SEROTONIN has an unusual effect upon

Transcription

1 The Influence of Tone upon Responses of Small and Large Vessels to Serotonin By P. J. HADDY, M.D., PH.D., P. GORDON, M.S., AND D. A. EMANUEL, M.D. With the assistance of J. Scott, M. Fleishman and M. IApton Downloaded from by on November 19, 218 In the dog foreleg, serotonin antagonizes extremes of vascular tone induced by neurogenic means. It produces net dilatation when the bed is constricted and net constriction when the bed is dilated. This bidirectional response derives ultimately from the facts that changes in nervous activity change calibers of small vessels without greatly altering calibers of large vessels, and that serotonin produces small vessel dilatation at the same time that it constricts large vessels. When small vessels are already neurogenically dilated, serotonin cannot dilate them further, but continues to constrict large vessels. Thus, the net effect is constriction. When small vessels are highly constricted, serotonin dilates small vessels more than it constricts large vessels. The net effect is dilatation. The study also indicates why it is more difficult to demonstrate a similar antagonism when tone is varied by humoral means. SEROTONIN has an unusual effect upon blood vessels in the dog foreleg. 1 " 4 It decreases pressures in small arteries without regularly affecting the rate of blood flow. This is to be compared to the effects of epinephrine and acetylcholine. Epinephrine increases small arterial pressures and decreases the rate of flow, 1 " 5 whereas acetylcholine decreases small arterial pressures and increases the rate of flow. 1 ' 4 6 ' These changes have been interpreted as indicating that serotonin actively constricts large arteries at the same time that it dilates arterioles. Under usual conditions, the constriction in arteries approximately equals the dilatation in arterioles. As a result, total resistance, and therefore flow rate, do not change greatly. The present study concerns the effect of serotonin when conditions are other than usual. In a few of the experiments, total resistance to blood flow across the limb was spontaneously high. Serotonin decreased total resistance in these legs. In others, total resistance was spontaneously low. Here, total resistance increased upon serotonin administration. Examination of the change in From the Departments of Medicine and Physiology, Xorthwestern University and the V.A. Research Hospital, Chicago, 111. and the U.S. Army Medical Research Laboratory, Fort Knox, Ky. Received for publication August 4, resistance in large and small vessels appeared to explain this bidirectional response. In constricted preparations, the decrease in resistance in small vessels exceeded the increase in resistance in large vessels. The reverse was the case in dilated preparations. In a further attempt to examine the significance of this mechanism, tone was varied by both nervous and humoral mechanisms in the same animal. Serotonin was then administered and the responses of the entire bed as well as those of the various vascular segments were compared as different levels of tone. METHODS Caliber changes in arteries, small vessels, and veins of the foreleg of the dog under pentobarbital anesthesia were inferred from calculated values for resistance. The rate of blood flow to the foreleg was held constant with a perfusion pump* interposed between the right femoral and braehial arteries. The output of the pump was independent of pressure over the range to 25 mm. Hg. Inasmuch as foreleg size and resistance to flow varied greatly between animals, the rates of flow ranged from 38 to 16 ml./min. Pressure were measured at 4 sites along the length of the vascular bed. These sites included the braehial artery just distal to the pump, a small artery (.5 mm.) in the foot pad, a small vein (.5 mm.) in the dorsal subcutaneous tissue of the paw, and the cephalic vein at about the level of the elbow. Pressure *Sigmamotor Pump, Model T-6, Sigmamotor, Inc., Middleport, N.Y. 123 Circulation Research, Volume Vll, January 1959

2 124 IIADDY, GORDON, EMANUEL 2; Brachial Artery o Small Artery * Small Vein o CepholicVein a: g Total a Small Vessels x Arteries o Veins».5 : V /Min. Serotonin Creatinine Sulphate Time in Minutes FIG. 1 Left. Pressures and resistances as a function of rate of infusion of serotonin ereatiniiie sulfate into the brachial artery of a dog foreleg. Blood flow rate in the brachial artery maintained at 1 ml./min. throughout experiment. All measurements steadj' state. Entire range observed in 12 min. Progression of infusion rate from low values to high. FIG. 2 Right. Average effect of brachial artery infusion of serotonin creatiniiie sulfate, 1 y/min., upon vascular pressures and resistances in 11 dog forelegs immediately before and after nerve section high in the leg. Blood flow rates were maintained constant at average values of 65 and 74 ml./min. with nerves intact and sectioned respectively. Downloaded from by on November 19, 218 gradients, from brachial artery to cephalic vein, brachial artery to small artery, small artery to small vein and small vein to cephalic vein, were calculated. Resistance values for the entire bed, arteries, small vessels and veins were separately derived by dividing the respective gradients by the rate of blood flow in the brachial artery. Details of these technics and those utilized for retrograde catheterization of small vessels have been published. 1 - " 7 Serotonin creatiniiie sulfatet was either injected instantaneously, or infusedt at a constant rate, into the brachial artery. Multiple injections or infusions were made in the same animal with vascular tone in the foreleg adjusted to different levels. Pressures were recorded continuously following injection, and the maximal changes noted. In the case of infusion, pressures were recorded as soon as they reached a steady state. This occurred within 1 to 2 min. Vascular tone within the leg was varied by both nervous and humoral means. Tone was lowered by denervation of the foreleg, by denervation plus *This segment includes arteries smaller than.5 mm., arterioles, capillaries, venules, and veins smaller than.5 mm. fdonated by Abbott Laboratories, Xorth Chicago, III. ^Constant Infusion Machine, Model ES-4B, Engineering Specialties, Madeira, Ohio. intra-arterial infusion of phentolamine, or by intra-arterial infusion of methacholine. Tone was elevated by bilateral vagotomy or by intraarterial infusion of levarterenol. Denervation was accomplished by cutting all visible deep nerves just below the brachial plexus. A circular incision was made in the skin between the shoulder and elbow for section of superficial nerves. The object was not complete denervation but denervation enough to decrease total resistance. In some of these experiments, resistance was lowered further by an infusion of phentolamine methanesulfonate into the brachial artery at the rate of 5 y/min. In innervated legs, tone was lowered by an infusion of methacholine chloride into the brachial artery with a second infusion pump. The rate of infusion varied from 5 to 15 y salt/min. Tone was elevated from the usual level in innervated legs by bilateral vagotomy in the neck or by infusion of levarterenol (norepinephrine) bitartrate into the brachial artery. It was elevated from low levels in denervated limbs by infusion of levarterenol. Infusion rates varied between.5 to 17. y levarterenol base/min. RESULTS Serotonin was infused into the brachial arteries of 9 normal limbs at progressively faster rates (fig. 1). Brachial arterial pressure either increased, decreased, or did not change

3 SEROTONIN AND VASCULAR RESISTANCE 125 Downloaded from by on November 19, 218 as a function of serotonin infusion rate in different limbs. However, in a given limb, the direction of the change remained the same over the range 5 to 85 y serotonin salt/min. Pressure in the small artery always decreased and that in the small vein frequently increased as the rate of infusion was increased. Inasmuch as the direction of changes of pressures and calculated resistances were the same at all rates of infusion, a rate of 1 y/ min. was selected for the following experiments. This rate always caused measurable changes and, by calculation, produced concentrations of serotonin in the leg which might occur naturally. Table 1 presents the f requency of the direction of changes observed in 35 limbs infused with serotonin at a rate of 1 y/min. Control total resistance was spontaneously different between animals. The gradient changes indicate that total resistance frequently increased but sometimes decreased. Control total resistance averaged 1.47 mm. Hg/ml./min. in those that increased, and 2.1 mm. Hg/ml./min. in those that decreased. Resistance to flow through arteries of.5 to 5. mm. diameter alwaj r s increased, whereas resistance always decreased through vessels having diameters of less than.5 mm. Resistance frequently increased through veins of.5 to 5 mm. diameter. Inasmuch as cephalic vein pressure occasionally increased, resistance probably increased through veins of even larger diameter (those central to the needle in the cephalic vein). The above interindividual comparisons suggest that the net effect of serotonin upon limb vessels is dilatation when they are constricted and constriction when they are dilated. The following intraindividual comparisons show that this is true when dilatation is brought about by nervous means. Further, the comparisons offer an explanation for these bidirectional responses. Figure 2 presents the average pressure and resistance changes caused by serotonin in 11 vascular beds before and after dilatation caused by denervation just below the brachial plexus. Serotonin decreased total resistance when the nerves were intact. It greatly increased total resistance when nerves were sectioned. This difference is re- TABLB 1. Effect of Serotonin Creatinine Sulfate (1 y/min.) upon Absolute Pressures and Pressure Gradients in 35 Dog Forelegs* Brachial arterial pressure Small arterial pressure Small venous pressure Large venous pressure Total gradient Arterial gradient Small vessel gradient Venous gradient Increase Decrease No change f *Perfused with blood at a constant rate. fdepressor responses of 1-2 mm. Hg were occasionally observed. These are included in the "no change" category. lated to changes within the small vessel segment. Nerve section decreased total resistance by virtue of a decrease in small vessel resistance. At this new level, serotonin caused a lesser decrease in small vessel resistance. On the other hand, nerve section failed to affect the control levels of resistance in the arterial and venous segments, and their responses to serotonin remained the same as before nerve section. That the bidirectional behavior of total resistance is related to the initial level of resistance in small vessels is shown in Figure 3. The initial level of small vessel resistance is plotted against the change in total resistance before and after nerve section for each animal. It may be seen that reduction of small vessel resistance by nerve section resulted in either conversion of a decrease in total resistance to an increase, or an enhancement of the increase in each instance. A similar relationship can also be shown for the initial level of total resistance and the change in total resistance caused by serotonin. One of the 6 experiments in which a total resistance decrease was converted to an increase after nerve section is presented in Figure 4. It may be seen that with nerves intact and resistance spontaneously high, total resistance decreased because of a reduction in small vessel resistance which was greater than the combined increment in arterial and venous resistances. On the other hand, with total resistance low after nerve section, total resistance increased because of increases in

4 126 HADDY, GORDON, EMANUBL Downloaded from by on November 19, 218 Innervated Denervated Change in Total Resistance mm.hg/ml./min. FIG. 3. Eelation of change in total resistance to initial level of small vessel resistance in 11 dog forelegs before and after section of nerves high in foreleg. arterial and venous resistances which exceeded the decrease in resistance in the small vessel segment. The above relationship between tone and direction of change of net resistance was not apparent when 2.5 y serotonin creatinine sulfate was administered into the brachial artery by instantaneous injection (table 2). This amount of serotonin was administered with tone at 4 different levels in each of 1 forelegs. Tone was elevated by vagotomy, decreased below the prevagotomy control by nerve section in the leg, and then further decreased with an intra-arterial infusion of phentolamine. Vagotomy increased total resistance mainly because of a large increase in small vessel resistance but also because of a small increase in arterial resistance. Denervation reduced total resistance below the prevagotomy control almost entirely because of a decrease in small vessel resistance. The addition of phentolamine further decreased total resistance, mainly because of dilatation of small vessels, although a slight decrease in arterial resistance occurred in half of the cases. Serotonin, 2.5 y by instantaneous injection, increased total resistance by small amounts at all 4 levels of resistance. However, the significance of the effects of instantaneous injection may be legitimately questioned. Following instantaneous injection, the maximal decrease in small arterial pressure occurs considerably earlier than the maximal increase in small vein pressure. 4 It is possible, therefore, that out-ofphase segmental responses mask the steady state changes in net resistance which are seen during constant infusion. Page and McCubbin 18 have also called attention to the differences between injection and infusion of serotonin. It is also difficult to demonstrate serotonin's bidirectional action when tone is varied by infusion of either levarterenol or methacholine (fig. 5). Five innervated legs were greatly dilated with constant infusions of the latter. Upon infusion of serotonin (4.5 to 6 y base/min., the methaeholine infusion being maintained, total resistance increased in all 5. However, the amounts of the elevations were small. Nine legs (2 innervated, 7 denervated) were progressively constricted with constant infusions of levarterenol. Serotonin (4.6 to 6 y base/min.) increased total resistance in 8 of the 9 at all levels of tone. It decreased total resistance in 1 only at the highest level of tone. The reason for the absence of a bidirectional change in net resistance when tone is changed by humoral means is apparent upon examination of the changes in segmental resistance. Unlike nerve section or block, which affects only small vessels (fig. 2 and table 2) 8 ' acetylcholine and methacholine infusions reduce tone in part by dilating large arteries (fig. 5). 4 ' 6 In the presence of methacholine, serotonin has a lesser constricting effect upon these vessls (fig. 5). The increase in net resistance under such circumstances is, therefore, a limited one. Levarterenol administered by infusion increases tone in part by constricting arteries and veins (fig. 5). 3 In the presence of this amine, serotonin has a greater constricting effect upon these vessels (fig. 5). The resulting effect, even though serotonin continues to dilate small vessels, is a net resistance increase at all levels of tone. DISCUSSION These studies show that serotonin antagonizes extremes of vascular tone in the dog foreleg when the changes in tone are produced

5 SEROTONIN AND VASCULAR RESISTANCE 127 TABLE 2. Maximal Effect of Instantaneous Brachial Artery Injection of 2.5 y Serotonin Creatinine Sulfate upon Average Pressures (mm. Hg) and Resistances (mm. Rg/ml./min.) in 1 Dog Forelegs* at Varying Levels of Besting Resistance Vagotomy Control Change Intact Control Change Vagotomy denervated Control Change Vagotomy denervated phentolaminized Control Change Brachial artery P Small artery P Small vein P Large vein P Total E Arterial R Small vessel E Venous R *Blood flow rate maintained constant at average value of 56 ml./min. Downloaded from by on November 19, 218 neurogenically. Total resistance is lowered when it is high and elevated when it is low. This bidirectional action is possible because changes in nervous activity change calibers of small vessels while scarcely affecting those of large. Therefore, upon administration of serotonin, the ratio of large vessel constriction to small vessel dilatation is altered. The small vessels dilate more when they are constricted than when they are dilated, whereas large vessel constriction remains the same. Net resistance, therefore, increases when it is low and decreases when it is high. The bidirectional action of serotonin is not as easily demonstrated when tone is changed by infusion of vasoactive substances. This is because these substances, when administered by infusion, affect large vessels as well as small vessels. Therefore serotonin's activity upon large vessels is also altered, resulting in a limitation or abolition of its bidirectional action at extremes of tone. The technics utilized appear to provide a good estimate of changes in cross sectional area of the various vascular segments as well as of the entire bed. Pressure changes in the small vessels selected for catheterization are representative of changes in all small vessels of the same size in the limb. Small arteries and veins of.5 mm. diameter have been catheterized at multiple sites in subcutaneous tissue and muscle. Serotonin decreases pressures in all small arteries and increases pressures in most small veins. Depressor responses have been observed in muscle small veins. 1 Changes in flow rate in the brachial artery are probably representative of changes in flow rate in both skeletal muscle and subcutaneous tissue. Intra-arterial injection of serotonin causes similar changes in the rate of flow in the brachial artery in intact and skinned forelegs. 1 The results of these experiments probably are not significantly related to changes in collateral flow. The foreleg was used in preference to the hindlimb in these and previous studies because the brachial artery carries a greater proportion of total extremity flow than does the femoral artery. The demonstration of collateral arteries entering the foreleg is difficult. 1 Retrograde flow from the distal portion of the ligated brachial artery does occur, but it represents only 14 per cent of the total flow to the limb. Furthermore, when the brachial artery pump is shut off, pressures in the 4 vessels fall from 144, 91, 11 and 3 to 4, 33, 4 and 2 mm. Hg respectively, and all pulsations disappear. Anomalous changes in viscosity do not contribute measurably to changes in calculated resistance in the dog foreleg. The relation of pressure to flow 1 hour after death is the same with dextran or blood. The reports of Burton, 11 Levy, 12 and Rennie 13 support this observation. Even if this were not true, any contribution this factor makes to change in resistance would have been minimized in the

6 128 HADDY, GORDON, EMANUBL 15-1 oo I 1 Innervated Braxhial Artery Denervated Serotonin o Small Artery Serotonin * Small Vein Cephalic I 2 \ _, 15 Brachial Artery D Small Artery * Small Vein Cephalic Vein Sioo Total X Arterial = SmaMVessel Venous 2.5 Downloaded from by on November 19, 218 8= =B S A A N S Time in Minutes FIG. 4 Left. Example of the bidirectional effect of serotonin upon total resistance in ;i spontaneously constricted limb. Blood flow rate constant at 5 ml./min. before and after nerve section. Fio. 5 Right. Two experiments illustrating that serotonin's bidirectional effect is demonstrated only with difficulty when tone is changed by humoral means. The letters C, S, A and N indicate control, serotonin, acetyl-b-methylcholine (methacholine) and norepinephrine (levarterenol) respectively. Drugs administered by infusion into the brachial artery, the rates being 24 7 serotonin base/min., 4 y norepinephrine base/min. and 7 (exp. 1) and 15 (exp. 2) methacholine chloride/min. All measurements steady state. Blood flow rate maintained constant at 15 ml./min. throughout both experiments. See text. present study by the fact that the rate of blood flow was held constant. Under this condition, changes in linear velocity of flow necessarily are initiated and preceded by changes in caliber. The changes in resistance in the arterial and small vessel segments are not related to arteriovenous shunts. The oxygen contents of small and cephalic venous blood do not change during infusion of serotonin at the rate of 1 y/min. This might have been predicted, since opening of shunts would tend to lower total resistance in the limb. Total resistance increases in most instances under usual conditions (table 1). Further evidence, that the decrease in calculated resistance in the small vessel segment truly indicates small vessel dilatation, is provided by the fact that the perfusion rate of saline at constant pressure through the small arterial catheter abruptly increases upon administration of serotonin. The findings of this study may help to explain peculiar observations of others. Administration of serotonin produces irregular changes in systemic arterial pressure. 14 " 1 Page and McCubbin have presented evidence suggesting that the direction and magnitude of change in pressure may in part be related to the pre-existing level of neurogenic vasoconstrictor tone. They frequently observed depressor responses in dogs with neurogenic hypertension and pressor responses in animals with suppressed nervous activity. 17 ' 18 Because of this, they suggested that serotonin is a humoral antagonist to neurogenic vasomotor tone, and as such provides the body with a chemical buffering system. 16 Their experiments also suggested that serotonin's buffering action may in part result from some peripheral mechanism. They reported 17 that administration of serotonin into the femoral artery caused a decrease in resistance to flow through the hindlimbs of 2 neurogenic hypertensive dogs. Following administration of tetraethylammonium chloride and section of sciatic and femoral nerves respectively, sero-

7 SEROTONIN AND VASCULAR RESISTANCE 129 Downloaded from by on November 19, 218 tonin increased resistance. The findings presented in this study are in accord with the latter observation, and in addition offer an explanation for it. The}' also indicate that the irregular changes in systemic arterial pressure reported by others may indeed be related to impingement of serotonin upon vascular beds having varying degrees of neurogenic tone. A complete explanation, however, must await systematic studies on cardiac output and on other vascular beds under various conditions. In regard to the latter, serotonin is only constrictive in the pulmonary and renal vascular beds. 1 ' 2 This may be related to the fact that the arterioles in these beds are dilated relative to those in the limb. The mechanism whereby serotonin constricts arteries and veins and simultaneously dilates small vessels is not definitely known. Even though Page and McCubbin 17 failed to obtain convincing evidence that serotonin interferes with the vasoconstrictor action of levarterenol, this remains an attractive hypothesis for serotonin's effect upon the small vessel segment. Gordon, Robinson and Lipton 21 have shown that pretreatment with serotonin suppresses levarterenol toxicity and its action on the pilomotor muscles in the mouse. Gordon, Haddy and Lipton 22 ' 23 noted that pretreatment with serotonin converts levarterenol-induced bradycardia to tachycardia, and diminishes epinephrine and norepinephrine pulmonary edema. They noted also that elevated small vessel tone, produced by exogenous norepinephrine, is relaxed by serotonin. These effects may result from either a molecular or a physiologic interaction between the 2 substances. That antagonism of levarterenol by serotonin cannot be a complete explanation is clear from the fact that serotonin has some effect upon both small and large vessels in a denervated limb subjected to infusion of phentolamine. Thus, serotonin has an effect upon blood vessels independently of extrinsic nerves and of circulating or locally released catecholamines. Other substances also constrict large vessels while dilating small vessels. Among these are high concentrations of potassium, 24 carbon dioxide and hydrogen ions 9 and histaniine. 25 Page and McCubbin 18 have suggested that part of serotonin's action may result from release of endogenous histaniine. This could explain serotonin's effect upon the small vessel and venous segments. It could not, however, explain its effect upon the arterial segment. Histaniine has only a small constrictor affect upon arteries even in very high concentrations. CONCLUSIONS The effect of serotonin upon small and large blood vessels of the dog foreleg has been examined with the bed constricted and dilated by both nervous and humoral means. The results indicate that serotonin antagonizes extremes of vascular tone produced neurogenically. Administration of serotonin creatinine sulfate, 1 y/min., into the brachial artery resulted in a decrease in total forelimb resistance when resistance was high, no change when resistance was intermediate, and an increase when resistance was low. This relationship results ultimately from the facts that changes in nervous activity change calibers of small vessels without altering calibers of large vessels, and that serotonin dilates small vessels at the same time that it constricts large ones. When small vessels are already maximally dilated by neurogenic means, serotonin does not dilate them further but continues to constrict large vessels. The net effect is constriction. When small vessels are intensely constricted, serotonin dilates them more than it constricts large vessels. The net effect is dilatation. The study also indicate? why it is more difficult to demonstrate a similar antagonism when tone is varied by humoral means. SUMMARIO IN INTERLINGUA Le effecto de serotonina super le micre e le grande vasos sanguinee in le gamba anterior de canes esseva exanimate con constriction e dilatation del vasculatura effectuate per medios nerval e humoral. Le resultatos indica que serotonina age como antagonista contra extremos de tono vascular producite neurogenicamente. Le administration de sulfato de creatinina a serotonina (1 gamma pei

8 13 HADDY, GORDON, EMANUEL Downloaded from by on November 19, 218 minuta) a in le arteria brachial resultava in un reduction del total resistentia antebrachial quando le resistentia esseva alte, in nulle alteration quando le resistentia esseva intermediari, e in un augmento quando le resistentia esseva basse. Iste relation resulta ultimemente ab le factos (1) que alterationes del activitate nervose altera le calibre de micre vasos sin alterar le calibre de graride vasos e (2) que serotonina dilata micre vasos durante que simultaneemente illo constringe grande vasos. Quando micre vasos es jam dilatate maximalmente per medios neurogene, serotonina non dilata los additionalmente sed continua constringer le grande vasos. Quando micre vasos es intensemente constringite, serotonina dilata los plus que illo constringe le grandes. Le effecto total es dilatation. Le studio etiam indica proque il es plus difficile demonstrar un simile antagonismo quando le tono es variate per medios humoral. REFERENCES 1. HADDY, F. J.: Physiological Studies of the Venous System. Ph.D. thesis, University of Minnesota, VISSCHER, M. B.: Means of evnluating state of performance of heart and of peripheral circulation. Symposium of Circulation and Homeostasis. Medical Science Publication No. 3, 1953, p HADDY, F. J., FLEISHMAN, M., AND EMANUEL, D.: Effect of epinephrine, norepinephrine and serotonin upon systemic small and large vessel resistance. Circulation Res. 5: 247, : Vasomotion in systemic arteries, small vessels and veins determined by direct resistance measurements. Minnesota Medicine 41: 162, 195S. 5., RICHARDS, A. G., AND VISSCHER, M. B.: Pressures in small and large veins and arteries. Am. J. Physiol. 171: 73], : Effect of histamine and acetyleholine upon systemic large and small vessel resistance. Fed. Proe. 17: 65, 195S. 7., RICHARDS, A. G., ALDEN, J. L., AND VIS- SCHER, M. B.: Small vein and artery pressures in normal and edematous extremities of dogs under local and general anesthesia. Am. J. Physiol. 176: 355, , FLEISHMAN, M., AND SCOTT, J. B.: Effect of change in air temperature upon systemic small and large vessel resistance. Circulation Res. 5: 5S, FLEISHMAN, M., SCOTT, J., AND HADDY, F. J.: Effect of ph change upon systemic large and small vessel resistance. Circulation Res. 5: 62, MILLER, M. E.: Guide to the Dissection of the Dog. Ed. 2. X. Y., Ithaca, BCRTON, A. C.: Laws of physics and flow in blood vessels. Symposium of Circulation and Homeostasis. Medical Science Publication Xo. 3, 1953, p LEVY, M. X.: Influence of anomalous blood viscosity on resistance to flow in the dog's hind limb. Circulation Res. 4: 533, RENNIE, D. W.: Pressure-flow relationships of human blood in capillary tubes at physiologic flow rates. Circulation Res. 1: 56, ERSPAMER, V.: Pharmacology of indolealkylamines. Pharm. Rev. 6: 425, PAGE, I. H.: Serotonin (5-hydroxytryptamine). Physiol. Rev. 34: 563, : Serotonin (5-hydroxytryptamine), the last four years. Physiol. Rev. 38: 277, , AND MCCOBBIN, J. W.: The variable arterial pressure response to serotonin in laboratory animals and man. Circulation Res. 1: 354, IS., AND : Arterial pressure response to infused serotonin in norinotensive dogs, cats, hypertensive dogs and man. Am. J. Physiol. 184: 265, , AND : Renal vascular and systemic arterial pressure responses to nervous and chemical stimulation of the kidney. Am. J. Physiol. 173: 411, EMANUEL, D. A., SCOTT, J., COLLINS, R., AND HADDY, F. J.: Effect of serotonin on renal vascular resistance and urine flow rate. Fed. Proe. 17: 42, 195S. 21. GORDON, P., ROBINSON, J. J., AND LIPTON, M. A.: Suppression of toxic and physiologic actions of the adrenalines by serotonin. Physiologist 1: 34, , LIPTON, M. A., AND HADDY, F. J.: The interaction of serotonin and the adrenalines upon limb resistance, cardiac rate and systemic arterial pressure. Fed. Proe. 17: 58, 195S. 23., HADDY, F. J., AND LIPTON, M. A.: Serotonin antagonism of norepinephrine in vivo. Science 128: 531, 195S. 24. HADDY, F. J., EMANCEL, D., AND SCOTT, J.: Influence of local cation concentration variation upon systemic small and large vessels and vessel responses to norepinephrine and acetyl-beta-methyleholine. Clin. Res. 6: S. 25. HADDY, F. J.: Effect of histamine upon large and small vessels of the dog forelimb. Circulation 18: 732, 195S.