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 adminis- tration of tyramine was investigated in morphine and pentobarbital anes- thetized 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 some- what attenuated through repeated administration of tyramine, the pressor effect action of ephedrine-like drugs was slightly reduced. After the defi- nite 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 norepine- phrine 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 pen- tobarbital 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 ef- fect 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 admi- nistrations 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 pro- duced 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 atte- nuation 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).