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

Watanabe, August M.; Parks, Leon C.; Kopin, Irwin J.

doi:10.1172/jci106611

Cited by 38 publications

(13 citation statements)

References 12 publications

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“…This compound is preferentially accumulated within the kidney when infused intravenously (10). Watanabe et al have recently reported that 50 mg/kg of carbidopa, infused over a period of 15 min in dogs, markedly inhibits L-dopainduced catecholamine synthesis in the kidn,ey3 (11).…”

Section: Introductionmentioning

confidence: 99%

Phosphaturic effect of dopamine in dogs. Possible role of intrarenally produced dopamine in phosphate regulation.

Cuche¹,

Marchand²,

Greger³

et al. 1976

J. Clin. Invest.

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A B S T R A C T A possible role for dopamine in phosphate handling by the dog kidney was investigated by intrarenal artery infusions of dopamine. Dopamine increased fractional phosphate excretion both in the presence and absence of control of parathyroid hormone and calcitonin. In addition, dopamine increased both renal blood flow and sodium excretion; however, the phosphaturia was independent of these changes; since 30 min after completion of dopamine infusion, renal blood flow and sodium excretion returned to control levels and phosphate excretion remained elevated. For comparison, the vasodilator isoproterenol increased renal blood flow and sodium excretion without a significant change in fractional phosphate excretion. Thus, the phosphaturic effect of dopamine is probably independent of its vasodilator effect. The phosphaturic effect of dopamine could not be accounted for by subsequent conversion to norepinephrine, since norepinephrine was antiphosphaturic in the dog.The effect of endogenous dopamine on renal phosphate excretion was investigated by intrarenal infusion of the precursor dopa. Dopa was phosphaturic both in the presence and absence of parathyroid hormone and calcitonin. In dogs pretreated with carbidopa, which blocks conversion of dopa to dopamine, dopa was no longer phosphaturic, although the kidney remained responsive to dopamine. It is postulated that dopamine may play a role in the intrarenal regulation of phosphate excretion.

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Section: Introductionmentioning

confidence: 99%

Phosphaturic effect of dopamine in dogs. Possible role of intrarenally produced dopamine in phosphate regulation.

Cuche¹,

Marchand²,

Greger³

et al. 1976

J. Clin. Invest.

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“…These results are also consistent with those previously obtained for normotensive cats and dogs. 19 ' 20 The extracerebral pressor effects of L-dopa masked the central inhibitory effects of the amino acid. Thus, when the arterial presssure was clamped to prevent the development of hypertension, it was found it both groups of rats that SNA was inhibited even when L-dopa was given alone.…”

Section: Discussionmentioning

confidence: 99%

“…19 " 24 The present study, in which we have assessed the effects of L-dopa on blood pressure, heart rate, and SNA in the SHR, was performed because of the demonstrated excessive SNA in these rats and the knowledge that Ldopa can reduce SNA. Our results show that L-dopa, when given with an extracerebral inhibitor of L-amino acid decarboxylase, is a potent depressor drug in the SHR.…”

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confidence: 99%

Effect of l-dopa on sympathetic nerve activity and blood pressure in the spontaneously hypertensive rat.

Judy¹,

Watanabe²,

Henry³

et al. 1978

Circulation Research

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SUMMARY We examined the effect of L-dopa, after peripheral L-amino acid decarboxylase inhibition, on sympathetic nerve activity (SNA) and blood pressure in spontaneously hypertensive rats (SHR) and in normotensive control rats. L-Dopa reduced SNA in both groups of animals. The SHRs were significantly more sensitive to the depressor effect of L-dopa than were the control animals, the threshold dose for reduction of SNA being 3 mg/kg in SHR and 15 mg/kg in control rats. Similarly, the magnitude of inhibition of SNA was substantially greater in the SHR than in normotensive rats. The reduction in SNA in the SHR was accompanied by a parallel fall in blood pressure. In contrast, blood pressure in control rats did not change significantly, even though SNA was diminished. Studies of the penetration of L-dopa into the cerebral parenchyma revealed that equivalent amounts of the amino acid entered the brains of the two groups of rats. These results suggest that the SHRs are more sensitive to the SNA-inhibiting effects of L-dopa than are normotensive rats. In addition, they confirm our previous suggestion that excessive SNA plays a causative role in the hypertension of the SHR.A GROWING body of evidence indicates that a significantly causative factor in the hypertension of the Okamoto strain of spontaneously hypertensive rat (SHR) is excessive sympathetic nerve activity (SNA). The major observations supporting such a conclusion are that pharmacological or surgical abolition of SNA leads to a reduction in blood pressure in the SHR, 1 " 4 and that directly measured SNA is markedly increased. 510 In addition, studies of baroreceptor regulation of blood pressure demonstrate a decreased baroreceptor sensitivity in the SHR compared to normotensive control rats.7 ' H> 12 Although the mechanism underlying the excessive SNA and decreased baroreceptor sensitivity is not known, it seems reasonable to postulate that the abnormality resides in certain vasomotor regulatory centers in the brain. Further, in light of the knowledge that the antihypertensive agents which are thought to act substantially or primarily in the central nervous system (CNS) interact with adrenergic nerves or receptors, it appears possible that a CNS abnormality in the SHR which leads to hypertension involves brain catecholamine metabolism, as previously suggested by other investigators. 13One approach to studying CNS adrenergic regulation of physiological responses in intact animals is to use drugs to either inhibit or activate CNS adrenergic systems. Such an approach, using agents such as reserpine, intra- Received October 31, 1977; accepted for publication February 22, 1978. cerebral 6-hydroxydopamine, alpha-methyl dopa, clonidine, intracerebral dopamine, or ergot derivatives, has been applied to the study of depression, extrapyramidal disorders, hypertension, and the regulation of hypothalamic releasing factors.14 " 18 By using L-dopa, an amino acid precursor of catecholamines, we and others have shown that an increase in CNS catecholamine content results i...

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“…There is evidence in animal experiments that the hypotension is due to a central action of L-DOPA (Henning & Rubenson, 1970;Watanabe, Parks & Kopin, 1971). However, Dhasmana & Spilker (1973) concluded that it was possible to distinguish between the mechanisms by which supine and postural hypotension were produced by L-DOPA.…”

Section: Introductionmentioning

confidence: 99%

THE CARDIOVASCULAR EFFECTS OF l‐DOPA IN THE PITHED RAT

Edén

Nasmyth

1974

British J Pharmacology

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I L-DOPA (1-2 mg i.v.) in the pithed rat reduced the arterial and increased the venous pressure responses to noradrenaline.2 Infusions of dopamine (4-8 ,ug kg-' min-) and noradrenaline (500 ng kg-min-') also reduced the pressor responses to noradrenaline. The pressor response did not recover after stopping dopamine infusions, but it usually did so after stopping noradrenaline infusions. 3 The effect of L-DOPA on the response to noradrenaline was prevented by the prior injection of the dopa decarboxylase inhibitor NSD 1024. 4 The prior injection of the dopamine-4-hydroxylase inhibitor diethyldithiocarbamate, only partially prevented the effect of L-DOPA on pressor responses to noradrenaline. 5 The perfusion of noradrenaline (400 ng kg-' min-) together with Krebs solution (10 ml/min) through an organ bath containing an isolated aortic strip, depressed the response of the strip to doses of noradrenaline after the infusion was stopped. Infusions of dopamine (0.5-8.0 ,g kg-' min-') had a similar effect. Fifteen minutes after adding L-DOPA (0.5 mg) to the bath and 10 min after washing it out, the response to noradrenaline was depressed in three out of four experiments. 6 Infusions of noradrenaline (1,Mg kg-min-) in an isolated heart perfused by Langendorf's method blocked the response to injected noradrenaline whilst perfusion was in progress.Infusions of dopamine (4-8 Mig kg-min-) or of L-DOPA (200 Mg kg-' min-') did not have this effect. 7 It is concluded that the effect of L-DOPA on pressor responses to noradrenaline in the pithed rat are mediated by its conversion to dopamine and noradrenaline.

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

Cited by 38 publications

References 12 publications

Phosphaturic effect of dopamine in dogs. Possible role of intrarenally produced dopamine in phosphate regulation.

Phosphaturic effect of dopamine in dogs. Possible role of intrarenally produced dopamine in phosphate regulation.

Effect of l-dopa on sympathetic nerve activity and blood pressure in the spontaneously hypertensive rat.

THE CARDIOVASCULAR EFFECTS OF l‐DOPA IN THE PITHED RAT

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