Releasing norepinephrine from storage sites

The Rauwolfia alkaloid reserpine, due to its strong central component of activity, is excluded from this review, even though it has the peripheral effect of releasing norepinephrine from storage sites where it can be metabolized by monoamine oxidase. This results in neurotransmitter depletion and it appears that good blood pressure control would be achieved by a drug which has this peripheral mechanism but lacks the central component. The Mead-Johnson compound MJ-10459-2 (LXI) shows activity in... 

Some adrenomimetic drugs act both directly and indirectly that is, they release some norepinephrine from storage sites and also directly activate tissue receptors. Such drugs are called mixed-action adrenomimetics. However, most therapeutically important adrenomimetic drugs in humans act either directly or indirectly. 

Recent studies on the mechanism of action of a-methyldihydroxyphenyl-alanine point to the possibility that it is decarboxylated to produce a-methyl-dihydroxydopamine and this substance by beta oxidation is converted into a-methyldihydroxynorepinephrine. These agents in turn are thought to bring about release of norepinephrine from storage sites (18, 19),... 

Dexamphetamine sulphate acts by stimulating the release of norepinephrine and dopamine from storage sites and may also slow down the metabolism of catecholamines by inhibiting MAO. Usually about 30% is excreted unchanged in the urine this urinary excretion reaches 60% when the urine is acidic (pH 5.5-6). It is metabolized by cytochrome P450. 

Many other adrenomimetic drugs, such as amphetamine, do not themselves interact with adrenoceptors, yet they produce sympathetic effects by releasing norepinephrine from neuronal storage sites (vesicles). The norepinephrine that is released by these compounds interacts with the receptors on the effector cells. These adrenomimetics are called indirectly acting adrenomimetic drugs. The effects elicited by indirectly acting drugs resemble those produced by norepinephrine. 

We compare the relative activity of DA, agonists on the following receptors beta, (both directly and indirectly by release of norepinephrine from myocardial storage sites), betap, alpha, and DAp. Table IV describes the spectrum of activity of several compounds studied in the pentobarbital anesthetized dog. The methods used have been described in detail (21,30). 

The action of tyramine on nerve receptors is mainly indirect by release of norepinephrine and dopamine from neuronal storage sites (363, 384). Tyramine and its /3-oxidized counterpart octopamine have been referred to as false neurotransmitters because these compounds can be taken up, stored, and released from nerve endings in a way similar to those of the principal neurotransmitters norepinephrine and dopamine (385). Octopamine was first discovered in salivary glands of octopods (386). The compound is widely distributed in the animal kingdom and is present in high amounts in the nervous system of several species of invertebrates such as molluscs and arthropods, where it acts as a specific transmitter substance (387). Octopamine may also play a role in the regulation of adrenergic neurotransmission in mammals (387). Administration of octopamine to intact animals produces a transient rise in blood pressure (388). 

MDMA increases the levels of neurotransmitters such as 5-HT, dopamine, and norepinephrine by causing release of the neurotransmitters from their storage sites. It causes a significant depletion of neurotransmitters, including 5-HT. The number of new MDMA users has risen since 1993, when there were 168,000 new users. By 2001, this number had reached 1.8 million. The National Survey on Drug Use and Health found that 15.1% of 18- to 25-year-olds surveyed in 2002 had used MDMA at least once in their lifetime. There were 676,000 who had used the drug within the month before the survey. 

---