Chronotropic Effects of Norepinephrine and Tyramine: a System Response Analysis.

• In 1958, Burn and Rand 1 proposed that the drug, tyramine, had no direct sympathomimetic effects and that its pharmacologic action was wholly mediated by the liberation of norepinephrine from endogenous stores. This was based upon the observation that preparations severely depleted of stored norepinephrine by pretreatment with reserpine responded poorly, if at all, to tyramine. Large amounts of norepinephrine infused into such preparations prior to tyramine administration restored the potency of the latter amine and this was interpreted as the result of storage site repletion. Such repletion of storage site with norepinephrine does not seem to be a necessary condition for the restoration of tyramine efficacy. Certain investigators have concluded that the presence of proportionately small amounts of unbound extracellular norepinephrine is sufficient to enhance tyramine effect. These authors argue that tyramine must have an effect different from, and in addition to, the simple release of norepinephrine from storage and that this superadded effect is functionally related to the presence of unbound norepinephrine. Direct evidence for the release of norepinephrine from organs responding to tyramine is abundant." However, the amounts of norepinephrine liberated by tyramine are small compared to those needed to achieve the same pharmacologic response by administration of exogenous norepinephrine. The