splenectomy prior to study, the blood volume decreased by 8.8 and 13.8 ml/kg. In contrast to the results observed with hypoxia, denervation of the cliemoreceptors did not modify the alterations of venous return or of intravascular blood volume induced by CO 2 ; in the two animals in which the carotid and aortic chemoreceptors had been denervated, the venous return increased, and the intravascular blood volume decreased by 11.0 and 12.9 ml/kg, respectively. In spite of the observation that CO has a direct dilating effect on veins, the present results indicate that in the whole animal this stimulus induces venoconstriction. The data obtained are compatible with the view that the chemoreceptor reflex arc is of little, if any, importance in mediating this CO2-induced venoconstriction. It appears likely that it occurs as a result of the direct action of CO2 on the central nervous system. The adrenal glands and spleen did not appear to play au important role in increasing venous return. In the dogs with intact cliemoreceptors, adrenal glands and spleen, the changes in mean aortic pressure during hypercapnea ranged from 0 to —27%, with a decline which averaged 9.8% of control values. In the three dogs previously subjected to adrenalectomy and splenectomy, the mean aortic pressure fell by an average of 21.0% of control values. The observation that a decrease in systemic vascular resistance occurred when hypercapnea was induced in the animals with intact chemoreceptors as well as in those in which the ehemoreceptors had been denervated, indicates that CO2 results in arteriolar dilatation, presumably because the local dilator effect predominates Circulation Research, Volume XII. May 19CS REFLEX CONTROL OF SYSTEMIC VENOUS BED over any possible arteriolar constriction mediated either through a reflex or through the central nervous system. In intact man, hypercapnca has been shown to result in an elevation of systemic arterial pressure, but this effect is accompanied by an elevation of cardiac output. RESERPINE AND GUANETHIDINE ON REFLEX VENOCONSTRICTION Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 The concept that some antihypertensive drugs act, at least in part, on the venous S3'Stem is not new. A number of "clinical studies indicated that following the administration of ganglionic blocking agents to many hypertensive patients, cardiac output and arterial pressure declined in parallel fashion, i.e., there was relatively little change in the calculated systemic vascular resistance. 32-36 RP^G j a jj j n c a r d i a c output was attributed to a decreased venous return and to failure of operation of the normal reflex venoconstrictor mechanism, particularly in the upright position. Support for this concept was obtained from the observation that the socalled "central blood volume" decreased in hypertensive patients who received ganglionic blocking agents,32 and from the finding of Restall and Smirk that immersion into a pool of water counteracted the hypotensive action of these drugs. 37 The experimental studies of Freis and collaborators,38 and of Trapold,39 showed that venous return was decreased by ganglionic blocking agents. A number of workers have also shown that reflex elevations of venous pressure in a segment of hitman forearm vein can be prevented by ganglionic blocking agents.40"*2 With this background of information, it was of considerable interest to determine whether some of the newer antihypertensive drugs, such as reserpine and guanethidine, affect reflex venoconstriction. The technique described by Bartelstone for the demonstration of reflex venoconstriction, was employed in these particular studies.1" In anesthetized, open-chest dogs, the simultaneous occlusion of the thoracic aorta distal to the left subclavian artery, and of the inferior vena cava Circviation Re.ch. Volume XII, May 196S 547 just below the right atrium, resulted in isolation of the circulatory bed below the clamps, while the circulation in the upper segment was maintained. Bartelstone has shown quite clearly, and in the course of these experiments we have confirmed,43 that in this preparation, the arterial and venous beds in the lower segment of the animal are functionally separated. Venoconstriction occurring during major vessel occlusion can be recognized by an abrupt rise in vena caval pressure which is associated with the distension of the "vena cava as the volume of blood contained by the smaller veins and venules is diminished during venoconstriction. After the major vessels were occluded, tests to determine the presence of reflex venoconstriction were carried out repeatedly in each experiment by occluding both common carotid arteries for 45 seconds, or by electrically stimulating the central end of the cut right vagus nerve for 30 seconds. Reflex venoconstriction was blocked in each of five dogs by the intravenous administration of 0.5 mg/kg of reserpine. Treatment of 10 dogs with intravenous guanethidine, in doses ranging from 1 to 10 mg/kg, also abolished, or markedly reduced, reflex venoconstriction. Reserpine eliminated reflex venoconstriction secondary to carotid occlusion and central vagal stimulation within 90 minutes after its intravenous administration, at a time when the heart rate response to cardioaccelerator nerve stimulation was only reduced. This difference in the degree of blockade of the venoconstriction and of cardiac acceleration suggests that different dose-response relationships may exist for these two responses. The venopressor response to carotid occlusion and central vagal. stimulation was blocked by guanethidine within the first five minutes after injection during the initial arterial pressor response.44 The time of onset of this blockade fits well with the observations of McCubbin et al. that during stimulation of the lumbar sympathetic chain the arteriolar constrictor response in the leg is blocked within five minutes after a guanethidine injec- 548 Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 tion.45 The observation that an infusion of norepinephrine did not restore the venopressor responses to carotid occlusion or central vagal stimulation at a time when these responses were blocked by reserpine OR guanethidine is consistent with the observation of McCubbin et al.,45 who reported that the infusion of norepinephrine did not restore the arteriolar constrictor response to sympathetic nerve stimulation in dogs treated with guanethidine. It is also consonant with other observations in this laboratory 46 that the antiadrenergic effect of guanethidine is not dependent upon depletion of the tissue norepinephrine stores. An infusion of norepinephrine also failed to restore reflex venoconstriction which had been abolished by reserpine. This observation was of interest in view of the report by Burn and Rand*7 that the abolition of the arteriolar constrictor response to direct sympathetic nerve stimulation in the reserpine-pretreated animal could be reversed by the administration of norepinephrine. However, it correlates with our finding that a norepinephrine infusion did not restore the response of the reserpiriized' animal's heart to stimulation of the right cardioaccelerator nerve.46 All of the observations presented thus far were carried out on open-chest, anesthetized dogs. These experimental conditions undoubtedly diminish the reactivity of the preparation, and it appears likely that they decrease the magnitude of the reflex venous responses. Accordingly, it was considered of great interest to extend some of these studies to intact man.48 The method employed for the estimation of venous tone in the veins of the forearm resembled that utilized by Gauer and Thron49 and represents a modification of the technique recently described by Sharpey-Schafer.50 The latter investigator utilizes a water-filled plethysmograph to record the rate at which blood accumulates in the venous system of the forearm during sudden venous occlusion. In addition, venous pressure in one of the veins is measured simultaneously and venous tone is calculated as the increment in venous BRATJNWALD ET AL. pressure divided by the increment in volume. Our modification of this technique consisted of the substitution of a Whitney mercuryfilled rubber tube strain gauge plethysmograph 51 for the more cumbersome water plethysmograph. By means of this method, it was shown in eight normal young adult subjects that the oral daily administration of 25 to 50 nig of guanethidine for three to five weeks abolished the reflex venous constriction which occurred when the opposite hand was placed into ice water or during leg exercise. Following discontinuation of the drug, the reflex venoconstriction to these stimuli returned. Similar results were obtained in four subjects treated with 0.5 mg of reserpine. In view of these findings, the likelihood that blockade of reflex venoconstriction is of importance in the antihypertensive action of reserpine and guanethidine must be considered. Summary In a series of investigations on the control of venous tone, it was shown in anesthetized, open-chest dogs on cardiopulmonary bypass that venoconstriction occurs during the infusions of norepinephrine and epinephrine, while trimethaphan results in venodilatation. Lowering the pressure acting on the carotid baroreceptors and on the receptors within the left atrium and left ventricle results in reflex venoconstriction, while stimulation of these receptors relaxes the veins. Hypoxia produces venoconstriction as a result of stimulation of the carotid chemoreceptors, but the venoconstriction which results from hypercapnia evidently is primarily central in origin. Reflex venoconstriction to carotid occlusion and central vagal stimulation can be blocked by the administration of guanethidine and reserpine. In intact, unanesthetized human subjects, to whom these drugs were administered orally in doses which are commonly utilized in clinical practice, reflex venoconstriction of the forearm veins was blocked. These investigations emphasize that the systemic venous bed reacts vigorously to neural and humoral stimuli, and that these reactions profoundly alter Circulation Research. Volume XII, May 19S3 REFLEX CONTROL OF SYSTEMIC VENOUS BED 549 the cardiac output. In this manner, by exerting control of the rate at which the blood is delivered into the systemic arterial bed. the venous side of the circulation plays AN important role in the control of the arterial pressure as well. system in prcssor reflexes. Circulation Research 2: 405, 1954. 15. SALZMAN, E. W.: Reflex peripheral venoconstriction induced by carotid occlusion. Circulation Research 5: 149, 1957. 16. SARNOFF, S. J.: Some physiologic considerations in the genesis of acute pulmonary edema. In Pulmonary Circulation, edited by W. R. Adams and I. Veith. New York, Grune &• Stratton, 1959, pp. 273-282. 17. BARTELSTONE, H. J.: Role of the veins in venous return. Circulation Research 8: 1059, 1960. Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 References 1. WIGGERS, C. J.: The circulation and circulatory research in perspective. In Handbook of Physiology : sect. 2: Circulation, edited by W. F. Hamilton and P. Dow. Washington, D.C., American Physiological Society, 1962, p. 9. 2. GREEN, H. D.: In Medical Physics, edited by 0. Glasser, vol. 1. Chicago, Tear Book Publishers, 1944, p. 210. 3. HBYMANS, C, AND NEIL, E.: Reflexogenic Areas of the Cardiovascular System. Boston, Little, Brown & Co., 1958. 4. FRANKLIN, K. J.: A Monograph on Veins. Springfield, 111., Charles C Thomas, 1937. 18. J. A.: Studies on digitalis: II. Extracardiac effects on venous return and on the capacity of the peripheral vascular bed. J. Clin. Invest. 39: 937, 1960. 19. ALEXANDER, R. S.: Influence of constrictor drugs on distensibility of splanchnic venous system, analyzed on basis of aortic model. Circulation Research 2: 140, 1954. 20. Ross, J., JR., FRAHM, C. J., AND BRAUNWALD, E.: The influence of the carotid baroreceptors and of va,soaetive drugs on vascular capacity and venous distensibility. Circulation Research 9: 75, 1961. 5. LANDIS, E. M., AND HORTENSTINE, J. C.: Func- tional significance of venous blood pressure. Physiol. Rev. 30: 1, 1950. 6. FOLKOW, B.: Nervous control of blood vessels. Physiol. Eev. 35: 629, 1955. Ross, J. JR., BRAUNWALD, E., AND WALDHAUSEN, 21. HEY MANS, C, AND BOUCKAERT, J. J.: Perfusion Relative importance of venous and arterial resistances in controlling venous return and cardiac output. Am. J. Physiol. 196: 1008, 1959. 8. FRANKLIN, K. J.: Pharmacology of isolated vein ring. J. Pharmacol. & Exp. Therap. 26: 215, 1925. des sinus carotidiens isoles avec la pompe de Dale-Schuster: Reflexes vasomoteurs. Compt. Rend. Soc. 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Circulation Research, Volume XII, May 196S 551 REFLEX CONTROL OF SYSTEMIC VENOUS BED Discussion Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 Dr. Edward D. Freis, Washington, D. C.: Some years ago, Dr. John Rose and 1 carried out a similar type of experiment in dogs; we replaced the left ventricle with a pump, the output of which could be kept constant at any given level. Under those circumstances, we found the administration of norepinephrine increased the volume of the reservoir which was receiving the drainage of blood from the left atrium by an amount which was comparable to the quantities Dr. Braunwald found after similar stimulation. The transfer of blood from the dog to the reservoir was so large in volume that it seemed inconceivable to us that it could be due to anything other than the constriction of the systemic venous system. We also observed that ganglion blocking drugs had the opposite effect; that is, there was a transfer of blood from the reservoir to the animal in a similarly large amount. In those experiments, we did not control possible changes in pulmonary vascular capacity since we had replaced only the left ventricle with a pump. Dr. Braunwald has used complete heart-lung replacement so that the observed changes in vascular capacity must have occurred on the systemic side of the circulation. In connection with the effects of guanethidine on catecholamine stores in man, Dr. Jay Cohn, in our laboratory, was unable to find any inhibition of the tyramine pressor response either after acute intravenous or continuous oral administration of guanethidine in hypertensive patients. Maintenance of the tyramine response was observed despite significant orthostatic hypotension and inhibition of the Valsalva overshoot following guanethidine. Dr. J. Edwin Wood, Augusta, ' Georgia: Dr. Braunwald, we have obtained information which suggests that the collection of carbon dioxide in exercising tissues acts as a stimulus for an afferent impulse to the central nervous system subsequently resulting in a sympathetic efferent discharge which in turn Circulation Research, Volume XII, May 196S causes venocoustriction. In essence, the evidence was accentuation of forearm venoeonstrictor responses to exercise of the legs following pretreatment of the patient with acetazolamide (Diamox). Do you have any evidence to suggest that this is true of your animals? Dr. Leroy J. Hirsh, Chicago: Concerning your experiments in which hypoxia was induced, did this hypoxia induce a change in heart rate and cardiac output? Recently, Mary Scott and de Burgh Daly published a paper in which they perfused the carotid chemoreceptors with hypoxic blood and observed that an increase or decrease in heart rate occurred which depended upon initial heart rate. When the initial rate was low, perf usion of hypoxic blood caused an increase in heart rate and when the initial rate was high, the hypoxia caused a bradycardia. Dr. Braunwald commented that although he was not measuring heart rate, it did appear that there were changes. Dr. Eugene Braunwald, Bethesda, Maryland: The results, which Dr. Freis mentioned, of tyramine injections in patients who have been treated with guanethidine are extremelj' interesting. His results are in accordance with our observations in experimental animals, which indicate that after the tissue norepinephrine stores have been markedly reduced, but not depleted, by the administration of reserpine, the effect of tyramine persists unchanged. Now, I do not know of any data in man which indicate the extent of the depletion of norepinephrine in the tissues of patients receiving the usual clinical doses of this drug. However, Dr. Chidsey, Dr. Morrow, and I have measured the norepinephrine content of the atrial appendages of patients receiving ordinary clinical doses of reserpine. Our values in patients not on reserpine averaged 1.82 /±g per g, while the values in five patients receiving reserpine for six weeks ranged between 0.04 to 0.34 /xg per g. These data indicate that reserpine, in dosages commonly employed clinically, results in 552 BRAUNWALD ET AL. marked reduction of myocardial norepinephthe reflex changes in heart rate during hyrine content. poxia were variable but that a decrease in In reply to Dr. Wood, we have no data heai't rate occurred most commonly. These to bear on your question as to whether COo data on heart rate have been published in in the peripheral tissues acts as a stimulant extenso.1 for venoconstriction. Our experiments, howReference ever, permit us to conclude that the chemo1. KAHLES, R. L., GOLDBLATT, A., AND BRAUNWALD, receptors are not an essential link in the E . : T l i e e f f e c t s o f a c u t e *rv<>™ °" t h e . , - , . , , . . systemic venous and arterial systems and on COo-induced venoconstriction. systemicvenousandarterialsystemsandonmyocarclhil c o n t r a c t i l e force. J . Clin. I n v e s t . In reply to Dr. Hirsh, T would agree that 41: 1553, 1962. Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 Circulation Ret Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017 Reflex Control of the Systemic Venous Bed: Effects on Venous of Vasoactive Drugs, and of Baroreceptor and Chemoreceptor Stimulation EUGENE BRAUNWALD, JOHN ROSS, Jr., RICHARD L. KAHLER, THOMAS E. GAFFNEY, ALLAN GOLDBLATT and DEAN T. 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