Neuronal reuptake of norepinephrine and production of dihydroxyphenylglycol by cardiac sympathetic nerves in the anesthetized dog

BACKGROUND. Reuptake of norepinephrine by cardiac sympathetic nerves before and during two levels of electrical stimulation of the left ansa subclavia was estimated in anesthetized dogs from the cardiac production of dihydroxyphenylglycol (DHPG), the intraneuronal metabolite of norepinephrine. METHODS AND RESULTS. The method depended on the effects of neuronal uptake blockade with desipramine on the cardiac production of [3H]DHPG from intravenously infused [3H]norepinephrine. The ratio of the desipramine-induced decrease in the cardiac extraction of [3H]norepinephrine to the production of [3H]DHPG was used to transform the cardiac production of DHPG from recaptured norepinephrine into a rate for norepinephrine reuptake. Cardiac spillover of norepinephrine into plasma increased from 49 +/- 12 to 205 +/- 40 and 451 +/- 118 pmol/min during sympathetic activation. Cardiac DHPG production increased from 108 +/- 18 to 166 +/- 34 and 240 +/- 47 pmol/min. Desipramine decreased resting cardiac DHPG production by 20% and completely blocked the stimulation-induced increase. Thus, most (80%) cardiac DHPG produced at rest was derived from norepinephrine leaking from storage vesicles. This amount remained constant, and that derived from recaptured norepinephrine increased during sympathetic activation. The cardiac extraction of [3H]norepinephrine (126,000 dpm/min) and production of [3H]DHPG (3,790 dpm/min) were decreased by 55-57% after desipramine. Thus, only 3% of the norepinephrine recaptured by cardiac sympathetic nerves appeared in plasma as DHPG. The remainder was sequestered into storage vesicles (more than 94%) or ultimately formed metabolites other than DHPG (less than 3%). Reuptake of norepinephrine by cardiac sympathetic nerves was 1,188 +/- 476 pmol/min and increased in parallel with cardiac norepinephrine spillover to 4,182 +/- 1,982 and 6,594 +/- 2,241 pmol/min during sympathetic stimulation. CONCLUSIONS. Of the norepinephrine released by cardiac sympathetic nerves, 16-fold more was recaptured than entered plasma. Combined estimation of norepinephrine reuptake and spillover offers an approach to assess the efficiency of neuronal reuptake in disorders of cardiac function.     

Cardiac sympathetic denervation in Parkinson disease

BACKGROUND: In Parkinson disease, orthostatic hypotension can result from L-dopa treatment or from sympathetic neurocirculatory failure. The latter is detected by abnormal blood pressure responses to the Valsalva maneuver and can be associated with loss of functional cardiac sympathetic nerve terminals. OBJECTIVE: To determine the frequency of cardiac sympathetic denervation in Parkinson disease, with or without sympathetic neurocirculatory failure, and its association with disease duration, severity, and L-dopa treatment DESIGN: Intergroup comparisons in resting patients. SETTING: National Institutes of Health Clinical Center, Bethesda, Maryland. PATIENTS: 29 patients with Parkinson disease (9 with sympathetic neurocirculatory failure, 10 who had stopped receiving or had never been treated with L-dopa), 24 patients with multiple-system atrophy (17 with sympathetic neurocirculatory failure, 8 receiving L-dopa), 7 patients with pure autonomic failure, 33 controls with episodic or persistent orthostatic intolerance without sympathetic neurocirculatory failure, and 19 normal volunteers. MEASUREMENTS: Beat-to-beat blood pressure responses to the Valsalva maneuver, interventricular septal 6-[18F]fluorodopamine-derived radioactivity, cardiac extraction fraction of [3H]norepinephrine, appearance rate of norepinephrine in coronary sinus plasma (cardiac norepinephrine spillover) and venous-arterial differences in levels of dihydroxyphenylglycol (DHPG) and endogenous L-dopa. RESULTS: Of the 29 patients with Parkinson disease, 9 with sympathetic neurocirculatory failure and 11 without had low septal 6-[18F]fluorodopamine-derived radioactivity (2861 +/- 453 Bq/mL per MBq/kg and 5217 +/- 525 Bq/mL per MBq/kg, respectively). All 6 patients with Parkinson disease and decreased 6-[18F]fluorodopamine-derived radioactivity who underwent right-heart catheterization had a decreased cardiac extraction fraction of [3H]norepinephrine and virtually no cardiac norepinephrine spillover or venous-arterial increments in plasma levels of DHPG and L-dopa. Sympathetic neurocirculatory failure and decreased 6-[18F]fluorodopamine-derived radioactivity were unrelated to disease duration, disease severity, or L-dopa treatment CONCLUSIONS: Many patients with Parkinson disease-including all those with sympathetic neurocirculatory failure-have evidence of cardiac sympathetic denervation. This suggests that loss of catecholamine innervation in Parkinson disease occurs in the nigrostriatal system in the brain and in the sympathetic nervous system in the heart     

Altered norepinephrine turnover and metabolism in diabetic cardiomyopathy

Cardiac norepinephrine turnover and metabolism were examined in rats 8 weeks after the induction of chronic diabetes by an intravenous injection of streptozotocin (65 mg/kg). Cardiac norepinephrine concentration, norepinephrine turnover, and norepinephrine uptake were markedly increased in chronic diabetes in comparison with control values; these changes were reversible by 28-day insulin therapy. When the animals were exposed to cold for 6 hours, norepinephrine turnover rate constant increased in control and decreased in diabetic animals; cold exposure also increased norepinephrine concentration in diabetic hearts. Both cardiac norepinephrine concentration and turnover rate in diabetic rats were restored toward control values by ganglionic blockade with pentolinium. The conversion of [3H]tyrosine to [3H]catecholamine was enhanced and tyrosine hydroxylase as well as dopa decarboxylase activities were increased in diabetic hearts. The higher concentrations of [3H]normetanephrine and deaminated catechols indicated a faster metabolic rate of norepinephrine metabolism in hearts from diabetic rats; both monoamine oxidase and catechol-O-methyltransferase activities were also increased. The increased activities of the enzymes for the synthesis and metabolism of norepinephrine were not evident on treating the diabetic animals with insulin. These data not only support the view that chronic diabetes in rats is associated with increased sympathetic activity but also indicate that the cardiac norepinephrine concentration in diabetic rats may be maintained at a higher than normal level by an increased synthesis and uptake of norepinephrine in the adrenergic nerve terminals.     

Differences in the neuronal removal of circulating epinephrine and norepinephrine

Neuronal uptake is an important mechanism for the removal of norepinephrine, but its contribution to the removal of epinephrine is unknown. This study compared the neuronal removal of circulating epinephrine and norepinephrine by examination of the cardiac extractions or plasma clearances of [3H]norepinephrine and endogenous or 3H-labeled epinephrine in healthy subjects, patients with cardiovascular disorders, and subjects administered desipramine to block neuronal uptake. In rabbits the plasma clearances of [3H]epinephrine and [3H] norepinephrine by neuronal uptake and the formation of dihydroxyphenylglycol (DHPG) from simultaneously infused [3H] norepinephrine and epinephrine were compared. In normal patients 51 +/- 3% of plasma epinephrine was extracted during one pass through the coronary circulation, significantly less than the cardiac extraction of [3H]norepinephrine (78 +/- 1%). In patients with cardiovascular disorders extractions of epinephrine (34 +/- 3%) remained lower than those of [3H]norepinephrine (63 +/- 2%). After desipramine, cardiac extraction of epinephrine was reduced to 12 +/- 2% and [3H]norepinephrine to 20 +/- 3%. In subjects infused simultaneously with [3H]epinephrine and [3H] norepinephrine, desipramine reduced the cardiac extraction of [3H]epinephrine by 28 +/- 6%, significantly less than the 49 +/- 7% reduction in [3H]epinephrine extraction; the plasma clearance of [3H]epinephrine was reduced by 4 +/- 5%, significantly less than the 20 +/- 6% reduction in [3H]norepinephrine clearance. In rabbits desipramine reduced the plasma clearance of [3H] epinephrine by 18%, significantly less than the 42% reduction in [3H]norepinephrine clearance; production of DHPG from epinephrine was less than half the production of [3H]DHPG from [3H]norepinephrine. The above differences indicated that epinephrine was removed 44-64% less avidly than norepinephrine by uptake into and metabolism within sympathetic neurons.     

Regional sympathetic effects of low-dose clonidine in heart failure

This study examined the effects of low doses of intravenous clonidine on regional and global sympathetic nervous system activity in heart failure. In heart failure, adrenoceptor-blocking treatments have a limited sphere of activity. Centrally acting sympatholytic therapies should be further investigated, with a specific emphasis on targeting cardiac and renal sympathetic overactivity. In 10 patients with moderate-severe congestive heart failure, we examined the effect of intravenous clonidine on systemic, cardiac, and renal sympathetic activity and on brain monoamine turnover using the norepinephrine spillover method. In addition, we assessed the effect of clonidine on cardiac release of the sympathetic cotransmitter neuropeptide Y. A dose of 1 microg/kg of clonidine resulted in a fall in cardiac (326+/-73 to 160+/-40 pmol/min, P<0.001), renal (2.5+/-0.6 to 1.5+/-0.3 nmol/min, P=0.01), and global norepinephrine spillover (4.0+/-0.6 to 3.1+/-0.5 nmol/min, P<0.01), with a significantly disproportionate reduction in cardiac versus total-body sympathetic activity (P<0.05). No significant changes in cardiac neuropeptide Y release or in central monoamine turnover were demonstrated. Clonidine, at modest doses, significantly attenuates cardiac and renal sympathetic tone in heart failure. In addition to the beneficial effects of antiadrenergic therapy in the heart, the renal sympatholytic effect may counter the salt and water retention that is a hallmark of the condition.     

Sympathetic augmentation in hypertension: role of nerve firing, norepinephrine reuptake, and Angiotensin neuromodulation

There is growing evidence that essential hypertension is commonly neurogenic and is initiated and sustained by sympathetic nervous system overactivity. Potential mechanisms include increased central sympathetic outflow, altered norepinephrine (NE) neuronal reuptake, diminished arterial baroreflex dampening of sympathetic nerve traffic, and sympathetic neuromodulation by angiotensin II. To address this issue, we used microneurography and radiotracer dilution methodology to measure regional sympathetic activity in 22 hypertensive patients and 11 normotensive control subjects. The NE transport inhibitor desipramine was infused to directly assess the potential role of impaired neuronal NE reuptake. To evaluate possible angiotensin sympathetic neuromodulation, the relation of arterial and coronary sinus plasma concentrations of angiotensin II to sympathetic activity was investigated. Hypertensive patients displayed increased muscle sympathetic nerve activity and elevated total systemic, cardiac, and renal NE spillover. Cardiac neuronal NE reuptake was decreased in hypertensive subjects. In response to desipramine, both the reduction of fractional transcardiac 3[H]NE extraction and the increase in cardiac NE spillover were less pronounced in hypertensive patients. DNA sequencing analysis of the NE transporter gene revealed no mutations that could account for reduced transporter activity. Arterial baroreflex control of sympathetic nerve traffic was not diminished in hypertensive subjects. Angiotensin II plasma concentrations were similar in both groups and were not related to indexes of sympathetic activation. Increased rates of sympathetic nerve firing and reduced neuronal NE reuptake both contribute to sympathetic activation in hypertension, whereas a role for dampened arterial baroreflex restraint on sympathetic nerve traffic and a peripheral neuromodulating influence of angiotensin II appear to be excluded.     

Increased cardiac sympathetic drive in renovascular hypertension

BACKGROUND : Patients with renovascular hypertension (RVH) have high cardiovascular mortality and morbidity. In these patients, overall sympathetic nerve activity is increased. It is unknown, however, whether this increase also involves the heart. OBJECTIVE : We tested the hypothesis that cardiac sympathetic activity is increased in patients with hypertension and renal artery stenosis. METHODS AND RESULTS : A total of 14 patients with hypertension were studied before angioplasty of angiographically identified renal artery stenosis. Nine out of 14 patients had renovascular hypertension proven at the 1-year follow-up visit. A total of 19 healthy subjects served as a control group. A right heart catheterization, including the positioning of a coronary sinus thermodilution catheter was performed for hemodynamic recordings and blood sampling. Using a radiotracer dilution technique with infusion of tritiated noradrenaline ([3H]NA) and adrenaline ([3H]A), fractional extraction and clearance were calculated. Total body and cardiac NA spillovers were used as indices of systemic and cardiac sympathetic nervous activity. The study group had normal left ventricular ejection fraction and cardiac pressures. Cardiac NA spillover was increased by 127% in the hypertensive patients compared with healthy subjects (200 +/- 53 versus 88 +/- 10 pmol/min in controls, P < 0.05). Total body NA spillover was similar in both groups. Cardiac fractional extraction of [3H]NA and [3H]A was decreased by 26 and 47%, respectively, compared with normotensive subjects (P < 0.01 for both). CONCLUSIONS : Patients with renovascular hypertension have altered cardiac sympathetic function with increased sympathetic drive and impaired catecholamine extraction. The increased cardiac sympathetic drive may have adverse long-term effects on prognosis in this patient group with high cardiovascular mortality.     

Preserved norepinephrine reuptake but reduced sympathetic nerve endings in hypertrophic volume-overloaded rat hearts

BackgroundIn congestive heart failure (CHF), an activation of the cardiac sympathetic nervous system results in depleted cardiac norepinephrine (NE) stores. The underlying regulatory mechanisms are discussed controversially and were investigated in the present study in CHF resulting from volume overload.Methods and ResultsAorto-caval shunt (AVS) was performed in rats. Plasma NE levels were determined by radioenzymatic assay, left ventricular NE by high-performance liquid chromatography, endothelin-1 by enzyme-linked immunosorbent assay. Tyrosine-hydroxylase (TH)– and nerve growth factor (NGF)–mRNA was determined by Northern blot analysis and ribonuclease-assay. Cardiac [³H]-NE uptake was measured in isolated perfused hearts. Glyoxylic acid–induced histofluorescence was used to quantify cardiac sympathetic nerves. Compared with sham-operated animals (SH), AVS rats were characterized by depleted cardiac NE stores and enhanced NE plasma levels. Neither TH-mRNA levels in stellate ganglia, nor cardiac [³H]-NE-uptake were reduced in AVS. The left ventricular density of sympathetic nerves was markedly decreased. Gene expression of myocardial NGF (a positive regulator of NE reuptake and cardiac sympathetic nerve density) and left ventricular endothelin-1 (a negative regulator of NE reuptake and positive regulator of cardiac NGF expression) were unchanged.ConclusionIn volume-overloaded hypertrophic hearts, depletion of cardiac NE stores is caused by a reduction of the sympathetic nerve density, whereas cardiac NE reuptake is preserved.     

Injection of nerve growth factor into stellate ganglia improves norepinephrine reuptake into failing hearts

An impairment of cardiac norepinephrine reuptake through the neuronal norepinephrine transporter promotes depletion of cardiac norepinephrine stores and local cardiac sympathetic activation in heart failure. Nerve growth factor regulates differentiation and survival of adult sympathetic cells and is decreased in failing hearts. We hypothesized that injection of nerve growth factor into stellate ganglia normalizes cardiac norepinephrine homeostasis in experimental heart failure. Rats with transverse aortic constriction characterized by heart failure, depleted cardiac norepinephrine stores, and impaired cardiac norepinephrine reuptake were used as an experimental model. Nerve growth factor (20 microg) or saline was directly injected into left stellate ganglia 4 weeks after transverse aortic constriction. Thirty-two hours after injection, determinants of cardiac norepinephrine homeostasis were measured. As compared with saline, nerve growth factor refilled depleted cardiac norepinephrine stores and improved cardiac [3H]-norepinephrine uptake into isolated perfused hearts of transverse aortic constricted rats. In addition, pharmacological blockade of the norepinephrine transporter led to a higher increase in the overflow of endogenous norepinephrine from hearts of nerve growth factor-injected than saline-injected transverse aortic constricted rats. Norepinephrine transporter mRNA levels and the density of cardiac sympathetic nerves were not changed. Thirty-two hours after nerve growth factor injection, echocardiography revealed an increase in fractional shortening as compared with 2 days before injection. In conclusion, nerve growth factor attenuates local cardiac sympathetic overdrive of hypertrophic hearts by improving cardiac norepinephrine reuptake and might represent a novel therapeutic principle in the treatment of heart failure.     

Cardiac and pulmonary norepinephrine release and removal in the dog

Norepinephrine extraction and spillover rates were determined in the heart and lungs of anesthetized dogs under resting conditions, during sympathetic stimulation, and during epicardial pacing. The fractional extraction of norepinephrine across the coronary and pulmonary vascular beds was measured from the venoarterial difference in tritiated norepinephrine after infusion of a tracer dose to a steady state level. Cardiac extraction averaged 0.299 +/- 0.03 and pulmonary extraction averaged 0.215 +/- 0.014; extraction was unaffected by sympathetic stimulation or pacing. Norepinephrine spillover from sympathetic nerve terminals in the heart and lungs was measured from the venoarterial difference in endogenous norepinephrine and plasma flow after correction for the extraction component. Cardiac norepinephrine spillover increased linearly with increasing frequency of sympathetic stimulation to 7.44 times resting levels at 2 Hz. During pacing, there was no change in cardiac norepinephrine spillover despite marked changes in heart rate. Norepinephrine spillover was demonstrated under resting conditions in the lung and was greater than observed in the heart. Pulmonary norepinephrine spillover increased with sympathetic stimulation to 4.15 times resting levels at 2 Hz. It is possible to separate the contributions of norepinephrine extraction and spillover to measured venoarterial differences of norepinephrine under physiological conditions in the dog.     

Evidence for increased renal norepinephrine overflow during sodium restriction in humans

To investigate the differentiated pattern of efferent sympathetic nerve activity by means of analyzing norepinephrine kinetics in response to sodium restriction, cardiorenal sympathetic activity during rest and mental stress was studied in 12 subjects (33.3 +/- 2.6 years old, SEM) exposed to a low and a normal sodium diet; 5-40 mmol and 160-200 mmol/24 hours, respectively (crossover design). Organ norepinephrine release was calculated from organ plasma flow, arteriovenous plasma concentration gradient across the organ and the organ's fractional extraction of radiolabeled norepinephrine. Body weight and urinary sodium/24 hr fell significantly and urinary potassium/24 hr and both supine and standing blood pressure remained unchanged. Total norepinephrine release to plasma and norepinephrine plasma clearance were similar in both phases (approximately 460 ng/min and 1.90 l/min, respectively). A 138% increase in renal norepinephrine overflow was observed during sodium restriction (from 112 to 267 ng/min, p less than 0.025), which was due to elevated renal vein norepinephrine (434 versus 290 pg/ml, p less than 0.01) because renal plasma flow and renal norepinephrine extraction were unaltered. Similarly, sodium restriction caused a 168% elevation of renal renin secretion (p less than 0.05). Resting cardiac norepinephrine spillover and cardiac norepinephrine reuptake were unchanged between the two salt phases. Total and cardiac norepinephrine release, supine blood pressure, and heart rate increased to about the same extent in response to mental testing regardless of salt phase. In conclusion, sodium restriction induced a differential and physiological increase in resting renal sympathetic nervous activity, leaving cardiac norepinephrine overflow unchanged. Cardiac norepinephrine uptake was normal, which further supports the concept of a true increase of efferent renal nerve activity.     

Spironolactone preserves cardiac norepinephrine reuptake in salt-sensitive Dahl rats

An impairment of cardiac norepinephrine (NE) reuptake via the neuronal NE transporter (NET) enhances the effects of increased cardiac NE release in heart failure patients. Increasing evidence suggests that aldosterone and endothelins promote sympathetic overstimulation of failing hearts. Salt-sensitive Dahl rats (DS) fed a high-salt diet developed arterial hypertension and diastolic heart failure as well as elevated plasma levels of endothelin-1 and NE. Cardiac NE reuptake and NET-binding sites, as assessed by clearance of bolus-injected [(3)H]NE in isolated perfused rat hearts and [(3)H]mazindol binding, were reduced. Treatment of DS with the mineralocorticoid receptor antagonist spironolactone preserved the plasma levels of endothelin-1 and NE, cardiac NE reuptake, and myocardial NET density. Moreover, the ventricular function and survival of spironolactone-treated DS were significantly improved compared with untreated DS. The alpha(1)-inhibitor prazosin decreased blood pressure in DS similar to spironolactone treatment, but did not normalize the plasma levels of endothelin-1 and NE, NE reuptake, or ventricular function. In a heart failure-independent model, Wistar rats that were infused with aldosterone and fed a high-salt diet developed impaired cardiac NE reuptake. Treatment of these rats with the endothelin A receptor antagonist darusentan attenuated the impairment of NE reuptake. In conclusion, spironolactone preserves NET-dependent cardiac NE reuptake in salt-dependent heart failure. Evidence is provided that aldosterone inhibits NET function through an interaction with the endothelin system. Selective antagonism of the mineralocorticoid and/or the endothelin A receptor might represent therapeutic principles to prevent cardiac sympathetic overactivity in salt-dependent heart failure.     

Central Nervous System Noradrenergic Control of Sympathetic Outflow in Normotensive and Hypertensive Humans

We applied transmitter washout methodology, sampling internal jugular venous plasma via a percutaneously placed catheter, to study CNS norepinephrine release in humans and its relation to peripheral sympathetic activity. Norepinephrine overflows into the venous drainage of the brain, as do its precursor, DOPA, and metabolites DHPG and MHPG, indicating that the blood-brain barrier provides an incomplete impediment to their outward flux from the brain. Pharmacological testing with two drugs which alterred CNS norepinephrine turnover, the tricyclic antidepressant desipramine and the ganglionic blocker, a-imethaphan, demonstrated a direct relation existed between CNS norepinephrine release and sympathetic nerve firing rates. In essential hypertension, the sympathetic activation commonly present was associated with, and possibly caused by increased CNS release of norepinephrine, manifested in elevated overflow of norepinephrine, MHPG and DHPG from the brain. Bilateral jugular sampling, coupled with a cerebral venous sinus scan to delineate the drainage pattern, demonstrated that this increased norepinephrine release was confined to subcortical forebrain regions.     

Differential Effect of Acute Baroreceptor Unloading on Cardiac and Systemic Sympathetic Tone in Congestive Heart Failure

Objectives. The present study was designed to identify the hemodynamic factor or factors that reflexly contribute to activation of the cardiac sympathetic nerves in patients with severe congestive heart failure (CHF).Background. We and others have previously shown that activation of the sympathetic nervous system is a key feature of CHF in humans. Furthermore, the degree of sympathetic activation shows marked regional heterogeneity and is most pronounced in the heart. Recent studies have shown a significant positive relation between pulmonary artery pressure and the magnitude of cardiac sympathetic activation. Of particular importance, the degree of cardiac sympathoexcitation has also been shown to be strongly associated with mortality in CHF.Methods. We assessed total systemic and cardiac sympathetic activity (norepinephrine [NE] spillover method) in nine patients with severe CHF and significantly elevated pulmonary artery pressure (mean [±SEM] pulmonary artery pressure 46 ± 3 mm Hg) at rest and during a titrated infusion of sodium nitroprusside (SNP).Results. SNP infusion significantly reduced mean arterial blood pressure, pulmonary artery pressure and pulmonary capillary wedge pressure. During SNP infusion, the total body NE spillover rate (NESR) increased (from 7.9 ± 1.7 to 11.2 ± 3.1 nmol/min, p < 0.01), whereas the cardiac NESR decreased (from 522 ± 86 to 409 ± 71 pmol/min, p < 0.05). The ratio of cardiac/total NE spillover was also substantially reduced (from 7.8 ± 1.3 to 4.9 ± 0.9%, p < 0.001).Conclusions. There is a directionally opposite change in whole-body (increase) and cardiac (reduction) sympathetic nervous activity during SNP infusion, most likely due to unloading of arterial baroreceptors and specific cardiopulmonary baroreceptors, respectively, in severe CHF. These observations support the concept of a positive feedback relation between pulmonary artery pressure/filling pressure and cardiac sympathetic tone in CHF and serve to reinforce the importance of vasodilator therapy in this condition.     

Oxygen consumption in the heart, hepatomesenteric bed, and brain in young and elderly human subjects, and accompanying sympathetic nervous activity

Although the reduction in whole-body energy expenditure with aging has been well documented, there is little information about the changes that individual organs undergo. We therefore measured oxygen consumption in the heart, hepatomesenteric bed, and brain in elderly subjects and young controls, using central venous catheter techniques and the application of Fick's principle. We also measured whole-body, cardiac, and hepatomesenteric sympathetic nervous activity using isotope dilution methodology. Cardiac, hepatomesenteric, and cerebral oxygen consumption was similar in both groups. Whole-body and hepatomesenteric sympathetic nervous activity was also similar in the study groups, whereas cardiac norepinephrine (NE) spillover was significantly higher in the elderly. In contrast to the young, cardiac sympathetic nervous activity as assessed from NE spillover was not related to either cardiac oxygen consumption or cardiac work in the elderly. The data suggest that although oxygen consumption in the heart, hepatomesenteric bed, and brain are not different between young and elderly individuals, the relationship between sympathetic nervous activity and oxygen consumption in individual organs may alter with aging.     

Selective enhancement of the cardiac sympathetic response to exercise by anginal chest pain in humans

Cardiac and whole body [3H]norepinephrine kinetics were used to evaluate the response of overall and cardiac sympathetic activity to supine bicycle exercise in 31 patients with coronary artery disease (CAD) and in nine normal control subjects (group 1). Of the 31 patients with CAD, 20 developed evidence of myocardial ischemia during exercise (group 2), typical angina occurring in 20 of 20 and ischemic ST segment changes in 13 of 20, whereas 11 patients developed no evidence of ischemia (no chest pain or electrocardiographic changes) (group 3). Exercise resulted in increased total and cardiac NE spillover in all groups of patients. Basal cardiac NE spillover was similar in the three groups (group 1, 5 +/- 1 ng/min; group 2, 8 +/- 1 ng/min; group 3, 7 +/- 2 ng/min; p = NS), but during exercise, cardiac NE spillover was greater in patients who developed angina (group 2, 30 +/- 5 ng/min) than in those who did not (group 1, 17 +/- 2 ng/min; group 3, 17 +/- 2 ng/min; p less than 0.05). The increases in total NE spillover were similar in the three groups. Supine bicycle exercise increases cardiac and overall sympathetic tone in normal control subjects and in patients with CAD. The occurrence of angina selectively enhances the cardiac sympathetic response to exercise. In the absence of angina, patients with CAD and control subjects without CAD have similar sympathetic responses to exercise.     

Cardiac sympathetic innervation in patients with idiopathic right ventricular outflow tract tachycardia

Objectives. This study investigated the neuronal reuptake of norepinephrine (uptake-1) and the beta-adrenoceptor density in patients with idiopathic right ventricular outflow tract tachycardia (RVO-VT).Background. Clinical findings, such as the inducibility of ventricular tachycardia by stress or catecholamine infusion, and the therapeutic efficacy of antiarrhythmic drugs with antiadrenergic properties suggest abnormalities of cardiac sympathetic innervation in patients with idiopathic RVO-VT.Methods. Eight patients with idiopathic RVO-VT and a total of 29 age-matched control subjects were investigated by positron emission tomography using [¹¹C]hydroxyephedrine (HED) (volume of distribution of [¹¹C]HED) to assess presynaptic norepinephrine reuptake; [¹¹C]CGP 12177 (maximal binding capacity of [¹¹C]CGP 12177) to measure postsynaptic beta-adrenoceptor density; and oxygen-15–labeled water for quantification of myocardial blood flow (MBF).Results. Both myocardial catecholamine reuptake and beta-adrenoceptor density were significantly reduced in patients with idiopathic RVO-VT. The volume of distribution of [¹¹C]HED in patients with RVO-VT was (mean ± SD) 41.0 ± 13.5 versus 71.0 ± 18.8 ml/g in control subjects (p < 0.002). The maximal binding capacity of the beta-adrenoceptor antagonist [¹¹C]CGP 12177 was 6.8 ± 1.2 pmol/g in patients with RVO-VT versus 10.2 ± 2.9 pmol/g in control subjects (p < 0.004). There were no significant differences in MBF at rest (0.98 ± 0.14 vs. 0.97 ± 0.24 ml/min per g, p = NS) between patients with RVO-VT and control subjects.Conclusions. The findings of the present study suggest that myocardial beta-adrenoceptor downregulation in patients with RVO-VT occurs subsequently to increased local synaptic catecholamine levels caused by impaired catecholamine reuptake.     

Regional norepinephrine spillover in response to angiotensin-converting enzyme inhibition in healthy subjects

OBJECTIVES: Even though most previous studies have shown that central nervous angiotensin II causes sympatho-excitation, there are data suggesting that blockade of the renin-angiotensin system (RAS) could activate the renal sympathetic nerves. The aim of the present study was to investigate overall, cardiac and renal sympathetic nerve activity, before and after intravenous enalaprilat, in healthy normotensive subjects without an activated RAS. METHODS: Thirty healthy subjects underwent catheterization of the radial artery, right renal and coronary sinus veins with blood sampling at baseline and 30-40 min after 1.25 or 2.5 mg of intravenous enalaprilat, respectively. Regional and overall sympathetic nervous activity was estimated using isotope dilution, calculating spillovers of norepinephrine. RESULTS: Mean arterial blood pressure decreased by 5% (P < 0.05) after the higher dose and remained unchanged after the lower dose of enalaprilat, whereas renal norepinephrine spillover increased after both doses by 49 and 26% respectively (P < 0.05 for both). Cardiac and total body norepinephrine spillover remained unchanged after both doses of enalaprilat. Pulmonary capillary wedge pressure, which was measured in eight subjects after 2.5 mg enalaprilat, fell by 43% (P < 0.05).CONCLUSIONS: In the absence of, or after a minor, blood pressure fall, intravenous enalaprilat selectively activates the renal nerves in healthy subjects without an activated RAS. Unloading of the low-pressure baroreceptor system and/or a central nervous effect of enalaprilat may be responsible for this differentiated sympathetic nervous response.     

Cardiac uptake-1 inhibition by high circulating norepinephrine levels in patients with pheochromocytoma

Neuronal reuptake (uptake-1) constitutes the main route of inactivation of the sympathetic neurotransmitter norepinephrine in the heart and therefore contributes importantly to cardiac sympathetic neuroeffector function. In laboratory animals and in vitro preparations, half saturation of the transporter occurs at norepinephrine concentrations of 0.1 to 1 micromol/L. This study addressed whether endogenous norepinephrine can attain high enough plasma concentrations in humans to inhibit cardiac uptake-1. Patients with increased plasma norepinephrine levels due to pheochromocytoma were assessed by 6-[18F]fluorodopamine positron emission tomography. Above an antecubital venous plasma concentration of 3 nmol/L (approximately 500 pg/mL), left ventricular myocardial 6-[18F]fluorodopamine-derived radioactivity varied inversely with the logarithm of the plasma norepinephrine concentration (r=-0.77, P<0.0001). Reduction of plasma norepinephrine levels by treatment of the pheochromocytoma increased myocardial 6-[18F]fluorodopamine-derived radioactivity. At sufficiently high plasma concentrations, endogenous norepinephrine can compete with sympathetic imaging agents for uptake-1. The results call for caution in drawing quantitative conclusions about uptake-1 in the setting of high circulating concentrations of endogenous norepinephrine.     

Differential expression of cardiac neurotrophic factors and sympathetic nerve ending abnormalities within the failing heart

In congestive heart failure (CHF), cardiac sympathetic nerve endings transdifferentiate from a balanced norepinephrine (NE) storage/release/uptake apparatus to a nerve that predominantly releases NE. Little is known about the neurotrophic factors that may trigger this process. In the present study, we evaluated the cardiac expression pattern of nerve growth factor (NGF), neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) in salt-sensitive Dahl rats (DS), which are characterized by profound alterations of the cardiac sympathetic nervous system. Experiments were performed in male DS and salt-resistant Dahl rats (DR) 30, 40 and 50 days after onset of high-salt intake. The sympathetic nerve density was measured by glyoxylic acid-induced histofluorescence. Cardiac NE re-uptake was assessed by isolated heart perfusion with [³H]-NE and norepinephrine transporter (NET) mRNA by real-time PCR. Cardiac expression of neurotrophic factors was determined by ribonuclease protection assay and Western blot analysis. DS rats displayed reduced left ventricular sympathetic nerve endings 40 days after onset of high-salt intake, which was preceded by an impaired cardiac [³H]-NE uptake. NGF, a positive regulator of NE re-uptake, and NT-3 were down-regulated already 30 days after onset of high-salt intake, whereas BDNF and CNTF protein expression were increased not before 40 days after onset of high-salt intake. In conclusion, during the development of CHF, a dysregulated NE storage/release/uptake apparatus within the sympathetic nerve endings might be triggered by differential expression of cardiac neurotrophic factors.