The Action of Dopamine on the Arterial Blood Pressure of the Guinea‐pig

Hornykiewicz, O

doi:10.1111/j.1476-5381.1958.tb00197.x

Cited by 29 publications

(12 citation statements)

References 8 publications

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“…In some experiments this initial hypertension is followed by a prolonged increase or depression of blood pressure. The secondary fall of blood pressure caused by tyramine was similar to the blood pressure fall caused by dopamine in the guinea-pig (Hornykiewicz, 1958;Burn & Rand, 1958b). It was also found that the hypertensive effect of tyramine gradually diminished after repeated injections.…”

Section: Discussionsupporting

confidence: 53%

Effect of Noradrenaline, Bretylium and Cocaine on the Blood Pressure Response to Tyramine in the Rat

Lešić

Varagić

1961

British Journal of Pharmacology and Chemotherapy

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Tyramine is mainly a pressor agent in the rat under urethane, although the hypertensive effect of tyramine in some experiments is followed by a prolonged increase or depression of blood pressure. Bretylium, in doses up to 10 mg/kg, prolonged the response to tyramine, whereas larger doses depressed or blocked its effect. When the hypertensive effect of tyramine was blocked by bretylium, both noradrenaline and dihydroxyphenylalanine, when slowly infused, were found to restore it. The well-known block by cocaine of the hypertensive response to tyramine could also be reversed by intravenous infusion of noradrenaline and dihydroxyphenylalanine. It is concluded that the infusion of noradrenaline and dihydroxyphenylalanine makes available noradrenaline in the postganglionic adrenergic nerves which is necessary for the action of tyramine.In spinal preparations made from cats previously treated with reserpine, tyramine and many other sympathomimetic amines which are not derivatives of catechol lose their pressor action. This action can be restored in the reserpine-treated animal by an infusion of noradrenaline (Burn & Rand, 1958a). These observations suggest that tyramine and similar substances normally act by releasing noradrenaline or adrenaline from the arterial walls. In fact it has been shown that under certain conditions intravenous injections of tyramine increase the concentrations of adrenaline and noradrenaline in a sample of plasma withdrawn from the lower aortae of cats under chloralose.Tyramine is also classified as a sympathomimetic substance acting on postganglionic adrenergic nerve fibres because it does not act on denervated effector organs (Burn & Tainter, 1931;Fleckenstein & Burn, 1953). Bretylium is found to depress conduction of impulses in adrenergic neurones with subsequent failure of noradrenaline and adrenaline release, leaving at the same time intact the adrenergic receptors of the effector cell (Boura & Green, 1959). It was therefore of interest to investigate the effect of bretylium on the vascular response to tyramine. It was expected that the effect of tyramine would be particularly easy to -block if this substance acted primarily on the postganglionic adrenergic fibres. This work was started in order to investigate the site and mechanism of action of tyramine in causing changes of blood pressure in the rat. The experiments with bretylium were compared with the results obtained with cocaine in order to show their similar modes of action.

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Section: Discussionsupporting

confidence: 53%

Effect of Noradrenaline, Bretylium and Cocaine on the Blood Pressure Response to Tyramine in the Rat

Lešić

Varagić

1961

British Journal of Pharmacology and Chemotherapy

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“…He showed it was resulting directly from dopamine and not a metabolite of dopamine that was responsible. He also tested l ‐dopa and found the same effect …”

Section: The Scientific Developments Underlying the Discovery Of Strimentioning

confidence: 74%

The medical treatment of Parkinson disease from James Parkinson to George Cotzias

Fahn

2014

Movement Disorders

138

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It took exactly 150 years since James Parkinson's description in 1817 of the illness bearing his name until the development of effective therapy for this disorder, namely, the introduction of high-dosage levodopa by George Cotzias in 1967. During the first 50 years, no effective therapy was available, but neurologists reported using different agents, including metals. Then, around 1867, Charcot found solanaceous alkaloids to be somewhat helpful, and these became the accepted and popular therapy for the next 75 years. When basic scientists discovered that these alkaloids had central antimuscarinic activity, pharmaceutical chemists developed synthetic chemical agents that were equally effective, with possibly less adverse effects, and around 1950 these synthetic drugs became the standard medical therapy for Parkinson's disease (PD). The link between dopamine and PD did not take place until 1957, 140 years after Parkinson's Essay. The clue came from research on reserpine, a drug derived from the Rauwolfia plant that caused a sedative effect, now recognized as a drug-induced parkinsonian state. Initial investigations revealed that reserpine caused the release and depletion of serotonin stores in the brain. With that knowledge, Arvid Carlsson, a young pharmacologist in Sweden, decided to explore the possibility that reserpine might also affect brain catecholamines. In his now famous, elegant, and simple experiment, he showed that injecting l-dopa, the precursor of catecholamines, alleviated the reserpine-induced parkinsonian state in animals, whereas the precursor of serotonin failed to do so. Carlsson then developed a highly sensitive assay to measure dopamine, and his lab found that dopamine is selectively present in high concentrations in the striatum and that administered l-dopa could restore the dopamine depleted by reserpine. Carlsson postulated that all these findings implicate dopamine in motor disorders. Oleh Hornykiewicz, a young pharmacologist in Vienna, on being aware of the regional localization of brain dopamine, decided to measure it in the brains of people who had PD and postencephalitic parkinsonism. In 1960, he reported finding markedly depleted dopamine in the striatum in these conditions. Immediately after, Hornykiewicz teamed up with the geriatrician, Walther Birkmayer, to inject small doses of l-dopa intravenously (IV) into PD patients. They found benefit and pursued this treatment, but the gastrointestinal side effects limited the dosage, and many neurologists were doubtful that the effects from l-dopa were any better than those with antimuscarinic agents. A number of neurologists tested such low doses of IV l-dopa and even higher oral dosages, but without showing any dramatic benefit, not better than the antimuscarinics. Some of these studies were small, controlled trials. This general lack of efficacy with l-dopa prevailed, and neurologists were discouraged about l-dopa until 1967, when George C. Cotzias, a neuropharmacologist in New York, reported his results. He thought that PD may be result...

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“…In short, my experiments fully confirmed Blaschko's notion of dopamine having some own functions in the body, independent of noradrenaline and adrenaline. 3 This was my first direct contact with dopamine. While writing up my experiments and ruminating on dopamine's own actions in the body (this was in the exceptionally hot Oxford summer of 1957) a short report in the August 3 issue of Nature attracted my special interest; it dealt with the occurrence of a new catechol compound in the brain, claiming that it actually was dopamine!…”

Section: )mentioning

confidence: 97%