Tachyphylaxis of Indirectly Acting Sympathomimetic Amines

THE KURUME MEDICAL JOURNAL Vol. 19, No. 1, 1972

TACHYPHYLAXIS OF INDIRECTLY ACTING SYMPATHOMIMETIC AMINES

II RECOVERY OF TYRAMINE TACHYPHYLAXIS AND CROSSED TACHYPHYLAXIS BETWEEN TYRAMINE AND OTHER INDI- RECTLY ACTING SYMPATHOMIMETIC AMINES IN DOGS

KOICHIRO TAKASAKI, MASANOBU URABE AND RYUICHI YAMAMOTO

Department of Pharmacology, Daiichi College of Pharmaceutical Sciences, Fukuoka, Japan

(Received for publication September 21, 1971)

The changes of blood pressure response produced by repeated administration of tyramine was investigated in morphine and pentobarbital anesthetized and atropinized dogs. Tyramine causes gradual attenuation of the pressor effect with repeated administration of doses of 0.5 to 1 mg/kg. A definite tachyphylaxis was obtained only with repeated administration of a large dose of tyramine in total doses averaging about 60 mg/kg. The tendency to cause tachyphylaxis of tyramine was more mild than that of ephedrine-like drugs (ephedrine, methamphetamine and pheniprazine). When the pressor effect was somewhat attenuated through repeated administration of tyramine, the pressor effect action of ephedrine-like drugs was slightly reduced. After the definite tachyphylaxis produced by tyramine, administration of ephedrine-like drugs caused a very small or no pressor effect. Sometimes only a slight fall of blood pressure was observed. On the other hand, after tachyphylaxis due to ephedrine-like drugs, the pressor effect in response to tyramine was suppressed considerably. The attenuated pressor effect after repeated dose of tyramine was restored to some extent towards the control pressor effect after about 1 / 2 to 1 hr intervals injections or norepinephrine infusion following the last administration of tyramine. However, if some dose of ephedrine-like drugs was administered during repeated administration of tyramine, the attenuated pressor effect of tyramine was not restored after the above-mentioned intervals. But it was restored slightly to some height after norepinephrine infusion. After tyramine tachyphylaxis the pressor effect to norepinephrine was observed in a normal and sufficiently intense rise. From these observations, it is most likely that the mechanism for producing tyramine tachyphylaxis is different from that of ephedrine-like drugs and primarily correlates with the entrance and accumulation of sufficient dose of tyramine into "labile store". This replaces norepinephrine in the store, althrough tyramine may not readily bind as easily as ephedrine-like drugs.

11 12 TAKASAKI, URABE, AND YAMAMOTO

It was believed that repeated intra- artery was recorded with a cannula, venous administration of tyramine in filled with heparine solution, inserted sufficient doses causes a gradual dec- in the artery. The cannula was con- rease of pressor response due to drug. nected to a marcury manometer or Ni- It also is well known that tyramine re- honkoden transducer (LPU-0.5) via a leases a "easily released" or "tyramine vinyl tube filled with saline. Drugs releasable" norepinephrine in the sto- used.: Norepinephrine (dl-norepineph- rage site of adrenergic nerve terminal rine hydrochloride, Sankyo Seiyaku Co. ), (Bhagat, Kopin et al. , Muskus, ephedrine (l-ephedrine hydrochloride, Trendelenburg and Weiner et al.), Dainihon Seiyaku Co. ), methamphet- On the other hand, the decrease of amine (d-methamphetamine hydrochlo- activity of tyramine was attributed to ride, Philopon, Dainihon Seiyaku Co. ), the gradual loss of the norepinephrine tyramine (tyramine monohydrochloride, from the store according to some re- Ishizu Seiyaku Cogyo Co. ), pheniprazine ports (Axelrod et al., Bhagat et al.. (pheniprazine hydrochloride, Catron, Bhagat, Maengwyn-Davies et al.) and Chugai Seiyaku Co.) were diluted in Potter et al.) saline and injected to the femoral vein. One of the authors briefly discussed 1) Tyramine in doses of 0.1-1 mg/kg (Takasaki) and again proposed that were repeatedly administered 8 to 10 the mechanism of tachyphylaxis pro- times at 10-15 min intervals. 2) After 8 duced by ephedrine-like drugs (ephedr- to 10 administrations of tyramine 1 mg ine, methamphetamine and pheniprazine) /kg, 2 or 3 mg/kg of tyramine was ad- depends on a binding ability in the ministered repeatedly until pressor of - norepinephrine storage site of adrener- f ect almost disappeared. 3) At various gic nerve terminal or adrenal gland stages of repeated administration of (Takasaki et al,) tyramine 0.5-1 mg/kg, 250 ƒÊg/5 ml/30 In the present experiments, a large min of norepinephrine was infused in- repeated dose of tyramine like ephed- travenously, and norepinephrine 1-3 ƒÊg rine and related compounds produced a /kg, ephedrine-like drugs 0.5-1 mg/kg definite tachyphylaxis. Crossed tachy- were injected to observe the influence phylaxis between tyramine and ephed- on the development of tyramine tachy- rine-like drugs was obtained in dis- phylaxis and to investigate the crossed agreement with the finding of some tachyphylaxis of each other. 4) The reports. change of heart rate was calculated The investigation was carried out from the blood pressure record. Experi- on the main cause of tachyphylaxis as mental procedures are detailed in Re- produced by tyramine. sults below.

METHODS RESULTS 1) Changes of pressor response through Thirty nine mongrel dogs, weigh- repeated administration of tyramine. ing 5 to 12 kg, anesthetized with pentobarbital sodium (15 mg/kg i, v.) after A rise of about 18-132 mmHg was morphine hydrochloride (10mg/kg s. c.) observed with tyramine 0.2 mg/kg. After were used. Atropine sulfate (1 mg/kg the 2 nd dose, no decrease occurred in s. c.) was administered along with mor- the rise of pressure until the 10 th dose. phine. The pressor effect sometimes increased Blood pressure in the right carotid slightly. TACHYPHYLAXIS OF TYRAMINE 13

With the use of 0.5 mg/kg, a rise cause tachyphylaxis was more mild than of about 80-140 mmHg was found. After that with ephedrine-like drugs (ephed- the 3 rd dose, on the average, the pres- rine and methamphetamine). A fall of sor effect somewhat decreased but it blood pressure never occurred. However, slightly increased transiently at the 6 th when tyramine 1-3 mg/kg was adminis- dose followed by a decrease again sli- tered repeatedly for 22-36 times (total ghtly after the 7 th dose. dose was 43-79 mg/kg), tyramine indu- With the use of 1 mg/kg, the pres- ced pressor effect almost disappeared sor effect was about 2/3 of the 1 st and a definite tachyphylaxis similar to dose, on the average, at the 2 nd admi- results for ephedrine-like drugs was nistration. After the 4 th administra- obtained. After the definite attenuation tion, the pressor effect even increased, of pressor effect of tyramine was pro- and it gradually decreased again after duced, tyramine was next administered 5 th dose. Almost no continuous dec- at about 1/2 to 1 hr intervals. The pres- rease of the elevation was seen until sor effect of tyramine 1-3 mg/kg was the 10 th dose. Even after the 5 th dose, restored to some degree towards the blood pressure rise of about 50 mmHg response of the 1 st administration(Fig. or more was noted and the tendency to 1).

Fig. 1 Repeated administation of tyramine. Tyramine (Ty) 1 mg/kg : 1 st and 8th administrations. Ty 2 mg /kg: 9 th and 12 th administrations. Ty 3 mg/kg : 13 th and 35th administrations. Ty 1 mg/kg : 36 th, and 37 th administration after 30 min interval. Scale is in mmHg. Time interval is 10 seconds. Drugs were injected at the arrow. Remarks are the same as those of Fig. 3, 4 and 5. 14 TAKASAKI, URABE, AND YAMAMOTO

On every occasion, heart rate inc- appearance of the pressor effect produ- reased constantly at almost the same ced by a large amount of tyramine rate, but the increase was somewhat administration, ephedrine-like drugs reduced by a large dose of tyramine. caused almost no pressor effect and in The experimental results with 1 mg many cases only a slight fall of blood /kg is summarized in Fig. 2. pressure appeared immediately (Fig. 4). Pheniprazine tachyphylaxis was accom - 2) Crossed tachyphylaxis to ephedrine- panied by a fall of blood pressure, and like drugs. a considerable more intense pressor effect to tyramine, was observed as corn- When tachyphylaxis of some degree paired with the effect after metham- was induced with 0.5-1 mg/kg of eph- phetamine or ephedrine tachyphylaxis. edrine-like drugs, administration of 0.5 -1 mg/kg of tyramine caused a decrease of the pressor effect due to tyramine ; in some cases it was somewhat intensi- f led after the 1 st or the several administrations of ephedrine-like drugs. Re- peated administration of tyramine after this caused more rapid decline of the degree of pressor response than without ephedrine-like drugs. However, even after the definite tachyphylaxis produced by ephedrine-like drugs several administrations of tyramine still elici- ted in some degree of pressor effect ; although it was considerable less intense and tended to diminish. When tyramine 0.5-1 mg/kg and ephedrine-like drugs 0.5-1 mg/kg were given alternately (10 to 15 min intervals between tyramine and ephedrine-like drugs, and 30 min interval between ephedrine-like drugs and tyramine), the pressor eff, ct of these drugs together was depressed (Fig. 2, 5 and 6). Additionally when the attenuation of the rise of blood pressure Fig. 2 Average blood pressure changes cau- caused by repeated administration of sed by repeated administration of tyramine tyramine, ephedrine-like drugs produced and methamphetamine. a somewhat milder degree of pressor o-o : tyramine (Ty) 1 mg/kg . •¢-•¢ : metham- response than that only under the ad- phetamine (Met) 1 mg/kg (This results was ministration of ephedrine-like drugs obtained in the previous experiment). (Fig. 3). As the attenuation of the •œ-•œ and •£-•£ : tyramine and methamphetamine blood pressure rise was more pronoun- 1 mg/kg were administered alternately until 8th and 5 th administrations respectively. ced in response to the repeated admi- Ordinate : percentage changes of blood pres- nistration of tyramine, the pressor sure from pre-injection level. Abscissa effect by ephedrine-like drugs occurred number of admistration. Vertical bars show more mildly. After the complete dis- a standard error on 3 to 5 experiments. TACHYPHYLAXIS OF TYRAMINE 15

Fig. 3 Crossed tachyphylaxis between tyramine and methamphetamine. Tyramine (Ty) 0.5 mg/kg : 1 st, 4 th and 9 th administrations ; methamphetamine (Met) 1 mg/kg after 9th administration of tyramine. Control response of methamphetamine 1 mg/kg from other dog.

Fig. 4 Crossed tachyphylaxis between tyramine and methamphetamine. Tyramine 1 mg/kg : 1 st and 7 th administrations. Ty 2 mg/kg : 8 th and 16 th administrations. Ty 3 mg/kg : 17 th and 22 nd administrations. Methamphetamine 1 mg/kg : 23 rd administration after tyramine.

3) The effect of norepinephrine after of tyramine. During the repeated ad- tyramine administrations and the ministration of tyramine at various influence of norepinephrine infu- stages, 250 ,ag/5 ml/30 min of norepi- sion for the development of tyra- nephrine was infused. Ten min after mine tachyphylaxis. the end of the infusion, 1-3 mg/kg of tyramine was administered again. The After single or repeated adminis- pressor effect was potentiated tempo- tration of 0.5-1 mg/kg of tyramine, rarily after the infusion of norepine- pressor effect of 1-3 ƒÊg/kg of norepi- phrine, but it was of a somewhat less nephrine was slightly potentiated. How- magnitude than after the definite ty- ever, on some occasions, it was decre- ramine tachyphylaxis. After the several ased slightly. Norepinephrine 1-3 ƒÊg/kg alternate administrations of tyramine caused a sufficient normal pressor res- 1 mg/kg and ephedrine-like drugs 1 mg ponse even after the definite tachphy- /kg at 10 to 30 min intervals, norepi- laxis produced by a large repeated dose nephrine was infused. Ten min after 16 TAKASAKI, URABE, AND XAMAMOTO the infusion the pressor effect of tyra- pronounced (Fig. 5). At the several mine 1 mg/kg was potentiated to some administrations of tyramine and ephed- extent but on the contrary, that of rine-like drugs about 1/2 to 1 hr inter- ephedrine-like drugs 1 mg/kg was at- vals was inserted after the last admi- tenuated. The fall of blood pressure nistration. After the interval the pres- produced by repeated administration of sor effect of tyramine was not restored ephedrine-like drugs was not altered by as in the results without ephedrine- norepinephrine infusion. It became more like drugs in 1) (Fig. 6).

Fig. 5 Alternate administration of tyramine and methamphetamine, and the effect of norepinephrine infusion. Tyramine (Ty) 1 mg/kg (5 times) and methamphetamine (Met) 1 mg/ kg (4 times) were administered alternately. After 5th administration of tyramine, norepinephrine 250 ƒÊg/ 5 ml/30 min was infused. Tyramine 1 mg/kg (6 th dose) and methamphetamine (5 th) dose were administered after norepinephrine infusion.

DISCUSSION pinephrine storage site, and competitively release the endogenous norepine- In the previous paper the mechanism phrine. Then the drugs accumulate in of tachyphylaxis produced by ephedrine, the stores and the restriction for ent- methamphetamine and pheniprazine was rance of subsequently administered discussed. In conclusion, it was stated drugs becomes more pronounced. It may that these drugs easily enter the nore- cause the gradual decrease of norepine- TACHYPHYLAXIS OF TYRAMINE 17

Fig. 6 Alternate administration of tyramine and methamphetamine and no recovery of pressor response to tyramine after 1 hr interval. Tyramine (Ty) 1 mg/kg (4 times) and methamphetamine (Met) 1 mg/kg (3 times) were administered alternately. Fifth administration of tyramine 1 mg/kg was given after 1 hr from the last administration of tyramine. phrine release and pressor response, or I) are depleted by reserpine (revie- and tachyphylaxis to these drugs is wed by Glowinski et al.) , Shore and accelerated (Takasaki). Trendelenburg). Moreover, norepi- In this experiment, the repeated nephrine released in response to tyra- administration of tyramine produced a mine is said to differ from that released slight and gradual decline of the pres- by ephedrine and amphetamine (Bhagat sor effect. But it was more difficult , Fawatz et al. Fawatz and Kopin to induce tachyphylaxis than by ephed- et al) . Fawatz et al.) Fawatz, rine-like drugs. Kopin et al., Kuntzman et al. and It has been well demonstrated that Weiner et al. have postulated that the there are at least two different stores third norepinephrine store which may be on norepinephrine storage. Indirectly called the "labile store" (compartment C acting sympathomimetic amines release or III) and tyramine releases the most the softly bound norepinephrine (pre- softly bound ("easily released" or "tyr- sumably active form, compartment B amine releasable") norepinephrine from or II) from the storage site, and other this "labile store". It may be a reason tightly bound norepinephrine (presu- that the crossed tachyphylaxis between mably inactive form, compartment A tyramine and other indirectly acting 18 TAKASAKI, URABE, AND YAMAMOTO sympathomimetic amines was not ob- partment B ) and tyramine releasable served (Bhagat, Day and De Moraes store ("labile store") are primarily dif- et al.) ferent but functionally connected (Day This norepinephrine in "labile store" ) and histologically close to each may be released and gradually depleted other. The capacity of these stores may by repeated administration of tyramine. be limited. Although tyramine probably It may cause tyramine tachyphylaxis to enters the norepinephrine storage gra- some extent (Axelrod et al., Bhagat nules ( Presumably compartment B ) et al. Bhagat and Potter et al. (Musacchio et al.), tyramine mainly ) . However, in the previous (Taka- liberates norepinephrine by displacement saki) and present experiments in from a portion of "labile store" (Axelrod spite of the pressor effect observed by et al. and Trendelenburg). When a tyramine administration, the tendency sufficient repeated dose of ephedrine- of the tachyphylaxis is less intense like drugs was administered, their re- than with other drugs. leasable store (compartment B) was Bhagat and Crout et al. have repleted with the drugs. Then the drugs shown that the reduction of norepine- may block the spontaneous release of phrine levels in the tissue is not parallel norepinephrine from the store (Chang and is unrelated to the reduction in et al.) . Thus a depleted norepineph - response to tyramine. Furthermore, rine from "labile store" after repeated there was no depletion of norepineph- dose of tyramine would not be repleni- rine from the tissue after tachyphylaxis shed from compartment B after a suf- to tyramine (Nasmyth). ficient dose of ephedrine-like drugs. It In the present experiment, after the eventually produced tachyphylaxis by tachyphylaxis by ephedrine-like drugs, ephedrine-like drugs crossed to tyramine the pressor effect of tyramine was at- and tyramine tachyphylaxis accelerated tenuated and the tendency towards ta- by a sufficient dose of ephedrine-like chyphylaxis was accelerated in disag- drugs. The pressor effect of tyramine reement with the finding of Bhagat was attenuated gradually by repeated and others. Additionally, the pres- administration of the drug but occasio- sor effect of ephedrine-like drugs was nally this reduced response was restored also slightly attenuated after the re- towards the control response range peated dose of tyramine. Especially was ("escape from tachyphylaxis"). This was this true after a definite tyramine ta- noted in agreement with the data of chyphylaxis administration of ephedrine- Bhagat et al.. This phenomenon may like drugs produced almost no pressor arise according to the view in which effect or only the frequent slight fall tyramine is said to stimulate catechol- of blood pressure. amine synthesis transiently (Bhagat et Furukawa et al. also have stated al.) and is itself a precursor of nor- that the pressor action of dopamine epinephrine (Chidsey et al.) . Thus seems to be the result of endogenous tyramine induces tachyphylaxis with catecholamines released from the sto- more difficulty than other drug. How- rage site. This was because the dop- ever, in the present experiment, the amine pressor action disappeared after attenuated pressor effect produced by the definite tachyphylaxis produced by repeated dose of tyramine was restored the large dose of tyramine. towards the control response level after It is most likely that ephedrine or about 1/2 to 1 hr intervals. Furthermore, methamphetamine releasable store (com- after the definite ephedrine-like drugs TACHYPHYLAXIS OF TYRAMINE 19 tachyphylaxis, tyramine still elicits effect of tyramine is very short-lasting some pressor effect, but if the further (Chidsey et al. and Musacchio et al. administration of ephedrine-like drugs ) and the rapid ƒÀ-hydroxylation of ty- is repeated, pressor response to tyra- ramine is said to occur immediately mine disappeared. Additionally, some- (Carlsson et al. and Fisher et al.) times the pressor effect of tyramine . In general, the amount of tyramine or was slightly potentiated after the ad- its metabolites stored in " labile store" ministration of ephedrine-like drugs in is limited and the intense binding ability agreement with the finding of Rudzik to the store and accumulation as in the et al.. On the other hand, when case of ephedrine-like drugs (Thoenen tyramine is in small doses, it may affect et al. and Young et al.) does not a release from the soluble fraction apparently take place. Therefore, ty- (presumably "labile store"). In large ramine may not be retained by the doses it causes release from the granu- store for a long time. Tyramine itself lar fraction (presumaly compartment B ) may not readily restricted the entrance (Bhagat). These findings may strongly of the subsequently administered tyra- support the above-mentioned opinion mine to the storage site, except after concerning the two stores (compartment a large repeated dose of the drug. B and "labile store"). On the other hand, ephedrine-like The most probable mechanism is as drugs are not substrate for monoamine follows : Ephedrine-like drugs may en- oxidase (MAO). On the contrary tyra- ter compartment B and competitively mine is a good substrate for MAO and release norepinephrine to "labile store" tachyphylaxis to tyramine may occur and then to the outside of the terminal when the ability of the MAO to destruct cell membrane. If the amount of nore- tyramine is exceeded by giving large or pinephrine in "labile store" is increased frequent doses of tyramine (Bhagat after some administration of ephedrine- and Day et al.) , According to the like drugs, the response to tyramine reports of Cowan et al. and Day et may be slightly and temporarily inten- al. the rate of development of ta- sified. When "labile store" is depleted chyphylaxis after pheniprazine or nial- gradually with a large repeated dose of amide (intense MAO inhibitors) becomes tyramine, norepinephrine would be sup- faster. However, nialamide decreased plied from compartment B. However, if the concentration of norepinephrine in the amount and frequency of tyramine tissue. In the treatment of nialamide, administration is enough to deplete "la- the norepinephrine content was higher bil store" and then also if compartment than that from control animals, even B makes good the loss of norepinephrine after sufficient tyramine had been given in "labile store", the pressor effect of to cause complete loss of tyramine res- tyramine disappears. When the suffici- ponse (Davey et al.) ent interval is given during repeated In the previous (Takasaki et al. 360 and administration of tyramine, some active the present experiments, the tachyph- form of norepinephrine may be reple- ylaxis to pheniprazine does not readily nished from compartment A (inactive occur as ephedrine or methamphetamine. form) to compartment B (active form) The pressor effect to tyramine after and then to "labile store". After this pheniprazine tachyphylaxis did not mar- replenishment of "labile store" tyramine kedly decline as after ephedrine or me- response may to some extent be restored. thamphetamine. This is presumably The norepinephrine release by the because MAO inhibiting action of phe- 20 TAKASAKI, URABE, AND YAMAMOTO niprazine does not accelerate and is not restores the pressor response to tyra- direetly correlated to tyramine tachy- mine even after the definite tachyphy- phylaxis. It is most probable that MAO laxis, contrary to the results with eph- inhibitor such as pheniprazine or nial- edrine-like drugs demonstrated in the amide enter and accumulates in the previous paper(Takasaki). This would compartment B and may block the spon- indicate that if norepinephrine is infu- taneous release of norepinephrine from sed continuously, some amount of the store to "labile store" as ephedrine norepinephrine could enter the storage or methamphetamine do. The "labile site in exchange for tyramine and per- store" could not be replenished by nore- haps also for its metabolites. pinephrine from compartment B after It seems likely that norepinephrine the repeated dose of ephedrine-like in "labile store" is a free form that drugs, including MAO inhibitors. Thus, exists inside the terminal cell membrane tyramine tachyphylaxis was accerelated and is easily replaced by tyramine. after a dose of ephedrine-like drugs. After the administration of tyra- REFERENCES mine, the pressor effect of exogenous norepinephrine is considerably intensi- 1) AXELROD, J., CORDON, E., HERTTING, G., fied on every occasion ; although it is KOPIN, I. J. and POTTER, L. T.: On the me- somewhat attenuated after a large dose chanism of tachyphylaxis to tyramine in of tyramine in few cases. This is pro- the isolated rat heart. Brit. J. 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22) GLOWINSKI, J. and BALDESSARINI, R. J. acutely administered reserpine in dogs. 22 TAKASAKI, URABE, AND YAMAMOTO

Ibid, 18, 89-102, 1971. 1968. 35) TAKASAKI, K. : Systemic arterial pressure 38) TRENDELENBURG,U. : Supersensitivity and changes caused by sympathomimetic ami- subsensitivity to sympathomimetic amines. nes and influence of norepinephrine in- Pharmacol. Rev., 15, 225-276, 1963.

fusion on chronically reserpinized dogs. 39) TRENDELENBURG,U. : Modification of the This J., 18, 111-116, 1971. effect of tyramine by various agents and 36) TAKASAKI, K., KITAGAWA, H. and ISHIBASHI, procedures. J. Pharmacol., 134, 8-17, 1961. S.: Tachyphylaxis of the indirectly acting 40) WEINER, N., DRASKOCY,P. R. and BURACK,

sympathomimetic amines. I Difference W. R.: The ability of tyramine to liberate of pressor effect produced by repeated catecholamines in vibo. Ibid, 137, 47-55, administration of ephedrine, methamphe- 1962.

tamine and pheniprazine in dogs. This 41) YOUNG, R. L. and GORDON, M. W.: The in- J., 19, 1•`10, 1971. fluence of epinephrine and norepinephrine

37) THOENEN, H., HURLIMANN, A. and HAEFELY, on the accumulation of amphetamine-1- W.: Mechanism of amphetamine accumu- 14C by rat brain. Biochem. Pharmacol., lation in the isolated prefused heart of 6, 273-277, 1961.

the rat. J. Pharm. Pharmacol., 20, 1-11,