Arterial Norepinephrine Levels Research Articles

Neuroadrenergic Dysfunction Along the Diabetes Continuum

Neuroadrenergic function in type 2 diabetic (T2D) patients without neuropathy is poorly characterized. We therefore compared sympathetic nervous system activity at rest and during an oral glucose tolerance test in obese metabolic syndrome (MetS) subjects classified as glucose intolerant (impaired glucose tolerance [IGT]; n = 17) or treatment-naive T2D (n = 17). Untreated subjects, matched for age (mean 59 ± 1 year), sex, BMI (32.4 ± 0.6 kg/m2), and family history of diabetes were studied. We measured resting muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine kinetics by isotope dilution, insulin sensitivity by euglycemic-hyperinsulinemic clamp (steady-state glucose utilization adjusted for fat-free mass and steady-state insulin concentration [M/I]), and MetS components. T2D subjects had higher resting MSNA burst incidence (67 ± 4 versus 55 ± 3 bursts per 100 heartbeats; P = 0.05) and arterial norepinephrine levels (264 ± 33 versus 167 ± 16 pg/mL; P = 0.02), lower plasma norepinephrine clearance (by 17%; P = 0.03), and reduced neuronal reuptake compared with IGT subjects (by 46%; P = 0.04). Moreover, norepinephrine spillover responses to glucose ingestion were blunted in T2D subjects. The M/I value independently predicted whole-body norepinephrine spillover (r = −0.47; P = 0.008), whereas fasting insulin level related to neuronal norepinephrine reuptake (r = −0.35, P = 0.047). These findings demonstrate that progression to T2D is associated with increased central sympathetic drive, blunted sympathetic responsiveness, and altered norepinephrine disposition.

393 NEUROADRENERGIC DYSFUNCTION ALONG THE DIABETIC CONTINUUM

Background: Neuroadrenergic function in type 2 diabetic (T2D) patients is poorly characterized, particularly in the early stages of disease, before the onset of peripheral neuropathy. We therefore compared sympathetic nervous system (SNS) activity at rest and during a standard oral glucose tolerance test (OGTT) in obese metabolic syndrome (MetS) subjects classified using WHO criteria as glucose intolerant (IGT) or treatment naïve T2D. Design and methods: Untreated subjects (17 IGT, 17 T2D) matched for age (mean 59 ± 1 yr), gender, body mass index (32.4 ± 0.6 kg/m2) and family history of diabetes were studied. We measured muscle sympathetic nerve activity (MSNA) by microneurography, whole-body noradrenaline kinetics by isotope dilution, neuronal noradrenaline re-uptake as the steady state tritiated 3,4-dihydroxyphenylglycol to tritiated noradrenaline ratio (3H-DHPG: 3H-NA), insulin sensitivity by euglycaemic hyperinsulinemic clamp (M/I) and MetS components. Results: T2D subjects had higher resting MSNA burst incidence (67 ± 4 versus 55 ± 3 bursts per 100 heartbeats, P = 0.05) and arterial noradrenaline levels (264 ± 33 versus 167 ± 16 pg/ml, P = 0.02), lower plasma noadrenaline clearance (by 17%, P = 0.03) and reduced neuronal re-uptake compared with IGT subjects (by 46%, P = 0.04). Moreover, noradrenaline spillover responses to glucose ingestion were significantly blunted in T2D subjects. The M/I value independently predicted whole-body noadrenaline spillover (r = −0.47, P = 0.008), whilst fasting insulin level related to neuronal noradrenaline re-uptake (r = −0.35, P = 0.047). Conclusions: These findings demonstrate that progression to T2D is associated with increased central sympathetic drive, blunted sympathetic responsiveness and altered noradrenaline disposition.

Propofol/Remifentanil Vs Desflurane/Fentanyl in Open Hemicolectomy Surgery

In a prospective, randomized, parallel-group study the aim was to compare TIVA (total intravenous anesthesia) with propofol / remifentanil and anesthesia with desflurane / fentanyl in open hemicolectomy surgery. 10 patients were randomly assigned each group. The primary endpoint hemodynamic stability was evaluated as number of dose-adjustments due to responses to surgery (hypertension, tachycardia, somatic or autonomic responses). Catecholamine levels, recovery times after anesthesia, postoperative variables and costs were also evaluated. There were no significant differences between the two groups in number of dose-adjustment due to responses to surgery (P = 0.88). One min after skin incision arterial noradrenaline levels were 59 ± 14 pg/ml in the TIVA-group and 262 ± 87 pg / ml in the desflurane-group (P < 0.01). Corresponding adrenaline levels were 16 ± 3 and 38 ± 12 pg/ml (P < 0.05), respectively. Recovery times after anesthesia were not significantly different between the two groups. In the TIVA-group we found significant increased use of opioids (P = 0.034), a trend towards increased use of epidural analgesia (P = 0.06) and about 30% higher costs (P = 0.03). We conclude that hemodynamic stability is not different between the two types of anesthesia in patients undergoing open hemicolectomy. TIVA reduces catecholamine levels and increases postoperative analgesic demands and costs.

Arterial Plasma Vasopressin and Aldosterone Predict Left Ventricular Mass in Men Who Develop Hypertension Over 20 Years

Left ventricular (LV) hypertrophy is related to blood pressure level and neurohormonal factors. The authors previously demonstrated that arterial norepinephrine levels predict LV mass in middle-aged men who developed hypertension through 20 years. The aim of this 20-year prospective study was to investigate arterial vasopressin, aldosterone, and renin as long-term predictors of LV mass. Normotensives (n=17), subjects who developed hypertension (n=17), and sustained hypertensives (n=22) were compared at baseline (42 years) and at follow-up (62 years). There were no significant differences in baseline vasopressin, aldosterone, or renin levels. The group with sustained hypertension had more LV hypertrophy (P=.025) at follow-up. Among new hypertensives, multiple regression analysis demonstrated that baseline arterial vasopressin (beta-0.53; P=.041) and aldosterone (beta-0.56;P=.032) independently explained LV mass index (R(2)=0.85; P=.035). In conclusion, baseline arterial vasopressin and aldosterone, but not renin, appear to predict LV mass in middle-aged men who developed hypertension over a 20-year period.

Parasympathetic inhibition of sympathetic neural activity to the pancreas.

The present study tested the hypothesis that activation of the parasympathetic nervous system could attenuate sympathetic activation to the pancreas. To test this hypothesis, we measured pancreatic norepinephrine (NE) spillover (PNESO) in anesthetized dogs during bilateral thoracic sympathetic nerve stimulation (SNS; 8 Hz, 1 ms, 10 mA, 10 min) with and without (randomized design) simultaneous bilateral cervical vagal nerve stimulation (VNS; 8 Hz, 1 ms, 10 mA, 10 min). During SNS alone, PNESO increased from the baseline of 431 +/- 88 pg/min to an average of 5,137 +/- 1,075 pg/min (P < 0.05) over the stimulation period. Simultaneous SNS and VNS resulted in a significantly (P < 0.01) decreased PNESO response [from 411 +/- 61 to an average of 2,760 +/- 1,005 pg/min (P < 0.05) over the stimulation period], compared with SNS alone. Arterial NE levels increased during SNS alone from 130 +/- 11 to approximately 600 pg/ml (P < 0.05); simultaneous SNS and VNS produced a significantly (P < 0.05) smaller response (142 +/- 17 to 330 pg/ml). Muscarinic blockade could not prevent the effect of VNS from reducing the increase in PNESO or arterial NE in response to SNS. It is concluded that parasympathetic neural activity opposes sympathetic neural activity not only at the level of the islet but also at the level of the nerves. This neural inhibition is not mediated via muscarinic mechanisms.

Effect of a selective rise in sinusoidal norepinephrine on HGP is due to an increase in glycogenolysis.

To determine the effect of a selective rise in liver sinusoidal norepinephrine (NE) on hepatic glucose production (HGP), norepinephrine (50 ng.kg-1.min-1) was infused intraportally (Po-NE) for 3 h into five 18-h-fasted conscious dogs with a pancreatic clamp. In the control protocol, NE (0.2 ng.kg-1.min-1) and glucose were infused peripherally to match the arterial NE and blood glucose levels in the Po-NE group. Hepatic sinusoidal NE levels rose approximately 30-fold in the Po-NE group but did not change in the control group. The arterial NE levels did not change significantly in either group. During the portal NE infusion, HGP increased from 1.9 +/- 0.2 to 3.5 +/- 0.4 mg.kg-1.min-1 (15 min; P < 0.05) and then gradually fell to 2.4 +/- 0.4 mg.kg-1.min-1 by 3 h. HGP in the control group did not change (2.0 +/- 0.2 to 2.0 +/- 0.2 mg.kg-1.min-1) for 15 min but then gradually fell to 1.1 +/- 0.2 mg.kg-1.min-1 by the end of the study. Because the fall in HGP from 15 min on was parallel in the two groups, the effect of NE on HGP (the difference between HGP in the two groups) did not decline over time. Gluconeogenesis did not change significantly in either group. In conclusion, elevation in hepatic sinusoidal NE significantly increases HGP by selectively stimulating glycogenolysis. Compared with the previously determined effects of epinephrine or glucagon on HGP, the effect of NE is, on a molar basis, less potent but more sustained over time.

Differences between the effects of metoprolol and prazosin on the forearm vasculature in primary hypertension.

To study the forearm vascular resistance in patients at rest and during ischaemia and cardiovascular responses to noradrenaline infusions during treatment with a beta1-adrenoceptor antagonist, metoprolol, and with an alpha1-adrenoceptor antagonist, prazosin. Eighteen previously untreated primary hypertension patients were selected for therapy either with 50-250 mg/day metoprolol (n = 11) or with 3-20 mg/day prazosin (n = 8). The minimal vascular resistance after ischaemic work was calculated from the forearm blood flow determined by venous occlusion plethysmography before treatment and after two and 16 months of treatment Arterial and venous plasma noradrenaline levels were determined and systemic pressor responses and forearm vasoconstriction were studied during intravenous infusion of noradrenaline. The resting mean arterial pressure was reduced differently by metoprolol and prazosin (by 20% versus by 8%; P < 0.001 for difference). The minimal vascular resistance decreased similarly after 16 months of metoprolol (17% decrease; P < 0.05) and of prazosin (24% decrease; P < 0.05) treatments. Arterial noradrenaline levels increased after 16 months of metoprolol treatment and after 2 and 16 months of prazosin treatment. The forearm noradrenaline spillover was reduced after 16 months on prazosin, but remained unchanged during metoprolol treatment. Pressor responses to intravenous noradrenaline were affected little by either treatment, whereas reflexogenic bradycardia was attenuated by prazosin treatment. The findings suggest that metoprolol and prazosin treatments reduce the minimal vascular resistance similarly, despite different reductions in blood pressure. Prazosin treatment might also reduce the forearm sympathetic nerve activity. Reductions in minimal forearm vascular resistance during antihypertensive therapy need not be related only to the lowering of the blood pressure per se.

Acclimatization to high altitude increase muscle sympathetic activity both at rest and during exercise

This investigation examined the relationship between alterations in plasma norepinephrine associated with 21 days of high-altitude exposure and muscle sympathetic activity both at rest and during exercise. Healthy sea level residents, divided into a control group (n = 5) receiving a placebo or a drug group (n = 6) receiving 240 mg/day of propranolol, were studied while at sea level, upon arrival (acute), and after 21 days of residence (chronic) at 4,300 m. Arterial norepinephrine levels and net leg uptake and release of norepinephrine were determine both at rest and during 45 min of submaximal exercise via samples collected from femoral arterial and venous catheters. Arterial norepinephrine levels increased significantly after chronic altitude exposure both at rest (84%) and during exercise (174%) compared with sea level and acute values. A net uptake of norepinephrine was found in resting legs at sea level (0.28 +/- 0.05 nmol/min) and with acute exposure (0.07 +/- 0.06 nmol/min); however, a significant switch to net leg norepinephrine release was observed with chronic altitude exposure (0.51 +/- 0.11 nmol/min). With exercise, a net release of norepinephrine by the leg occurred across all conditions with chronic exposure, again eliciting the greatest values (5.3 +/- 0.6, 8.0 +/- 1.7, and 14.4 +/- 3.1 nmol/min for sea level, acute, and chronic exposure, respectively). It was concluded that muscle sympathetic activity is significantly elevated both at rest and during submaximal exercise as a result of chronic high-altitude exposure, and muscle is a major contributor to the increase in plasma norepinephrine levels associated with prolonged altitude exposure. The presence of dense beta-blockade did not alter this adaptation to altitude.

Norepinephrine Infusion Following Cardiopulmonary Bypass: Effect of Infusion Site

The placement of left atrial catheters following cardiopulmonary bypass (CPB) allows accurate monitoring of left ventricular filling pressures, as well as access for the infusion of vasoactive drugs. While the left atrial administration of norepinephrine (NE) is thought to provide higher systemic arterial NE levels while minimizing any pulmonary vasoconstriction, no study critically compares central venous and left atrial NE infusion following cardiopulmonary bypass. A canine model was used to compare central venous and left atrial NE infusion at three dosages (0.2, 0.4, and 0.6 μg/kg/min) both prior to CPB and following 2 hr of hypothermic CPB at 27°C. Prior to CPB, there was no difference in the hemodynamic efficacy of central venous and left atrial NE infusion at any dosage. The pulmonary circulation metabolized 16-29% of circulating NE. Only at the 0.2 μg/kg/min dose was there a difference in the arterial NE level between central venous (3474 ± 486 pg/ml) and left atrial (5504 ± 751 pg/ml, P = 0.019) NE administration. Above this dose, no difference in the arterial NE level was identified. Following 2 hr of CPB, the pulmonary endothelium metabolized a significantly higher percentage of circulating NE (3542%). Despite this increased extent of pulmonary metabolism, there was no difference in the hemodynamic efficacy or the resulting arterial NE level of central venous and left atrial NE infusion at a given dose. In conclusion, the results demonstrate: (1) increased pulmonary NE uptake following CPB, and (2) no difference in hemodynamic efficacy between central venous and left atrial NE infusion over a wide range of three doses in a model with normal lungs.

New approaches to evaluate sympathoadrenal system activity in experiments on Earth and in space

In previous studies the activity of the sympathoadrenal system (SAS) in cosmonauts during space flights was evaluated by measuring plasma catecholamines (CA) levels and urinary CA and their metabolites concentrations. Plasma CA levels are accepted indicators of SAS activity, however, they are determined by the plasma clearances as well as the rates of CA release (spillover-SO) into the bloodstream. Nowadays methods are available which evaluate not only plasma levels of CA but also their release, spillover, uptake, reuptake, degradation and also CA synthesis in vivo measured by plasma levels of dihydroxyphenylalanine (DOPA). Plasma concentrations of DOPA, the CA noradrenaline (NE), adrenaline (ADR), and dopamine (DA), the deaminated catechol metabolites dihydroxyphenylglycol (DHPG) and dihydroxyphenylacetic acid (DOPAC), and the O-methylated metabolites methoxyhydroxyphenylglycol (MHPG) and homovanillic acid (HVA) were measured during immobilization stress (IMO) in conscious rats. Radiotracer methods were used to measure NE SO. IMO markedly increased arterial NE levels but NE SO was less elevated bacause the NE clearance was slightly reduced in IMO rats. Simultaneous measurements of plasma CA and their metabolites provide another means to obtain information about SAS function. For instance, dissociation between changes of plasma DHPG and NE levels can indicate changes in neuronal reuptake of NE. We found marked parallel increases in plasma NE and DHPG levels during acute IMO; however after repeated IMO, plasma NE levels were increased but DHPG responses were less pronounced suggesting a reduced NE reuptake. DOPA, the CA precursor, circulates in plasma at a concentration higher than NE. During stress, increased sympathoneural outflow stimulates DOPA synthesis and release into the circulation supporting the view that changes in plasma DOPA levels during stress reflect in vivo changes in the rate of CA synthesis. We propose to measure the new plasma indicators of SAS activity in cosmonauts and/or in animals before, during and after space flights.

Sympathetic response during 21 days at high altitude (4,300 m) as determined by urinary and arterial catecholamines

The sympathoadrenal system plays a major role in adjustments to both short- and long-term high-altitude exposure. Thus, this study investigated catecholamine responses in blood, urine, and muscle during 3 weeks' exposure to 4,300 m in control and β-blocked subjects. Eleven healthy, sea level (SL)-resident men (aged 26 ± 1 years) were studied under resting conditions at SL and on arrival and during 21 days at 4,300 m (Pikes Peak). Six subjects received 240 mg/d propranolol, and five were administered a placebo. Compared with SL values (38.7 ± 4.3 v 32.4 ± 2.8μg/d for control and β-blocked, respectively), urinary norepinephrine (NE) excretion increased significantly during altitude exposure, reaching peak values on days 6 to 7 (105.5 ± 16.1 v 88.4 ± 12.3μg/d, respectively). Furthermore, resting arterial NE levels (↑87%), as well as net NE release (↑219%) across the leg, both increased during acclimatization, indicating elevated sympathetic activity. Systemic vascular resistance and arterial pressures increased with time at altitude and correlated with NE measurements. Resting heart rates increased initially and then declined steadily after day 4 at altitude in both groups of subjects. Urinary epinephrine (EPI) excretion increased with initial exposure as compared with SL values (5.1 ± 0.8 to 6.6 ± 0.7 μg/d for control, 4.5 ± 0.5 to 5.2 ± 1.3 μg/d for β-blocked); however, no consistent pattern was observed for the following 20 days at altitude. Arterial EPI increased upon acute exposure, but declined after 21 days' acclimatization. No changes in dopamine excretion were observed with β-blockade or altitude exposure. It was concluded that although sympathetic and adrenal activity differ, alterations in sympathoadrenal activity correlate with several cardiovascular adjustments associated with acclimatization to high altitude.

Estimated central blood volume in cirrhosis: Relationship to sympathetic nervous activity, β-adrenergic blockade and atrial natriuretic factor

The estimated central blood volume (i.e., blood volume in the heart cavities, lungs and central arterial tree) was determined by multiplying cardiac output by circulatory mean transit time in 19 patients with cirrhosis and compared with sympathetic nervous activity and circulating level of atrial natriuretic factor. Arterial norepinephrine level, an index of overall sympathetic nervous activity (3.08 nmol/L in patients vs. 1.36 nmol/L in controls; p < 0.01) was negatively correlated (r = -0.54, p < 0.01) with estimated central blood volume (mean = 23 ml/kg in patients vs. 27 ml/kg in controls; p < 0.05). Similarly, renal venous norepinephrine level (an index of renal sympathetic tone; 4.26 nmol/L in patients vs. 1.78 nmol/L in controls; p < 0.01) was inversely correlated with estimated central blood volume (r = -0.53, n = 18, p < 0.02). No significant correlation could be established between arterial atrial natriuretic factor level (8.9 pmol/L in patients vs. 9.6 pmol/L in controls; not significant) and estimated central blood volume. Hemodynamic values were subsequently modified with oral propranolol (80 mg). During beta-adrenergic blockade, the mean estimated central blood volume was not altered significantly, except in six patients who exhibited decreases in mean arterial blood pressure (85 to 69 mm Hg; n = 6) and decreases in mean estimated central blood volume (23.2 to 20.6 ml/kg; n = 6, p < 0.05). Slight increases were observed in mean right atrial pressure (2.2 to 3.7 mm Hg; n = 14, p < 0.05); this change was positively correlated with the change in estimated central blood volume (r = 0.44, n = 14, p = 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)

Estimated central blood volume in cirrhosis: Relationship to sympathetic nervous activity, β-adrenergic blockade and atrial natriuretic factor

The estimated central blood volume (i.e., blood volume in the heart cavities, lungs and central arterial tree) was determined by multiplying cardiac output by circulatory mean transit time in 19 patients with cirrhosis and compared with sympathetic nervous activity and circulating level of atrial natriuretic factor. Arterial norepinephrine level, an index of overall sympathetic nervous activity (3.08 nmol/L in patients vs. 1.36 nmol/L in controls; p < 0.01) was negatively correlated (r = −0.54, p < 0.01) with estimated central blood volume (mean = 23 ml/kg in patients vs. 27 ml/kg in controls; p < 0.05). Similarly, renal venous norepinephrine level (an index of renal sympathetic tone; 4.26 nmol/L in patients vs. 1.78 nmol/L in controls; p < 0.01) was inversely correlated with estimated central blood volume (r = −0.53, n = 18, p < 0.02). No significant correlation could be established between arterial atrial natriuretic factor level (8.9 pmol/L in patients vs. 9.6 pmol/L in controls; not significant) and estimated central blood volume. Hemodynamic values were subsequently modified with oral propranolol (80 mg). During β-adrenergic blockade, the mean estimated central blood volume was not altered significantly, except in six patients who exhibited decreases in mean arterial blood pressure (85 to 69 mm Hg; n = 6) and decreases in mean estimated central blood volume (23.2 to 20.6 ml/kg; n = 6, p < 0.05). Slight increases were observed in mean right atrial pressure (2.2 to 3.7 mm Hg; n = 14, p < 0.05); this change was positively correlated with the change in estimated central blood volume (r = 0.44, n = 14, p = 0.06). In conclusion, reduced estimated central blood volume probably “unloads” volume receptors and baroreceptors, thus provoking enhanced overall and renal sympathetic nervous activity and thereby contributing to increased water and salt retention in cirrhosis. During β-adrenergic blockade estimated central blood volume changes correlated with alterations in preload and afterload. These findings indicate that central circulatory and arterial underfilling is a key element of the hemodynamic derangement observed in cirrhosis. (HEPATOLOGY 1992;5:1163–1170.)

Effect of oral propranolol administration on azygos, renal and hepatic uptake and output of catecholamines in cirrhosis

Circulating catecholamines are increased in cirrhosis with portal hypertension, and increase further after propranolol. In 23 cirrhotic patients, plasma norepinephrine and epinephrine were determined in an artery, the azygos vein, the right renal vein and a hepatic vein before and after an oral 80-mg dose of propranolol. Baseline azygos and renal venous norepinephrine levels were significantly higher than arterial norepinephrine levels (+ 20%, p < 0.005; and + 28%, p < 0.001, respectively). Hepatic venous norepinephrine and all venous epinephrine values were below the arterial values (all p < 0.05). After propranolol intake, arterial norepinephrine and epinephrine increased (+ 16%, p < 0.01; and + 93%, p < 0.001, respectively). Significant increases in norepinephrine and epinephrine were found in azygos and renal veins (all p < 0.01), whereas hepatic venous norepinephrine and epinephrine remained unchanged. Azygos and hepatic blood flow decreased after propranolol intake (−27%, p < 0.05; and − 16%, p < 0.01, respectively). Azygos spillover of norepinephrine (an estimate of locally released norepinephrine delivered to the circulation) and clearance of epinephrine remained unaltered. Hepatointestinal clearance showed no significant change for norepinephrine, but showed a borderline-significant decrease for epinephrine (−23%, p = 0.08). Our results show a net production of norepinephrine in the prehepatic splanchnic area drained through superior portalsystemic collaterals and in the kidneys. The increase in circulating catecholamines after propranolol intake is probably due to a combination of further enhancement of sympathetic activity and a decrease in catecholamine degradation. (HEPATOLOGY 1991;14:237–243.)

Effect of oral propranolol administration on azygos, renal and hepatic uptake and output of catecholamines in cirrhosis

Circulating catecholamines are increased in cirrhosis with portal hypertension, and increase further after propranolol. In 23 cirrhotic patients, plasma norepinephrine and epinephrine were determined in an artery, the azygos vein, the right renal vein and a hepatic vein before and after an oral 80-mg dose of propranolol. Baseline azygos and renal venous norepinephrine levels were significantly higher than arterial norepinephrine levels (+20%, p less than 0.005; and +28%, p less than 0.001, respectively). Hepatic venous norepinephrine and all venous epinephrine values were below the arterial values (all p less than 0.05). After propranolol intake, arterial norepinephrine and epinephrine increased (+16%, p less than 0.01; and +93%, p less than 0.001, respectively). Significant increases in norepinephrine and epinephrine were found in azygos and renal veins (all p less than 0.01), whereas hepatic venous norepinephrine and epinephrine remained unchanged. Azygos and hepatic blood flow decreased after propranolol intake (-27%, p less than 0.05; and -16%, p less than 0.01, respectively). Azygos spillover of norepinephrine (an estimate of locally released norepinephrine delivered to the circulation) and clearance of epinephrine remained unaltered. Hepatointestinal clearance showed no significant change for norepinephrine, but showed a borderline-significant decrease for epinephrine (-23%, p = 0.08). Our results show a net production of norepinephrine in the prehepatic splanchnic area drained through superior portalsystemic collaterals and in the kidneys. The increase in circulating catecholamines after propranolol intake is probably due to a combination of further enhancement of sympathetic activity and a decrease in catecholamine degradation.

Epinephrine Synthesis by Rat Arteries

Carotid artery and aorta homogenates synthesized epinephrine (E) from norepinephrine (NE) in the presence of S-adenosylmethionine. Aorta synthesized epinine by the N-methylation of dopamine (DA) about 3 times as well as it synthesized E from NE. In contrast, adrenal homogenates which contain phenylethanolamine N-methyltransferase (PNMT) methylated DA only 1% as well as NE. The PNMT inhibitor SKF 29661 had no significant effect on methylation of NE by aorta but inhibited adrenal PNMT by 88%. N-Methylating activity in arterial homogenates was increased by dexamethasone and following catecholamine depletion by 6-hydroxydopamine (6-OHDA) and reserpine. Nine days after adrenal demedullation blood E levels collected at decapitation were less than 7% of levels found in sham operated controls but artery homogenate E was unchanged. Demedullated rats given 6-OHDA followed by reserpine for 4 days also had unchanged arterial E levels despite arterial NE levels that were less than 15% of controls. We conclude that arteries synthesize E in vitro and appear to synthesize E in vivo using an extraneuronal N-methyltransferase. This enzyme differs from adrenal PNMT in substrate and inhibitor specificity and its activity is enhanced by catecholamine depletion and by glucocorticoid treatment.

Epinephrine-Induced Enhancement of Sympathetic Activity in Humans

To collect further evidence that epinephrine (EPI) facilitates norepinephrine (NE) release in humans, the effect of a low-dose intravenous (i.v.) infusion of EPI (20 ng kg-1/min) on arterial levels of NE and on local production of NE in the forearm was studied both before and during isometric exercise, cold provocation, head-up tilting, and mental stress in 10 subjects with borderline to mild hypertension. Studies were performed during placebo, during beta 1-selective beta-adrenoceptor blockade with atenolol, 50 mg once daily, and during nonselective beta-blockade with bopindolol, 1 mg once daily. Atenolol and bopindolol were administered for 1 week, 2 weeks apart, in a randomized double-blind cross-over design. During infusion of EPI, which increased plasma EPI levels to within the high physiologic range, resting levels of NE increased from 214 +/- 20 to 263 +/- 26 pg/ml (p less than 0.01) and resting NE forearm production increased from 296 +/- 48 to 529 +/- 98 pg 100 ml/min-1 (p less than 0.01). The enhancement of these two indices of sympathetic activity by EPI, observed during placebo, was abolished by bopindolol as well as by atenolol. The response of arterial NE, but not the response of forearm NE production, to three of the four stress tests was also enhanced (p less than 0.05) by EPI. This enhancement was also abolished by both beta-adrenoceptor antagonists. Our findings support the hypothesis that physiologic levels of EPI are capable of enhancing sympathetic activity in humans. This effect is mediated by beta-adrenoceptors and can be blocked not only by a nonselective but also by a beta 1-selective beta-adrenoceptor antagonist.

Plasma levels of catechols during reflexive changes in sympathetic nerve activity

Relationships between changes in levels of catechols and directly recorded sympathetic nerve activity were examined using simultaneous measurements of renal sympathetic nerve activity and arterial and renal venous concentrations of norepinephrine (NE), dihydroxyphenylalanine (dopa), and dihyroxyphenylglycol (DHPG) during reflexive alterations in renal sympathetic nerve activity in anesthetized, adrenal-demedullated rats. Nitroprusside infusion increased renal sympathetic nerve activity by 90%, arterial levels of dopa by 96%, NE by 326%, and DHPG by 141%. Phenylephrine infusion increased arterial DHPG levels by 81% and decreased renal sympathetic nerve activity by 37% and NE levels by 26%; arterial dopa levels were unchanged. Ganglionic blockade by chlorisondamine (with concomitant phenylephrine infusion to maintain MAP) decreased renal sympathetic nerve activity by 65% and NE concentrations by 37%; arterial dopa concentrations were unchanged, and DHPG concentrations increased by 60%. Proportionate responses of arterial levels of NE were strongly related to proportionate changes in renal sympathetic nerve activity. Clearance of DHPG from arterial plasma was prolonged by phenylephrine-induced hypertension and by nitroprusside-induced hypotension. The results suggest that changes in arterial NE levels reflect changes in sympathetic activity; changes in dopa levels reflect changes in catecholamine biosynthesis; and changes in DHPG levels depend on reuptake of released NE and on hemodynamic factors affecting DHPG clearance.

Venous versus arterial forearm catecholamines as an index of overall sympatho-adrenomedullary activity.

The metabolism of norepinephrine (NE) and epinephrine (EPI) in peripheral tissues limits the use of venous plasma levels of these parameters as an index of overall sympathetic or adrenomedullary activity. Therefore venous (deep antecubital vein) and arterial (brachial artery) concentrations of NE and EPI were compared in 16 hypertensive subjects. NE and EPI were determined after 30 min supine rest, and immediately before and after isometric exercise, cold provocation, head-up tilting (OST) and Stroop's colour word test (CWT). At rest venous NE exceeds arterial NE. Assuming similar fractional extractions (FE) of NE and EPI, 46 +/- 14% (mean +/- SD) of venous NE appeared to be produced locally. Despite this considerable local production venous and arterial levels of NE were closely correlated (r = 0.92). At rest venous EPI was 42 +/- 13% lower than arterial EPI, but since the interindividual variation of the FE of EPI was relatively small and independent of arterial levels, venous and arterial levels were also closely correlated (r = 0.82). All four tests caused an increase in arterial and venous NE, whereas EPI did not change. Responses of arterial and venous NE were only correlated after OST and CWT. It is concluded that at rest, but not invariably so during different forms of sympatho-adrenal activation, arterial plasma concentrations of NE and EPI can be substituted for by their respective venous equivalents.

Extraction of epinephrine and norepinephrine by the dog pancreas in vivo

This study determined the fractional extraction of epinephrine and norepinephrine by the in situ dog pancreas. Plasma samples for epinephrine measurements were taken simultaneously from the femoral artery and the superior pancreaticoduodenal vein. Pancreatic extraction of epinephrine was 73 ± 5% when basal arterial epinephrine levels were 380 ± 93 pg/mL, 76 ± 4% when arterial levels were 896 ± 123 pg/mL (epinephrine infused intravenously at 20 ng/kg/min), and 84 ± 1% when arterial levels were 2,956 ± 414 pg/mL (epinephrine infused intravenously at 80 ng/kg/min) suggesting that the process of epinephrine extraction by the pancreas is not saturable over this range. During a similar sampling protocol, norepinephrine was infused intravenously at 4 μg/kg/min; pancreatic extraction of norepinephrine was then 65 ± 7% when arterial norepinephrine levels were 107,000 ± 28,000 pg/mL. In separate experiments, lower rates of norepinephrine (12 to 1,200 ng/min) were infused directly into the pancreatic artery and pancreatic norepinephrine extraction was calculated; it ranged between 66% and 75%. Because the pancreas produces as well as extracts norepinephrine, a third technique was required to determine pancreatic norepinephrine extraction at the lower endogenous levels of norepinephrine; 3H-norepinephrine was infused intravenously and the arteriovenous difference of 3H-norepinephrine was measured. Fractional extraction of 3H-norepinephrine was 74 ± 4% both in the basal state (arterial norepinephrine level = 202 ± 44 pg/mL) and during systemic, glucopenic, stress induced by 2-deoxy-glucose (arterial norepinephrine level = 636 ± 70 pg/mL). These data suggest that also the norepinephrine extraction process by the pancreas is not sarurable. Further, since the pancreatic extraction of norepinephrine is so avid, these data suggest that measurement of the arteriovenous concentration difference of endogenous norepinephrine alone will markedly underestimate local norepinephrine spillover. Correcting these measurements for the extraction would, however, provide an index of the endogenous activity of pancreatic adrenergic nerves. Finally, this study also determined whether pancreatic catecholamine extraction is altered by α-or β-adrenoceptor antagonists; phenoxybenzamine was found to reduce the extraction of both epinephrine ( P < .001) and norepinephrine ( P < .05) whereas propranolol did not. Thus, one must consider how changes of pancreatic catecholamine extraction might alter the interpretation of experiments using α-adrenoceptor antagonists to study local norepinephrine release or catecholamine effects on pancreatic hormone secretion. In summary, (1) at steady state 60% to 80% of either epinephrine or norepinephrine is extracted in one pass by the dog pancreas, (2) this process of extraction appears nonsaturable, and (3) the pancreatic extraction of catecholamines is impaired by the α-adrenoceptor antagonist phenoxybenzamine, but not by the β-adrenoceptor antagonist propranolol.