The effects of neuronal uptake blockade on the cardiac responses to sympathetic nerve stimulation and norepinephrine infusion in anesthetized dogs

Masuda, Yukitaka; Levy, Matthew N.

doi:10.1016/0165-1838(84)90063-8

Cited by 16 publications

(3 citation statements)

References 26 publications

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“…These abnormalities of NE reuptake function have a physiological importance because this function is the principal means of terminating the action of the neurotransmitter. Indeed, in animals, blockade of neuronal NE uptake increases postsynaptic exposure to NE, and cardiac response to exogenous NE is prolonged by the uptake-1 (neuronal) blockade but is unchanged by uptake-2 (extraneuronal) blockade (19,24). The cause of impaired myocardial uptake-1 is unclear.…”

Section: Discussionmentioning

confidence: 99%

Effects of 5-day hypoxia on cardiac adrenergic neurotransmission in rats

Mardon¹,

Merlet²,

Syrota³

et al. 1998

Journal of Applied Physiology

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Chronic hypoxia induces an overall sympathetic hyperactivation associated with a myocardial beta-receptor desensitization. The mechanisms involved in this desensitization were evaluated in 32 male Wistar rats kept in a hypobaric pressure chamber (PO2 = 40 Torr, atmospheric pressure = 450 Torr) for 5 days. In hypoxic compared with normoxic conditions, plasma norepinephrine (NE) levels were higher (2.1 +/- 0.7 vs. 0.6 +/- 0.2 ng/ml) with no difference in the plasma epinephrine levels (2.2 +/- 0.7 vs. 1.8 +/- 0.3 ng/ml). In hypoxia neuronal NE uptake measured by [3H]NE was decreased by 32% in the right ventricle (RV) and by 35% in the left ventricle (LV), and [3H]mazindol in vitro binding showed a decrease in uptake-1 carrier protein density by 38% in the RV and by 41% in the LV. In vitro binding assays with [3H]CGP-12177 indicate beta-adrenoceptor density reduced by 40% in the RV and by 32% in the LV, and this was due to reduced beta1-subtype fraction (competition binding experiments with practolol). Hypoxia reduced the production of cAMP induced by isoproterenol (36% decrease in the RV and 41% decrease in the LV), 5'-guanylylimododiphosphate (40% decrease in the RV and 42% decrease in the LV), and forskolin (39% decrease in the RV and 41% decrease in the LV) but did not alter the effect of MnCl2 and NaF. Quantitation of inhibitory G-protein alpha-subunit by immunochemical analysis showed a 46% increase in the cardiac-specific isoform Gialpha2 in hypoxic hearts. The present data demonstrate that in rats 5-day hypoxia leads to changes in pre- and postsynaptic myocardial adrenergic function. The myocardial desensitization associated with both a reduction in externalized beta1-adrenoceptor and an increase in inhibitory G-protein subunit may be caused by increased synaptic NE levels due to impaired uptake-1 system.

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Section: Discussionmentioning

confidence: 99%

Effects of 5-day hypoxia on cardiac adrenergic neurotransmission in rats

Mardon¹,

Merlet²,

Syrota³

et al. 1998

Journal of Applied Physiology

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“…[1][2][3] A second technique was based on the fact that the synthetic catecholamine isoproterenol (ISO) is not a substrate for neuronal uptake.4 A difference in regional removal of NE and ISO therefore would indicate Uptake-1 activity if the removals of these catecholamines did not differ importantly in any other way. This approach was validated in the human forearm5 and canine hindlimb4 by the observation that the regional removal of tracer-labeled NE in desipramine-treated patients was similar to that of tracer-labeled ISO in untreated patients.…”

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confidence: 99%

In vivo measurement of neuronal uptake of norepinephrine in the human heart.

et al. 1988

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Neuronal uptake (Uptake-i) of the sympathetic neurotransmitter norepinephrine from the circulation in the human heart was assessed in vivo with three techniques. 1) Cardiac removal of intravenously infused tracer-labeled norepinephrine was measured before and after Uptake-i blockade with desipramine; 2) the difference between the fractional extraction of radioactive norepinephrine and of radioactive isoproterenol, which is not a substrate for neuronal uptake, was used to estimate the removal of norepinephrine by Uptake-i in the heart compared with other vascular beds (arm, leg, brain, and lungs); and 3) regional arteriovenous differences in radioactive and endogenous dihydroxyphenylglycol (DHPG), an exclusively intraneuronal metabolite of norepinephrine, were compared in these beds. In untreated patients, cardiac removal of radioactive norepinephrine averaged 79%, whereas in desipramine-treated patients, cardiac removal of radioactive norepinephrine averaged 19%, a value similar to that of isoproterenol in untreated patients (14%), confirming that in the heart the non-neuronal removals of isoproterenol and norepinephrine were similar. In the heart, 69% of delivered norepinephrine was estimated to be removed by Uptake-i, a much higher percentage than that in the arm (14%), leg (7%), brain (10%), and lungs (4%). The cardiac arteriovenous increment in endogenous DHPG (137%) far exceeded that of the other beds (49%, 26%, 39%, and -19%, respectively), and radioactive DHPG in the great cardiac vein exceeded arterial levels by 113%, whereas in the other beds, arterial radioactive DHPG exceeded venous levels. The results indicate that the human heart is exceptionally dependent on neuronal uptake for in vivo removal of circulating norepinephrine. (Circulation 1988;78:41-48) S everal pathophysiological and therapeutic concepts in cardiology have been based on sympathetic neuroeffector mechanisms in the heart. A limitation in evaluating these concepts has been the inability to measure cardiac sympathetic function in vivo, especially the activity of the neuronal uptake process (Uptake-1), which is the predominant means for terminating the actions of the sympathetic neurotransmitter norepinephrine (NE). The present study introduces three clinical techniques to examine cardiac neuronal uptake of NE.In the first technique, cardiac removal of tracerlabeled NE was measured before and after Uptake-1 blockade with desipramine, a procedure previously used in laboratory animals. 1-3From the Hypertension-Endocrine Branch, National Heart, Lung, and Blood Institute (D.S.G., R.S), Cardiology Branch, National Heart, Lung, and Blood Institute (J.E.

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“…The response to DMI developed slowly, with an estimated VA of 7.9 ± 0.7 minutes, resulting in marked carry-over effects during the consecutive infusions. Second, during U, inhibition NE release also is likely to be inhibited by presynaptic a 2 -adrenergic receptors, 14 ' " because of the increased NE concentration in the synaptic cleft. This inhibition of uptake and, indirectly, of release cannot be estimated separately in the forearm circulation.…”

Section: Discussionmentioning

confidence: 99%

Demonstration of neuronal and extraneuronal uptake of circulating norepinephrine in the forearm.

Chang¹,

Krogt²,

Brummelen³

1987

Hypertension

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SUMMARY Disturbances in peripheral norepinephrine release or removal by neuronal and extraneuronal uptake may have pathogenetic significance in cardiovascular disease states. We investigated the mechanisms of removal of norepinephrine in the forearm of healthy subjects under basal conditions, using measurements of arterial and venous plasma norepinephrine concentrations, blood pressure, heart rate, and forearm blood flow. The specific inhibitor of neuronal uptake, desipramine, was infused intra-arterially into the brachial artery of five subjects. Net norepinephrine overflow from the forearm increased markedly, revealing considerable local release of norepinephrine. Six other subjects received four intra-arterial infusions of norepinephrine, 1.18 pmol/kg/min, with various doses of desipramine and the extraneuronal uptake-inhibiting drug hydrocortisone. The forearm extraction rate for circulating norepinephrine decreased with increasing doses of desipramine (from 69.4 ± 3.0 [SEM] to 35.3 ± 8.4%; p<0.001). Increasing doses of hydrocortisone during continued inhibition of neuronal uptake resulted in decreased forearm extraction of norepinephrine (from 63.3 ± 4.9 to 40.6 ± 4.4%; p< 0.01). In six other subjects who received the highest dose of hydrocortisone without concomitant inhibition of neuronal uptake, forearm extraction of norepinephrine decreased from 57.1 ± 4.9 to 51.5 ± 4.7% (p<0.05). These results suggest that neuronal uptake contributes markedly to the removal of circulating and endogendusly released norepinephrine in the forearm. For circulating norepinephrine, a corticosteroid-sensitive mechanism of extraneuronal uptake was also demonstrated. These results indicate that neuronal and extraneuronal uptake can be estimated separately in this vascular bed. Similar organ-specific studies in patients may reveal disturbances in mechanisms of norepinephrine removal. (Hypertension 9: 647-653, 1987) KEY WORDS * neuronal uptake • extraneuronal uptake * norepinephrine epinephrine * norepinephrine release * desipramine • hydrocortisone * forearm blood flow A VITAL link between sympathetic nerve activity and cardiovascular responses is the release . of the neurotransmitter norepinephrine (NE) from sympathetic nerve endings. After release by exocytosis from storage vesicles, NE activates both postsynaptic and presynaptic adrenergic receptors, which respectively mediate cardiovascular responses and exFrom the Departments of Nephrology

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The effects of neuronal uptake blockade on the cardiac responses to sympathetic nerve stimulation and norepinephrine infusion in anesthetized dogs

Cited by 16 publications

References 26 publications

Effects of 5-day hypoxia on cardiac adrenergic neurotransmission in rats

Effects of 5-day hypoxia on cardiac adrenergic neurotransmission in rats

In vivo measurement of neuronal uptake of norepinephrine in the human heart.

Demonstration of neuronal and extraneuronal uptake of circulating norepinephrine in the forearm.

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