Effect of L‐dopa alone and in combination with an extracerebral decarboxylase inhibitor on blood pressure and some cardiovascular reflexes

Watanabe, August M.; Chase, T. N.; Cardon, Philippe V.

doi:10.1002/cpt1970115740

Cited by 51 publications

(17 citation statements)

References 6 publications

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“…Dihydrogenation decreases their ability to cause peripheral vasospasm. The overall cardiovascular effect of both ergot derivatives is, like levodopa, to induce hypotension (Watanabe, Chase & Landon, 1970;Greenacre, Teychenne, Petrie, Calne, Leigh & Reid, 1976); however, as with levodopa, continued administration of lergotrile induces tolerance to this hypotensive effect (Calne & Teychenne, 1977).…”

Section: Discussionmentioning

confidence: 99%

Cross tolerance between two dopaminergic ergot derivatives‐ bromocriptine and lergotrile.

Teychenne¹,

Rosin²,

Plotkin³

et al. 1980

Brit J Clinical Pharma

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1 When initially given to patients with idiopathic parkinsonism, lergotrile induced marked supine arterial hypotension. Tolerance to this hypotensive effect developed and larger doses of lergotrile were administered without this adverse effect. 2 Cross tolerance occurred between lergotrile and a structurally related ergot derivative, bromocriptine. A high dose of lergotrile given to patients who had been on long term bromocriptine therapy did not induce any significant hypotension when compared to placebo whereas hypotension still occurred when lergotrile was given after previous treatment with levodopa.

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Section: Discussionmentioning

confidence: 99%

Cross tolerance between two dopaminergic ergot derivatives‐ bromocriptine and lergotrile.

Teychenne¹,

Rosin²,

Plotkin³

et al. 1980

Brit J Clinical Pharma

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“…This evidence, however, does not support the possibility raised by Gross et al (1972) that postural hypotensionc can be explained by a central mechanism. Calne et al (1970) and Watanabe et al (1970) both presented clinical evidence that patients treated with L-DOPA who had supine hypotension had a greater fall in blood pressure when erect (postural hypotension). These two groups (Watanabe et al, 1970;Calne, Petrie, Rao, Reid & Vakil, 1972) reported that postural hypotension was not improved when lower doses of L-DOPA were combined with a peripheral dopa-decarboxylase inhibitor, although Calne et The results of the present investigation as well as other studies have been examined in terms of hypotheses which may possibly explain the extracerebral mechanism of L-DOPA-induced postural hypotension.…”

Section: Discussionmentioning

confidence: 99%

“…Both orthostatic (postural) and supine hypotension (usually referred to as hypotension) have been observed in man (Calne, Brennan, Spires & Stern, 1970;Watanabe, Chase & Cardon, 1970). There is substantial evidence from animal experiments that hypotension is due to a central mechanism whereby L-DOPA is effective after conversion to dopamine and/or noradrenaline in certain areas of the brain (Henning & Rubenson, 1970a;Robson, 1971;Minsker, Scriabine, Stokes, Stone & Torchiana, 1971).…”

Section: Introductionmentioning

confidence: 99%

On the mechanism of l‐DOPA‐induced postural hypotension in the cat

Dhasmana

Spilker

1973

British J Pharmacology

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Summary1. The effects of L-DOPA on postural hypotension and carotid occlusion pressor effect were studied, mainly in cats; the recovery of the blood pressure upon tilting was used as a measure of postural hypotension. 2. L-DOPA (30 mg/kg) partially depressed the carotid occlusion pressor effect and caused some degree of postural hypotension, L-DOPA (100 mg/kg) had more marked effects; the responses returned to control after 90 to 150 minutes. L-DOPA itself caused a pressor response in all cats.3. The dopa decarboxylase inhibitor NM-(DL-seryl)-N2-(2,3,4-trihydroxybenzyl) hydrazine (RO4-4602, 50 and 10 mg/kg) had no effect itself on the tilt response but completely prevented the effects of L-DOPA on the carotid occlusion pressor effect and postural hypotension. 4. After R04-4602 (3 and 1 mg/kg), L-DOPA (100 mg/kg) caused a brief rise of blood pressure followed by a longer lasting fall in horizontally-orientated cats (i.e. 'supine' hypotension). No postural hypotension was observed after L-DOPA under these conditions. 5. Noradrenaline elicited only small and transient effects on postural hypo--tension, but dopamine's effects were more marked and longer lasting. Pressor dose-response relationships for noradrenaline were the same before and after L-DOPA, as well as in cats pretreated with L-DOPA for 4 days. 6. In cats with kidneys and intestines removed, the tilt reflex was still present. Dose-response curves to L-DOPA were the same as in normal animals. R04-4602 (3 mg/kg) prevented postural hypotension and block of the carotid occlusion pressor effect; supine hypotension was also observed after L-DOPA. 7. The recovery response to tilting in spinal cats was markedly depressed or absent unless the blood pressure was elevated by angiotensin, in which experiments L-DOPA depressed the recovery upon tilting (i.e. induced postural hypotension).8. Blood pressure responses to tyramine were increased after 10 mg/kg of L-DOPA, but depressed after 100 mg/kg. The response to tyramine was not depressed, however, when R04-4602 was given to block the dopa-dopamine conversion.9. The response to sympathetic stimulation in pithed rats was depressed after L-DOPA and dopamine, but not after a-methyldopa. K. M. Dhasmana and B. A. Spilker 10. a-Methyldopa (300 mg/kg) given acutely caused a moderate degree of postural hypotension and a more marked postural hypotension if given for two days. 11. It is concluded that it is possible to differentiate between the supine and postural hypotension caused by L-DOPA and that supine hypotension is due to a central effect and postural hypotension to an extracerebral effect. Postural hypotension is discussed in relation to six hypotheses presented to explain its effect. Postural hypotension after L-DOPA is probably not due to a-adrenoceptor blockade, a central effect or any effect on the kidney. The most likely hypothesis is that L-DOPA forms dopamine which acts as a false transmitter in the peripheral sympathetic nervous system.

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“…Rather, patients became hypotensive. Hypotension is especially marked in the standing position but recumbent blood pressure also appears to be lowered (4,19). Furthermore, inhibition of extracerebral decarboxylase appears to potentiate the hypotensive effect of L-dopa (19).…”

Section: Effect Of L-dopamentioning

confidence: 99%

Modification of the cardiovascular effects of l-dopa by decarboxylase inhibitors

Watanabe¹,

Parks²,

Kopin³

1971

J. Clin. Invest.

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A B S T R A C T Intravenously infused L-dopa (0.3 mg/ kg per min) produced hypertension and cardiac arrhythmias in halothane anesthetized dogs. Biochemical studies showed that the heart, kidney, and brain of these animals accumulated significant amounts of catecholamines formed from the administered precursor.Pretreatment of dogs with an extracerebral inhibitor of dopa decarboxylase [D,L-a-hydrazino-a-methyl--(3,4-dihydroxyphenyl) propionic acid] prevented the development of hypertension and arrhythmias with infusion of L-dopa. Instead, these animals developed significant hypotension. The heart and kidney of these animals accumulated markedly reduced amounts of catecholamines formed from L-dopa compared with dogs receiving L-dopa alone; the amount of catecholamines accumulated in brain was unchanged. L-dopa, after extracerebral decarboxylase inhibition, appeared to produce hypotension by reducing peripheral vascular resistance without altering sympathetic nerve function. During hypotension, cardiac output was not altered and arterial pressure in perfused hindlimbs fell, even though flow was maintained.The pressor response to intravenous injections of norepinephrine and dopamine was unchanged. Hindlimb arterial pressure response to direct electrical stimulation of the lumbar sympathetic trunk was also unchanged.Pretreatment with a drug which inhibits brain as well as extracerebral dopa decarboxylase [D,L-seryl-2,3,4-trihydroxybenzylhydrazine hydrochloride] abolished all effects of L-dopa on blood pressure. In these animals, there was a marked reduction of catecholamine formation from L-dopa in the brain as well as the heart and kidney.

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Effect of L‐dopa alone and in combination with an extracerebral decarboxylase inhibitor on blood pressure and some cardiovascular reflexes

Cited by 51 publications

References 6 publications

Cross tolerance between two dopaminergic ergot derivatives‐ bromocriptine and lergotrile.

Cross tolerance between two dopaminergic ergot derivatives‐ bromocriptine and lergotrile.

On the mechanism of l‐DOPA‐induced postural hypotension in the cat

Modification of the cardiovascular effects of l-dopa by decarboxylase inhibitors

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