Synthesis, Binding, Release, and Metabolism of Norepinephrine in Normal and Transplanted Dog Hearts

Potter, Lincoln T.; Cooper, Theodore; Willman, Vallee L.; Wolfe, David

doi:10.1161/01.res.16.5.468

Cited by 87 publications

(24 citation statements)

References 27 publications

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“…3H-OM metabolites were increased in the 6-OH-DA group using a low perfusion concentration of either 3H-DA or 3H-NA. Similarly, an increase in 0-methylation was observed under conditions in which the uptake of NA into the sympathetic nerves was inhibited by cocaine (Eisenfeld et al, 1967), by immunosympathectomy (Iversen et al, 1966) or by surgical denervation (Potter et al, 1965). At a high perfusion concentration of 3H-DA or 3H-NA there was no difference in the 0-methylated metabolites between controls and the 6-OH-DA group, although the relative proportion of 0-methylation was increased in the latter group.…”

Section: Discussionmentioning

confidence: 91%

Effect of pretreatment with 6‐hydroxydopamine on the uptake and metabolism of catecholamines by the isolated perfused rat heart

Hellmann

Hertting

Peskar

1971

British J Pharmacology

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Summary1. Isolated rat hearts from control and 6-hydroxydopamine pretreated animals -were perfused with 3H-noradrenaline or 3H-dopamine, either at a low perfusion concentration (150 x 10-10 mol/ml 3H-dopamine; 1.18 x 10-10 mol/ml 3H-noradrenaline) or a high perfusion concentration (296-69 x 10-10 mol/ml 31H-noradrenaline, 327 45 x 10-10 mol/ml 3H-dopamine) for 8 minutes.2. At the low perfusion concentration, the total activity, the radioactivity in the alumina eluates (sum of 3H-dopamine, 3H-noradrenaline and deaminated catechol metabolites) and the concentration of 3H-dopamine, 3H-noradrenaline and the deaminated catechol metabolites were decreased in the hearts of the pretreated rats as compared with the controls. The 0-methylated amine metabolites were increased. The deaminated 0-methylated metabolites were increased in the experiments with 3H-noradrenaline and decreased in the 3H-dopamine experiments. 3. Uptake of 3H-dopamine and 3H-noradrenaline by the hearts of 6-hydroxydopamine pretreated rats was decreased to a much smaller extent when perfused with the high concentration than with the low concentration. 4. At the high perfusion concentration there was a significant difference between control and pretreated animals with regard to the total radioactivity and the radioactivity in the alumina eluates only. The absolute and relative amounts of metabolites were not significantly changed by pretreatment with the exception of the deaminated catechol metabolites in the 3H-dopamine experiments. 5. It is concluded that neuronal Uptake 1 is greatly impaired in the hearts from rats pretreated with 6-hydroxydopamine, but extraneuronal Uptake 2 remains intact.

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Section: Discussionmentioning

confidence: 91%

Effect of pretreatment with 6‐hydroxydopamine on the uptake and metabolism of catecholamines by the isolated perfused rat heart

Hellmann

Hertting

Peskar

1971

British J Pharmacology

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“…Thus, catecholamine metabolism in transplanted human hearts may differ in some quantitative or qualitative aspects from the described animal models. [1][2][3] Reinnervation occurs frequently in canine hearts but has not been documented in human hearts. 9 The presence of all three myocardial catecholamines in unusual concentrations in some of the transplanted hearts may be explained by the storage of catecholamines in the remaining nervous structures, in postganglionic parasympathetic nerves, or by binding or storage of plasma catecholamines in nonneural structures.2'9 Finally, ingrowth of nerve endings together with blood vessels from the surgically manipulated pericardium cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

Myocardial catecholamine content after heart transplantation.

et al. 1990

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Myocardial catecholamine levels have not yet been determined in the transplanted human heart. We measured norepinephrine, epinephrine, and dopamine in endomyocardial biopsies from 19 short-term (organ age, 6.6±+6 months) and five long-term (organ age, 62±2 months) heart transplant patients. Results were compared with those from 10 normal control subjects. In 17 of 19 short-term heart transplant patients, myocardial catecholamines were undetectable, indicating values below 0.1 pg/,ug noncollagen protein, which was the detection threshold of our assay. In the remaining two patients, myocardial catecholamines (pg/pg noncollagen protein)were norepinephrine (1.4 and 3.2), epinephrine (0.8 and 1.9), and dopamine (0.9 and 2.3), respectively. In the five long-term heart transplant patients, myocardial catecholamines were not detected. Catecholamine concentrations in 10 healthy control subjects were norepinephrine (10.3 +2.9), epinephrine (0.36 ±0.51), and dopamine (0.52 ±0.40). Low myocardial norepinephrine levels (<20% of control values) with unexplained high levels of epinephrine and dopamine were found in single transplant patients. In most heart transplant patients, however, myocardial catecholamines were undetectable up to five years after transplantation, indicating that the adrenergic response of these hearts probably depends on variations in plasma catecholamines or cardiac 3-receptor density. (Circulation 1990;82:620-623) M cyocardial norepinephrine and epinephrine are depleted in all portions of short-term autotransplanted canine hearts.12 In longterm autotransplanted canine hearts about 50% of control norepinephrine and epinephrine are found.1'2 Dopamine content, however, is only modestly decreased in short-and long-term autotransplanted canine hearts.23 Corresponding data for the transplanted human heart do not yet exist. Therefore, we measured the myocardial norepinephrine, epinephrine, and dopamine content in endomyocardial biopsies of patients that had undergone heart transplantation less than 18 months or more than 5 years ago. The concentrations measured were compared with those in 10 healthy control hearts. Methods PatientsEndomyocardial biopsies were obtained from the right ventricular septum in 19 patients 1-18 months From the German

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“…Such neuronally independent uptake of systemically administered norepinephrine has been demonstrated in the denervated, transplanted canine heart. 13 Therefore, the measurable myocardial norepinephrine levels present in 8% of Regitz et al's subjects offer only equivocal evidence of reinnervation. In contrast, the absence of measurable norepinephrine in 22 of 24 tissue samples measured by Regitz et al' appear to be good evidence for a lack of routine reinnervation in the transplanted human heart.…”

Section: See P 620mentioning

confidence: 96%

The surgically denervated, transplanted human heart.

Bristow

1990

Circulation

122

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In this issue of Circulation, Regitz et all provide evidence that the transplanted human heart remains denervated for as long as 5 years after transplantation. These authors measured myocardial catecholamines in right ventricular septal endomyocardial biopsies taken from 24 orthotopically transplanted hearts and found measurable norepinephrine levels in only two samples, both of which were from subjects who had had their transplant within 18 months. High-performance liquid chromatography assay with electrochemical detection was used and was sufficiently sensitive to detect levels of norepinephrine as low as 20 ng/g/wet wt tissue, which is 1-2% of the norepinephrine content of innervated, nonfailing human heart.1,2 The data confirm an earlier ultrastructural analysis that found a marked and sustained reduction in nerve density in transplanted human hearts that were examined 1-12 years after surgery.3 The findings are also consistent with several investigations4-6 that have demonstrated denervation physiology and pharmacology in the transplanted human heart. See p 620The observations of Regitz et all are important because of the issue of whether reinnervation can occur in the transplanted human heart. This question arises in part because of data from models of surgical denervation that have demonstrated functional autonomical reinnervation in the majority of animals examined 3-6 months after autotransplantation or allotransplantation.78 In addition, reports9 and anecdotes of the reestablishment of sensory innervation in cardiac transplant recipients continue to appear in the form of angina pectoris in subjects with documented graft atherosclerosis. Moreover, recent work measuring "myocardial production" of norepinephrine in response to tyramine provocationl' suggests that cardiac release of norepinephrine can occur in subjects more than 1 year after transplanThe opinions expressed in this editorial comment are not

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Synthesis, Binding, Release, and Metabolism of Norepinephrine in Normal and Transplanted Dog Hearts

Cited by 87 publications

References 27 publications

Effect of pretreatment with 6‐hydroxydopamine on the uptake and metabolism of catecholamines by the isolated perfused rat heart

Effect of pretreatment with 6‐hydroxydopamine on the uptake and metabolism of catecholamines by the isolated perfused rat heart

Myocardial catecholamine content after heart transplantation.

The surgically denervated, transplanted human heart.

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