The Tachyphylaxis Caused by Mephentermine and Tyramine

Abstract

The sympathomimetic action of mephentermine, like that of tyramine, is considerably reduced by procedures that deplete noradrenaline stores, such as administration of reserpine. We have, however, observed important differences between these two sympathomimetic amines in the speed with which tachyphylaxis to the pressor action develops, in their behaviour in dogs treated with reserpine before and after infusions of noradrenaline and in their action on the heart-lung preparation. Blaschko (1962) and Day & Rand (1963) concluded that the differences in behaviour, with regard to tachyphylaxis, between tyramine and a-methylated sympathomimetic amines could be explained by the resistance of the latter to attack by monoamine oxidase. The experiments reported in this paper suggest a more complex situation. METHODSMongrel dogs weighing 8 to 12 kg were anaesthetized with chloralose (150 mg/kg). In the heart-lung preparations the experimental dogs were anaesthetized with pentobarbitone (30 to 40 mg/kg) and the donors with chloroform. The blood pressure was measured from a common carotid artery by a mercury manometer and both cervical vagosympathetic trunks were cut. Heart rates were measured from electrocardiograph records. The heart-lung preparations were of the conventional type (Fawaz & Simaan, 1963). Reserpine was given as intraperitoneal injections of0.5 mg/kg 48 hr and 24 hr before the experiment; such animals usually required less anaesthetic. Noradrenaline was estimated by the method described by Fawaz & Simaan (1963). Noradrenaline was used as the bitartrate, tyramine as the hydrochloride and mephentermine (Wyamine) as sulphate, and the doses quoted are expressed in terms of the bases. Injections into anaesthetized dogs were intravenous. RESULTSThe action of tyramine and mephentermine in dogs treated with reserpineIn twelve dogs not treated with reserpine, the first injection of tyramine (2 mg) caused a rise in arterial pressure of 63±6.8 mm Hg (mean and standard error). In sixteen similar dogs mephentermine (4 mg) caused a mean rise of 70±5.7 mm Hg. But the intravenous injection of either tyramine or mephentermine caused only a slight rise in arterial blood pressure in dogs treated with reserpine (Table 1). When 2 mg of noradrenaline was infused over 50 min and tyramine (2 mg) or mephentermine (4 mg) was injected 5 to 10 min after the end of the infusion (when the blood pressure had reached a steady level), the pressor action was fully restored. The pressor action of mephentermine after the infusion was even greater than in normal dogs. These results are in harmony with those of Burn & Rand (1958) on spinal cats treated with reserpine. After the infusion of noradrenaline a

The Mechanism by Which Noradrenaline Restores the Pressor Action of Indirectly Acting Sympathomimetic Amines in Reserpinized Dogs

“…The indirectly acting sympathomimetic amine has to be injected during the noradrenaline infusion (0.5 Pg/kg/min) but not after. In contrast to the situation in the normal animal (Fawaz & Simaan, 1965), consecutive injections of tyramine result in no diminution of the pressor response as long as the noradrenaline infusion continues. The pressor action of mephentermine is also restored but only for the first dose, the second dose being very slightly effective.…”

“…In a previous publication (Fawaz & Simaan, 1965) we postulated the presence in nonreserpinized animals of a large store from which noradrenaline can be released by tyramine and a "small" store from which noradrenaline can be released by tyramine or mephentermine. The small store, equivalent to that described by Burn & Rand (1958), but apparently not the large store, is the one that is repleted in a reserpinized animal after the acute infusion of excess noradrenaline.…”

“…In eitherinstance, injection of mephentermine or cocaine before the noradrenaline infusion cancels the postinfusion pressor response due to cocaine just as it does for tyramine and mephentermine (Fawaz & Simaan, 1965). This indicates that the pressor effects of tyramine, mephentermine or cocaine in reserpinized animals after infusion of noradrenaline are due to release of noradrenaline from repleted stores and that the repletion by noradrenalinewas blocked by prior treatment with mephentermine or cocaine (Fawaz & Simaan, 1965). Cocaine rarely shows a pressor effect in a normal, nonreserpinized dog, but it exhibits a pressor effect if administered immediately after a large single dose of noradrenaline (10 ,ug/kg) or after a noradrenaline infusion (4 ,ug/kg/min for 50 min) when the blood pressurejust returns to the preinfusion level.…”

“…It thus appears that in a " repleted " reserpinized dog only the " small" noradrenaline store is filled, since the pressor action of tyramine resembles that of mephentermine in a nonreserpinized dog where we postulated that mephentermine liberates noradrenaline from the small store. The so-called small noradrenaline store (Fawaz & Simaan, 1965) and the store described by Burn & Rand (1958) may thus be the same. A " repleted" store in a reserpinized dog is not indefinitely stable: if tyramine is injected 30 min instead of 5 to 10 min after the end of the infusion the pressor response is not fully restored and may sometimes be absent.…”

Crossed Tachyphylaxis Between Tyramine and Some Alpha Methylated Sympathomimetic Amines

“…Eble and Rudzik [1965], Bhagat [1965] and Dag [1967] suggested that the lack of crossed tachyphylaxis be tween tyramine and the alpha methylated amines could be ex plained by the different mechanisms of norepinephrine releasing action of the drugs. According to Blaschko [1962] and Day and Rand [1963], it was proposed by Fawas and Simaan [1965] that the alpha methylated sympathomimetic amines first release nor epinephrine from the stores and then block their own entry, as well as, that of subsequent doses of other indirectly acting amines into the stores. Rudzik [1965), Bhagat [1965] and Day [1967], The lack of crossed tachyphylaxis between tyramine, a non-alpha methylated amine, and the alpha methylated amines, in the animal not pretreated with MAO inhibitor suggest an action of the drugs on two different, functionally connected, storage sites of the adrenergic transmitter.…”