The Effect of “Sympatholytic” Drugs on the Cardiovascular Responses to Epinephrine and Norepinephrine in Man By Epwarp D. Freis, M.D., J. Catvin MacKay, M.D., anp Witiiam F. Ouiver, M.D. Under controlled conditions the effects of various “sympatholytic” agents on the cardiovascular responses to epinephrine and norepinephrine were compared in man. The dosages of the sympath- olytic drugs administered approximated those usually employed clinically. Such basic data are given for the following agents: Dibenamine, the imidazoline derivatives [Priscoline and Regitine (C-7537)|, the dihydrogenated alkaloids of ergot (D.H.K. and C.C.K.), L-hydrazinophthalazine (C-5968), tetraethylammonium, and hexamethonium (C6). been introduced which inhibit the motor activities of the sympathetic nervous sys- tem. Determination of the mode oi action of such drugs has not been clarified completely especially in man. According to Nickerson! “adrenergic blockade” refers only to compounds which specifically inhibit the responses of ef- fector cells to both epinephrine and sympa- thetic nervous impulses. Thus, adrenergic blocking agents such as Dibenamine should be differentiated from drugs which inhibit transmission through the sympathetic nervous system either in the ganglia, such as tet- raethylammonium? or the central nervous sys- tem, such as pentaquine,? but do not block the pressor effects of epinephrine. The present investigation was designed to determine under controlled conditions the ef- fects of the various ‘“‘sympatholytic” drugs on the pressor responses to an excess of circulating epinephrine in man. In addition, it seemed of interest to test the effectiveness of such drugs in inhibiting the hypertension associated with LT: RECENT yearsa variety of agents have From the Medical Service, Veterans Administra- tion Hospital, Washington, D. C. Sponsored by the VA and published with the ap- proval of the Chief Medical Director. The statements and conclusions published by the authors are a result of their own study and do not necessarily reflect the opinion or policy of the Veterans Administration. The norepinephrine used in this study was gen- erously supplied by Ciba Pharmaceutical Products, Summit, New Jersey. 254 an excess of circulating norepinephrine. This substance has assumed greater importance since it has been found in mammalian chromaffin tissues‘ and in human pheochromocytomas' and since the hypertension produced by norepineph- rine in man resembles essential hypertension in many respects.® Finally, a systematic study in which various drugs are tested under iden- tical conditions in doses customarily used clin- ically seemed worthwhile in order to supply basic data as to the comparative value of these compounds as adrenergic blocking agents in man. MATERIALS AND METHODS The subjects were young or middle-aged adult men admitted to the wards of the Veterans Ad- ministration Hospital, Washington, D. C. All were convalescing from nonfebrile illnesses at the time of testing and none exhibited cardiovascular ab- normalities. Commercial epinephrine in a concentration of 1 ug. per cc. in saline and norepinephrine in a con- centration of 1.5 yg. per ce. were infused intrave- nously. The rate of infusion was controlled by an adjustable clamp and calibrated Murphy drip bulb. With the patient reclining in the supine position an infusion of isotonic saline was introduced through an antecubital vein. The needle used in this infusion was connected to a three way stopcock to permit introduction of the norepinephrine and epinephrine solutions as well as the blocking agents studied without disturbing the patient. The arterial pres- sure was measured in the opposite arm with an arm cuff and mercury manometer while the heart rate was counted at the wrist. In the control period, after the arterial pressure Circulation, Volume Il, February, 195! E. D. FREIS, J. C. MacKAY AND W. F. OLIVER 255 and heart rate had become stabilized, the epi- nephrine solution was introduced through the three way stopcock and the rate of infusion regulated by adjusting the clamp of the Murphy drip. The re- sponses of arterial pressure and heart rate were measured at both low and high infusion rates of epinephrine. Following these control determinations using epinephrine, the three way stopcock was turned so that saline was again infused. After the arterial pressure and heart rate had returned to basal values the norepinephrine infusion was con- nected and the responses to this agent measured at low and high infusion rates. It should be noted that the dose ranges of both epinephrine and norepi- nephrine were considerably lower in these studies on human subjects than the dosages of such sub- stances usually employed in investigations in ani- mals. Following the control determinations the par- ticular blocking agent under study was given through the intravenous tubing of the saline infusion follow- ing which epinephrine and norepinephrine again were infused at the same rates as had been admin- istered during the control period. An exception to this procedure was used in testing the adrenergic blocking action of benzodioxane. Because of its fleeting action, this drug was given during the in- fusions of epinephrine and the dose was repeated again during the infusion of norepinephrine. ReEsvLtTs Effect of Epinephrine and Norepinephrine Alone At low infusion rates (below 0.10 ug. per Kg. per minute), epinephrine frequently re- sulted in a decrease rather than an increase in the mean [(systolic + diastolic) /2] arterial pres- sure. This was due primarily to a reduction in diastolic blood pressure although systolic pres- sure frequently was depressed as well. As the mean pressure fell, the cardiac rate increased. With higher infusion rates of epinephrine (0.10 microgram per Kg. per minute or above) the mean arterial pressure usually rose. This ele- vation was due to the fact that the percent- age increase in systolic pressure was greater than the percentage decrease in diastolic pres- sure. However, there was considerable variation in response among different patients, some ex- hibiting very little depressor response, while others showed depressor responses exclusively even at the high infusion rates. Following ces- sation of the epinephrine infusion, the cardio- vascular responses disappeared rather slowly over a period of 2 to 10 minutes. In contrast, the responses to norepinephrine were uniform in all patients. Immediately fol- lowing infusion of an effective dose (0.1 to 0.2 microgram per Kg. per minute) both the sys- tolic and diastolic pressure rose and the heart rate decreased. These cardiovascular responses disappeared in one to three minutes after the infusion was discontinued. Effects of Dibenamine Dibenamine was administered to 4 subjects in doses of 170 to 360 mg. (2.3 to 6 mg. per Kg.). In every case the pressor responses to epinephrine were reversed even with doses of epinephrine as high as 0.5 microgram per Kg. per minute (table 1). The hypertension that resulted from the infusion of norepinephrine was 90 to 100 per cent abolished. In 2 subjects complete abolition occurred at low rates of norepinephrine infusion but not at high in- fusion rates. Nevertheless, marked inhibition of the norepinephrine hypertension occurred even at high infusion rates (0.5 to 1.0 ug. per Kg. per minute of norepinephrine). Dibenamine tended to exaggerate the tachy- cardia which accompanied the infusion of epi- nephrine, while in 3 of the 4 cases it completely abolished the bradycardia that occurred dur- ing norepinephrine infusion. Effect of Benzodioxane Benzodioxane was administered to 3 subjects in doses of 10 to 20 mg. during the infusions of epinephrine and norepinephrine. Two subjects received 10 mg. intravenously during the in- fusion of epinephrine. No significant inhibition of the pressor response occurred although there was an increased tachycardia in one of the cases. These 2 subjects received an additional 10 mg. of benzodioxane during the norepi- nephrine infusion. Thirty-one and 54 per cent inhibition of the norepinephrine hypertension resulted. However, this inhibition was quite fleeting, lasting only one to two minutes. The third subject (W.S.) received 20 mg. of benzodioxane during the infusion of epinephrine with resulting “reversal”? which was of less extent and of much briefer duration (four min- utes) than was observed in the subjects who received Dibenamine. An additional dose of 20 256 SYMPATHOLYTIC DRUGS TasLe 1 Control After Drug , Epinephrine Norepinephrine Epinephrine Norepinephrine e * Arterial Dose| a, BS] Dose | a; oe Dose | Dose! ai ds] Dose! a: | In- a pe. [We | Pree Heart Me/ ef vie Me’ | 8 : Drug me | Me/|@< | Re. ei Mel ee iibi, bie g sure . i g. ‘ zg, j,o! Versa io} tion’ man Hig) 2. | nf B28 BRE) min, (BAe sae min. [B= ane net Bes “| gam B.T. | 76 | 114/76 | 62 | 0.10 | +20 | +16] 0.12 | +20 | ~20 |Dibenamine | 170 0.10; —7] + | +66 | 0.13 2; 90 | —10 L. B. { 84 | 120/60] 92 { 0.10} +8 / +13 | 0.10 | +20 | —18 “ 350 0.10} -16; + | +8 | 0.15 0 | 100 0 0.13 | +13 | +17 | 0.25 | +33 | —22 “ . 13/-16; + | +13 10.25) +3] 91 0 ALS 69 | 118/70 | 70 | 0.07 | ~ 4] +9 {| 0.23 | +31 | —26 “ 350 0.085] —10 | + | +53; 0.23) +3] 90 0 0.10 | — 6} +54 W.S. | 61 | 110/70] 68 | 0.23 | +8) +23 | 0.15) +11 | —20 “ 380 0.26} -15| + | +6 | 0.37 0 | 100 0 0.33 | +16 | + 5 | 0.18 | +17 | —20 0.50 | —14] + | +24] 0.68 | + 8 0 1,01 | +13 0 w.- 61 | 110/60 | 70 | 0.20 | +11 | +31 | 0.35 | +29 | —9 |Benzodioxane|10 + 10} 0.20 | +14} — | +31 | 0.20] +20] 31 | — 5 C. W. | 69 | 110/70.) 70 | 0.00 | +9 | +13 | 0.15 | +24 | —10 “ 10 + 10} 0.001 +5] O | +38 | 0.15 | +11] 54 0 W.S. | 61 | 120/80) 70 | 0.15) +3 | +29] 0.10 | + 8 | —23 “ +20 | 0.168; — 5 + +48 | 0.10 | + 2 75 —6 Ww. 61 | 110/60 | 70 | 0.08 | +10 | +28 | 0.22 | +19 | — 6 (C6 50 0.08 | +14) — 0 | 0.22 | +20 0 | —10 R. B, | 65 | 118/78 | 72 | 0.16} —17| +5] 0.20) +9 | — 5 /C6 35 0.16 0 - +13 | 0.20 | +52 12 T. W. | 61 | 130/60 | 100 | 0.10 0 | +24 | 0.18 | +14 | ~ 4 [C6 50 0.10) +7) — | +16 | 0.18 | +28 -8 Cc. Ww. 110/70 | 70 | 0.00 | +9 | +14 | 0.15 | +14 | ~—14 [TEA 400 0.00 | +12) — | —32 | 0.15 | +31 —18 J.L. 100/68 68 | 0.14] —3 | +90 | 0.15 | +14 | -18 [TEA 350 0.14) +6) — | +5] 0.15 | +26 0 | —23 A.C. | 80] 118/72 | 64 | 0.08 | +2] +31 | 0.26 | +17 | —22 |Priscoline 25 0.08|—6) + | +30| 0.26; +7] 60 | —18 C.T. | 70} 125/70 | 80 | 0.07 | — 6 | +15 | 0.17-| +14 | —19 |Priscoline 25 0.07 | —16} + | +35 | 0.17 | +19 0o|-7 , 125 0.17) +7] 50 | —10 A. T. | 65 | 125/74 | 60 | 0.00 O| +33 C-7337 35 0.09; —8)/ + | +65 0.08 | +17 | —20 “ 50 0.00/+4/] 76 )/+4 0.14 | +22 | —20 “ 50 0.14 | +16 27 —7 W. HL | 57 | 112/60] 60 | 0.10) +7 | +17 | 0.20 | +15 | ~13 | “ 25 0.10) — 5] + | 422/020! +7; 53 | 16 0.45 | +27 | —23 0.46 | +12 56 —16 8. P. | 64] 130/95 | 68 | 0.18} — 1] +30] 0.15 | +12] —14] “ 50 0.18} -11] + | 442/015 | +4] 75 0 0.24 | + 6 | +28 | 0.23 | +25 |) —24 0.24; —11 + 442 | 0.23 | +6] 76 0 0.34 | —23| + | +89 | 0.52 | +11 > 1-8 W.W. | 48 | 105/60 | 68 | 0.12 | +33 | +37 | 0.28 | +51 | —24 |C-5068 18 0.12 | +12} — | +40] 0.28 | +45) 12 | ~ 4 R. W. | 80 | 140/80; 72 | 0.23 | + 6 | +11 | 0.31 | +22 | —22 “ 25 0.23 | +14 ~ +11} 0.82 | +12 | 45 -& F.R. | 94 | 120/88) 76 | 0.11 | — 3 | +40] 0.16 | +22) -16|] “ 30 O11; +7) — | +14 | 0.16| +16) 36 | -— 4 . 0.32 | —31 -4 J.8. 91 | 108/70 | 84 | 0.05 | — 8 | +14 | 0.09 | +24 | —14 |D.H.K. 0.5 0.09 | +25 o | -4 0.10 | — 9 | +19 | 0.26) +41 | —24 0.10 | —11 | — | +18 | 0.26} +37) 10 | —23 0.20 | + 9 | +24 0.20 | +10 - +22 E. w. 60 | 102/62 | 76 | 0.25 | +41 | +10 | 0.13 | +20 | —11 |C.C.K. 0.3 | 0.28! +67] — | — 5 | 0.13 | +23 Oo | —33 0.40 | +53 | —31 0.40 | +58 o | —40 *M.A.P, = “Mean” Arterial Pressure = +t % Inhibition = Control B.P. Change — Byatolic + Diastolic 2 After Drug B.P. Change Control B. P. Change E. D. FREIS, J. C. MacKAY AND W. F. OLIVER 257 mg. of benzodioxane was also administered during the infusion of a minimal pressor dose of norepinephrine (0.1 microgram per Kg. per minute) with a resulting 75 per cent inhibition of the hypertensive response. The duration of the inhibiting effect was only two minutes. It is of interest. that one week previously the same patient had received Dibenamine in a dose of 6 mg. per Kg. (table 1). Following Dibenamine the norepinephrine pressor response was com- pletely abolished even with infusion rates of norepinephrine which were four times greater than those used during the benzodioxane ex- periments. . Effect of the Imidazoline Derivatives, Priscoline and C-7337 Two subjects received 25 to 125 mg. of. Priscoline while 3 others received 25 to 50 mg. of C-7337. All doses were given intravenously. The effects of both drugs were essentially simi- lar. In all cases epinephrine reversal occurred even at relatively high infusion rates (case 8. P., table 1). The tachycardia that resulted from epinephrine infusion was exaggerated. However, in contrast to the results obtained with Dibenamine, the imidazoline compounds only partially inhibited (0 to 76 per cent; average 60 per cent inhibition) the pressor response to norepinephrine. Effect of Tetraethylammonium (TEA) and Hex- amethonium (C6) Since both of these drugs inhibit transmission through autonomic ganglia they are considered together. It was more convenient to study the effects of ganglionic blocking agents using C6 since this drug has a longer duration of action than TEA.’ Three subjects received 35 to 50 mg. of C6 intravenously. In all of these cases the pressor effects of both epinephrine and norepinephrine were intensified (table 1). The results were similar in 2 subjects who received 350 and 400 mg. respectively of TEA intra- venously. Effect of L-Hydrazinophthalazine Three subjects were given L-hydrazinoph- thalazine (C-5968) in doses of 18 to 30 mg. (0.31 to 0.37 mg. per Kg. body weight) intra- venously. A fall in arterial pressure occurred in one case and an increase in heart rate developed in 2 cases approximately 15 minutes after the drug was administered. Twenty min- utes after C-5968 was given the responses to epinephrine and norepinephrine were tested. No consistent effects were observed in re- gard to the epinephrine response. In one in- stance there was slight inhibition of the epineph- rine pressor response and in 2 cases there was slight potentiation. The degree of tachycardia was uninfluenced in 2 cases and slightly in- hibited in the other. The pressor response to norepinephrine, however, was moderately re- duced in all instances (12 to 45 per cent inhibi- tion). In addition, there was almost complete abolition of the bradycardia accompanying the norepinephrine induced hypertension. This marked inhibition of heart rate occurred de- spite elevation of mean arterial pressure as high as 30 to 45 per cent above the basal values. Effect of the Dihydrogenated Alkaloids of Ergot Previous studies® utilizing the same technics have demonstrated that the dihydrogenated alkaloids of ergot were very weak adrenolytic agents in the dosages customarily used in man. For the sake of completeness, however, and to test the effects of these drugs on the cardio- vascular responses to norepinephrine, 2 pa- tients were studied before and after the intra- venous administration of the dihydrogenated alkaloids. One case was given 0.5 mg. of di- hydroergokryptine while the other received 0.3 mg. of the combined dihydrogenated alkaloids (C. C. K.). In neither instance was significant inhibition of the cardiovascular responses to either epinephrine or norepinephrine observed. Discussion The effects of the various “sympatholytic” drugs on the pressor response to epinephrine appear to be similar in both man and animals. Thus, in animals, epinephrine reversal has been demonstrated after Dibenamine,® Priscoline,'® C-7337"" and benzodioxane. In addition, in- hibition of epinephrine induced hypertension has been demonstrated in man after Dibena- mine,” Priscoline” and benzodioxane.* How- ever, it was apparent from this study that the 258 SYMPATHOLYTIC DRUGS epinephrine reversal produced by therapeutic doses of Dibenamine, Priscoline and C-7337 was more complete and lasting than that pro- duced by similar doses of benzodioxane. The fleeting adrenolytic effect of benzodioxane has been noted previously by Prunty and Swan.'® In contrast, the effects of these agents on the hypertension resulting from norepinephrine has not been extensively investigated. In the pres- ent study Dibenamine produced the most com- plete inhibition of norepinephrine hypertension while Priscoline and C-7337 produced only par- tial inhibition. Benzodioxane also produced par- tial blockade, but, as with epinephrine, its action was fleeting, lasting less than two min- utes. It seems remarkable that benzodioxane which has such fleeting and relatively weak adrenolytic effects should be so reliable in pre- dicting the presence of pheochromocytoma." The results of this investigation suggest that a small dose of 15 to 20 mg. of Priscoline or C-7337 might be as reliable or perhaps more reliable than benzodioxane since such small doses of the imidazolines seldom produce sig- nificant reduction of basal arterial pressure; yet they would be expected to have a hypoten- sive effect in the presence of an excess of cir- culating epinephrine. As has been observed in animal experiments ganglionic blocking agents such as TEA and C6 exaggerated rather than suppressed the hy- pertensive effects of both epinephrine and nor- epinephrine. It appears'*: '7 that this intensified response is due to blockade of the cardiovas- cular “moderator” reflexes of the autonomic nervous system, especially those reflex arcs originating in the carotid sinus and aortic arch. Although the number of cases studied was small, there seemed to be a consistent quanti- tative difference in the action of Dibenamine as compared with the imidazoline compounds, Priscoline and C-7337. Although all of these agents produced epinephrine reversal, there was more complete inhibition of the effects of nor- epinephrine following Dibenamine than follow- ing the imidazolines. These results apparently were not due to dosage differences since the degree of norepinephrine blockade was greater after minimal effective doses of Dibenamine than after relatively large doses of Priscoline and C-7337. These data suggest, therefore, that Dibenamine is an active blocking agent for both epinephrine and norepinephrine whereas the imidazoline compounds, while qualitatively similar, are potent blocking agents for epineph- rine but are less active against norepineph- rine. In this regard it may be of interest that in animals the dosages of Priscoline and C-7337 required to produce epinephrine reversal are far less than the amount required to block sympathetic nerve stimulation," whereas with Dibenamine this difference in dosage is less.! The action of L-hydrazinophthalazine (C- 5968) differs from that of any of the other agents. In animals given larger doses than those used clinically in man the drug moderates but does not block epinephrine and norepinephrine hypertension nor does it produce epinephrine reversal.!®-20 In the present study there ap- peared to be slight inhibition of the norepineph- rine but not the epinephrine pressor response. However, the most striking observation was the marked inhibition of the bradycardia induced by norepinephrine. The significance of this ob- servation is not clear; since the bradycardia probably is reflex in nature, it may be that C-5968 interrupts the reflex arc at an unknown point. The present study demonstrates the diffi- culty in classifying autonomic blocking agents according to a simple schema. The concept of central, ganglionic and peripheral blocking agents is a useful but crude approximation. Thus, Dibenamine, the imidazolines and L- hydrozinophthalazine all appear to exhibit dis- tinctive differences in their ability to inhibit the cardiovascular effects of epinephrine and nor- epinephrine. This suggests that each of these drugs may act at different points in the chain of reactions involved in the activation of effec- tor cells. SUMMARY The effects of various ‘“‘sympatholytic” drugs on the pressor responses to epinephrine and norepinephrine were investigated under con- trolled conditions in man. The dosages used approximated those customarily employed clin- ically. E. D. FREIS, J. C. MacKAY AND W. F. OLIVER 259 1. Following Dibenamine there was ‘‘rever- sal’ of the pressor response to epinephrine and complete or nearly complete abolition of the pressor response to norepinephrine. 2. The imidazolines (Priscoline and C-7337) also produced epinephrine reversal but only partially inhibited the hypertension induced by norepinephrine. 3. Benzodioxane irregularly produced epi- nephrine reversal and only partially inhibited the pressor response to norepinephrine. The adrenolytic effect was of fleeting duration. 4. L-hydrazinophthalazine failed to affect epinephrine responses, slightly inhibited the norepinephrine pressor response and almost completely blocked the bradycardia induced by norepinephrine. 5. Ganglionic blocking agents such as tetra- ethyl ammonium and hexamethonium inten- sified the pressor effects of both epinephrine and norepinephrine. 6. Clinical doses of the alkaloids of ergot had little or no inhibiting affect. of epinephrine and norepinephrine pressor responses. 7. Although, in general, agents which inhibit or reverse epinephrine hypertension also modify the norepinephrine pressor response, there ap- pear to be quantitative differences in the de- gree of inhibition obtained with different agents. REFERENCES 1 Nickerson, M.: The pharmacology of adrenergic blockade. J. Pharmacol. and Exper. Therap. 95: 27, 1949. 2 AcHEsoN, G. H., anp Mog, G. K.: The action of tetraethylammonium ion on the mammalian circulation. J. Pharmacol. and Exper. Therap. 87: 220, 1946. 3 RicHarDson, A. P., WALKER, H. A., AnD MILLER, B. S.: The effect of pentaquine on the cardio- vascular system of unanesthetized dogs. Proc. Soc. Exp. Biol. & Med. 65: 258, 1947. 4y. Eurer, U. S.: A specific sympathomimetic ergone in adrenergic nerve fibers (sympathin) and its relation to adrenaline and nor-adren- aline. Acta physiol. Scandinav. 12: 73, 1946. 5’ GOLDENBERG, M., Faser, M., Auston, E. J., AND Cuaraarr, E. C.: Evidence for the occurrence of nor-epinephrine in the adrenal medulla. Sci- ence 109: 534, 1949. , Pines, K. L., Batpwiy, E. pe F., GREENE, D. G., anv Rou, C. E.: The hemodynamic re- sponse of man to nor-epinephrine and epineph- rine and its relation to the problem of hyper- tension. Am. J. Med. 5: 792, 1948. 7Finnerty, F., anp Freis, . D.: Experimen- tal and clinical evaluation in man of hexame- thonium (C6), a new ganglionic blocking agent. Circulation 2: 828, 1951. *Freis, bE. D., Stanton, J. R., Lirrer, J., Cun- BERTSON, J. W., Haurerin, M. H., Moisrer, F. C., anp Witkins, R. W.: The hemodynamic effects of hypotensive drugs in man. II. Di- hydroergocornine. J. Clin. Investigation 28: 1387, 1949. 9 NICKERSON, M., AND Goopman, L. 8.: Pharma- cological properties of a new adrenergic block- ing agent: N,N-dibenzyl-g-chloroethylamine (Dibenamine). J. Pharmacol. & Exper. Therap. 89: 167, 1947. 10CHEss, D., AND YONKMAN, F. F.: Adrenolytic and sympatholytic actions of Priscol (benzyl- imidazoline). Proc. Soc. Exper. Biol. & Med. 61: 127, 1946. 1 Merer, R., YonkmMan, F. F., Craver, B. N. AnD Gross, F.: A new imidazoline derivative with marked adrenolytic properties. Proc. Soc. Exper. Biol. & Med. 71: 70, 1949. 2 Hecut, H. H., anp Anprerson, R. B.: The influ- ence of dibenamine (N,N-dibenzyl-s-chloro- ethylamine) on certain functions of the sympa- thetic nervous system in man. Am. J. Med. 3: 3, 1947. 13 Grimson, K. S., Rearpon, M. J., Marzoni, F. A., AND Henprix, J. P.: The effects of Priscol (2-benzyl-4 ,5-imidazoline HCl) on peripheral vascular diseases, hypertension and circulation in patients. Ann. Surg. 127: 968, 1948. 4 GoLDENBERG, M., Snyper, C. H., anp ARANow, H., Jn.: New test for hypertension due to circu- lating epinephrine. J. A. M. A. 135: 971, 1947. 18 Prunty, F. T. G., anp Swan, H. J. C.: The ac- tion of benzodioxane in man. Lancet 1: 759, 1950. 16 Mor, G. K.: Potentiation of pressor action of epinephrine by tetraethylammonium. J. A. M. A. 137: 1115, 1948. 4 Page, I, H., anp Taytor, R. D.: Augmentation of vasoactive substances by tetraethylammo- nium chloride. Circulation 1: 1233, 1950. 1% Gross, F., Drury, J.. aND Meier, R.: A new group of depressor substances with a special type of effect. Experientia 6: 19, 1950. 19 Craver, B. N., AND YONKMAN, F. F.: Some phar- macological properties of L-hydrozinophthal- azine, a hypotensive agent. Federation Proc. 9: 265, 1950. 2 WaLKER, H. A., Witson, S., AND RICHARDSON, A. P.: Effects of L-hydrozinophthalazine (C-5968) on cardiovascular system of unanes- thetized dogs. Federation Proc. 9: 323, 1950.