Dopa in plasma increases during acute exercise and after exercise training

Plasma dihydroxyphenylalanine (dopa) has been shown to originate in sympathetic neurons, and it has been suggested that plasma level reflects activity of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines. In this study, we measured the effects of acute exercise and exercise training on the levels of dopa and catecholamines in the plasma of healthy, older individuals. Venous blood was drawn from 19 men, from 52 to 75 years of age, at rest, at a standard submaximal work load, at peak exercise, and 3 minutes after exercise on a cycle ergometer. Ten of 12 men then completed 12 to 16 weeks of supervised training, and seven continued normal activity. All 17 men were then retested. The seven control subjects subsequently underwent exercise training as above and were retested again. Levels of dopa and catecholamines in plasma samples were measured by high-performance liquid chromatography with electrochemical detection. Dopa levels at rest were considerably higher than free dopamine, epinephrine, and norepinephrine. During short-term exercise, levels of dopa and catecholamines increased. The absolute increase in dopa was greater than the increase in epinephrine or dopamine but was not greater than that in norepinephrine. After the training period, basal dopa levels increased significantly and correlated with the increase in peak oxygen uptake. There was no change in basal conjugated norepinephrine or dopamine levels with exercise or training, but the level of conjugated epinephrine decreased slightly. No changes occurred in levels of dopa or catecholamines in the untrained group. Free dopamine, norepinephrine, and epinephrine levels at peak exercise were increased after exercise training.(ABSTRACT TRUNCATED AT 250 WORDS)     

Free and conjugated catecholamines in patients with cirrhosis

A defect of conjugation may play a role in the elevated plasma free norepinephrine observed in patients with cirrhosis. Plasma free, sulfoconjugated, and glucuronoconjugated catecholamine concentrations were assessed in 15 patients with cirrhosis and in 15 age-matched control subjects. Plasma free norepinephrine and epinephrine levels were significantly higher in patients with cirrhosis (481 +/- 75 and 96 +/- 16 pg/ml, respectively) than in those of the control group (307 +/- 33 and 42 +/- 10 pg/ml, p less than 0.05 and p less than 0.01, respectively). Plasma free dopamine levels were similar in both groups. Sulfoconjugated catecholamines were the predominant form in plasma from both cirrhotic patients and control subjects. The ratio of conjugated to total catecholamines was similar in the two groups. Therefore, it is unlikely that a defect in conjugation of catecholamines is contributing to the excessive plasma free norepinephrine and epinephrine concentrations found in patients with cirrhosis. Moreover, in patients with cirrhosis, no significant relation was found between plasma conjugated catecholamines and the severity of liver disease. This study shows that cirrhosis does not induce alteration in conjugation of catecholamines and that hepatocellular function is not essential for conjugation of circulating catecholamines.     

Distribution of free and conjugated catecholamines between plasma, platelets and erythrocytes: different effects of intravenous and oral catecholamine administrations

Plasma, platelet and erythrocyte contents of free and conjugated norepinephrine, epinephrine and dopamine were determined by radioenzymatic assay in 12 resting healthy volunteers. Mean platelet/plasma concentration ratios were 533 for free norepinephrine, 502 for free epinephrine and 149 for free dopamine. Corresponding erythrocyte/plasma ratios were 1.04, 1.13 and 4.5, respectively. The presence of conjugated catecholamines in platelets and erythrocytes could be confirmed; however, their relative proportion within these cells, particularly in platelets, was lower than that in plasma. Upon intravenous infusion of dopamine for 3 hr at 5 micrograms kg-1 min-1, concentrations of free dopamine in plasma increased rapidly (280-970-fold), whereas conjugated dopamine only reached maximal values (14-19-fold increase) at 30 to 60 min after cessation of the infusion. The relative distribution of unconjugated dopamine in whole blood between plasma, platelets and erythrocytes changed from mean values of 1:0.33:3.7 at rest to 1:1.1:0.5 at the end of the infusion. As a result of the subsequent rapid decrease of dopamine in plasma and erythrocytes, this distribution was 1:17:1 shortly thereafter and remained constant up to the end of the investigation period. The relative distribution for conjugated dopamine of 1:0.001:0.5 at rest changed to about 1:0.2:0.1 at the termination of the infusion. Oral administration of norepinephrine and dopamine led to increases in the plasma concentrations of these amines in their conjugated forms only, whereas epinephrine concentrations remained constant. These elevations were not accompanied by corresponding increases in platelet and erythrocyte norepinephrine, epinephrine and dopamine contents.(ABSTRACT TRUNCATED AT 250 WORDS)     

What stimulates atrial natriuretic factor release during exercise?

Prior studies have shown that circulating atrial natriuretic factor (ANF) increases during short-term exercise, but the mechanism controlling ANF release, as well as the effect of exercise training on ANF release, remains unclear. Fifteen healthy mongrel dogs underwent short-term exercise testing before and after a 12-week period of exercise training (n = 8) or cage confinement (n = 7). ANF, norepinephrine, epinephrine, right atrial pressure, and heart rate were measured simultaneously at rest and during exercise at the time of each acute exercise study. Data were analyzed for all animals with normal baseline ANF values. Exercise training had no modulating effect on circulating ANF levels at rest or during exercise. Therefore, data before and after exercise training or cage confinement were grouped (n = 24) to determine the effects of short-term exercise. ANF levels increased from 49 +/- 2 pg/ml at rest to 60 +/- 4 pg/ml during exercise (p less than 0.05). Heart rate, norepinephrine, and epinephrine values also increased, but right atrial pressure actually decreased from 2.3 +/- 0.9 mm Hg at rest to -3.8 +/- 0.9 mm Hg during exercise (p less than 0.05). There was no correlation between ANF concentrations and levels of these other variables either at rest of during exercise. By demonstrating an increase in ANF with a simultaneous decrease in right atrial pressure, this study clearly shows that increased right atrial pressure is not the secretory stimulus for ANF release during exercise in the normal dog. The lack of correlation between ANF and right atrial pressure, heart rate, norepinephrine, and epinephrine levels suggests that factors other than these variables stimulate ANF release during short-term exercise.     

Association between renal and sympathetic responses to nonhypotensive systemic sepsis

We investigated the association between plasma catecholamines and the renal response to nonhypotensive sepsis. Arterial plasma catecholamines were measured in 16 sheep, before and 24 h after surgical induction of peritonitis. Animals were volume loaded with lactated Ringer's solution (8 L/24 h) before and after surgery; non became hypotensive. For analysis, animals were retrospectively divided into those with increased serum creatinine after 24 h of sepsis (group 1, n = 8) and those without (group 2, n = 8). Group 1 showed increased cardiac index and decreased systemic vascular resistance typical of severe sepsis, with decreased glomerular filtration rate (GFR), oliguria, sodium retention, increased plasma renin activity (PRA), decreased urinary kallikrein excretion, and increased urinary 6-keto-prostaglandin-F1 alpha excretion. Group 2 showed insignificant hemodynamic disturbance, and no significant renal response. Plasma catecholamines were equal in both groups at baseline. In group 1, there were uniform increases after 24 h in plasma norepinephrine (474 +/- 115 to 1183 +/- 158 [SEM] pg/ml; p less than .01) and plasma epinephrine (108 +/- 8 to 309 +/- 70 pg/ml; p less than .05). In group 2, neither plasma norepinephrine (343 +/- 59 to 330 +/- 56 pg/ml) nor plasma epinephrine (116 +/- 16 to 116 +/- 13 pg/ml) changed significantly. Plasma norepinephrine correlated inversely with GFR; plasma epinephrine correlated with PRA. The sympathetic nervous system may be involved in the renal response to nonhypotensive sepsis, both directly and via effects on other vasoactive hormone systems.     

Emergency medical service transport-induced stress? An experimental approach with healthy volunteers

This randomized controlled trial was designed to evaluate the effects of simulated emergency medical service (EMS) transport related stress on hemodynamic variables, and catecholamine plasma levels. A total of 32 healthy male volunteers were randomized to being carried by paramedics from a third-floor apartment through a staircase with subsequent high-speed EMS transport with lights and sirens (stress; n = 16); or sitting on a chair for 5 min, and lying on a stretcher for 15 min (control; n = 16). Blood samples and hemodynamic variables were taken in the apartment before transfer, at the ground floor, and at the end of EMS transport in the stress group, and at corresponding time points in the control group. The stress versus control group had both significantly (P < 0.05) higher mean +/- SEM epinephrine (71 +/- 7 versus 37 +/- 3 pg/ml), and norepinephrine (397 +/- 29 versus 299 +/- 28 pg/ml) plasma levels after transport through the staircase. After EMS transport, the stress versus control group had significantly higher epinephrine (48 +/-6 versus 32 +/- 2 pg/ml), but not norepinephrine (214 +/- 20 versus 264 +/- 31 pg/ml) plasma levels. Heart rate increased significantly from 72 +/- 2 to 84 +/- 3 bpm after staircase transport, but not during and after EMS transport. In conclusion, volunteers being carried by paramedics through a staircase had a significant discharge of both epinephrine and norepinephrine resulting in increased heart rate, but only elevated epinephrine plasma levels during EMS transport. Transport through a staircase may reflect more stress than emergency EMS transport.     

Role of circulating catecholamines in the control of pancreatic polypeptide and gastrin release

The influence of circulating catecholamines on the release of pancreatic polypeptide (PP) and gastrin was studied in volunteers. Physical exercise increased plasma epinephrine by 374 +/- 123% and plasma norepinephrine by 167 +/- 30%, but plasma PP concentrations remained unchanged during standardized bicycle ergometry. Immediately after cessation of exercise catecholamine levels decreased rapidly, whereas PP concentrations increased by 55%. In a second series, epinephrine infusion (5, 25, and 75 ng.kg-1.min-1) increased epinephrine levels by 38 +/- 12, 331 +/- 69, and 1229 +/- 131%, respectively, whilst norepinephrine was unaffected. Neither during nor after catecholamine infusion PP secretion was affected. Gastrin release increased by a maximum of 85 +/- 38% (at epinephrine 75 ng.kg-1.min-1). It is concluded, that (1) changes in circulating adrenaline do not significantly influence PP secretion in man; (2) the PP increase immediately following physical exercise cannot be attributed to a rapid fall of catecholamine levels; (3) endogenous catecholamines are of minor importance in the control of gastrin secretion.     

The Plasma Catecholamine Responses to Ventricular Pacing: Implications for Rate Responsive Pacing

Many patients with WI and WIR pacemakers will alternate between periods of sinus rhythm and ventricular pacing. These rhythm shifts may be poorly tolerated by some patients. Changes in plasma Catecholamine levels during these rhythm shifts may contribute to these patients'symptoms. We measured blood pressure, ejection fraction and plasma norepinephrine, epinephrine, and dopamine serially in nine patients with normal left ventricular ejection fractions and WI pacemakers during sinus rhythm and at paced rates of 10 beats per minute (bpm) above sinus rates (10 + NSR), 100 bpm, and 130 bpm. The mean norepinephrine level at baseline was 143 ± 16 pg/mL and increased to 166 ± 36 pg/mL at 10 + NSR, 204 ± 47 pg/mL at 100 bpm, and 182 ± 34 pg/mL at 130 bpm. These increases corresponded to mean percent changes from baseline of 17% (P = 0.02), 33% (P = 0.002), and 24% (P = 0.07), respectively. The magnitude of the norepinephrine response was not correlated with the pacing rate. The mean plasma epinephrine level at baseline was 57 ± 6 pg/mL and peaked at 51 ± 12 pg/mL at 10 + NSR, 89 ± 31 pg/mL at 100 bpm and 101 ± 28 pg/mL at 130 bpm. These increases corresponded to mean percent changes from baseline of- 10% (P = NS), 30% (P = 0.07), and 89% (P = 0.02), respectively. No trends in the dopamine response to pacing were noted. During ventricular pacing there were no significant changes in mean blood pressure and only slight changes in ejection fraction. The individual percent changes in plasma norepinephrine and epinephrine at 100 bpm were inversely correlated to the changes in systolic blood pressure (R =−0.68, P = 0.06, and R =−0.81, P = 0.03, respectively). These results suggest that plasma norepinephrine and epinephrine increase acutely in response to ventricular pacing at rates commonly seen during rate responsive ventricular pacing.     

Glucose turnover and its regulation during intense exercise and recovery in normal male subjects.

Intense exercise to exhaustion is expected to be associated with rapid and large changes in glucose production (Ra) and utilization (Rd). To quantify these, and to determine their mechanisms and those of the prolonged postexercise hyperglycemia, we measured circulating metabolic regulators and glucose kinetics, the latter by the method of enriched tracer [3-3H] glucose infusion during exercise. Eighteen fit, lean young male subjects exercised to exhaustion at 80% of maximal workload (approximately 100% VO2max) on a cycle ergometer. Plasma glucose was 4.90 +/- 0.08 mM/L at rest, increased during exercise, then abruptly to 6.91 +/- 0.40 mM/L at 4 min recovery then gradually declined. Plasma insulin was constant during exercise, then doubled to 162 +/- 28 pmol/l until 20 min recovery, before declining. Plasma glucagon increased by 71 +/- 11 pg/mL. Plasma norepinephrine increased 18-fold and epinephrine 14-fold, both declining by 20 min recovery. Ra increased 7-fold by exhaustion to 13.0 +/- 1.18 mg/kg/min, then decreased to 2.43 +/- 0.24 mg/kg/min by 9 min, then to about 2 mg/kg/min the rest of recovery. Rd rose 3-fold (6.61 +/- 0.70 mg/kg/min), and remained lower than Ra to 7 min recovery, but thereafter declined more slowly. Thus, the rapid and extremely large increase in Ra was not matched by the increment in Rd during exercise and early recovery. We suggest that unlike in exercise of lesser intensity, the major mediators of both the increase in Ra and the restraint of the increase in Rd are the catecholamines. The post exercise hyperglycemia and hyperinsulinemia are appropriate to muscle glycogen repletion.     

Catecholamines in CSF, plasma, and tissue after autologous transplantation of adrenal medulla to the brain in patients with Parkinson's disease

Catecholamine concentrations were measured in tissue samples of caudate and adrenal medulla in eight patients with Parkinson's disease who were taking L-dopa and were undergoing autologous transplantation of adrenal medulla to caudate nucleus. High-performance liquid chromatography with electrochemical detection was used for the measurement of analytes. Dopamine concentrations were quite similar in the caudate and the adrenal medulla; epinephrine and norepinephrine concentrations were some 600 times and 90 times higher, respectively, than that of dopamine in adrenal medulla but were barely detectable in caudate nucleus. Catecholamines and metabolites were also measured, before and after transplantation, in lumbar cerebrospinal fluid (CSF) and plasma 1 hour after the patients' first morning dose of L-dopa. The major fractions of the catecholamines in CSF were sulfoconjugated. The concentrations of sulfoconjugated but not free dopamine were modestly increased in CSF after the transplantation, although plasma concentrations were unchanged. CSF concentrations of free and conjugated norepinephrine and epinephrine, 3-methoxy-4-hydroxyphenylglycol, and homovanillic acid were unchanged after the transplantation. The data suggest that the grafted tissue does not retain its noradrenergic or adrenergic properties after transplantation, and that dopamine formation in the brain may be modestly increased. Plasma catecholamines were unaffected after the removal of one adrenal gland for the transplant.     

Evidence for central hypertyraminemia in hepatic encephalopathy.

In mongrel dogs, the effect of end-to-side portacaval shunt on plasma, cerebrospinal fluid (CSF) and brain tyramine, tyrosine, dopamine, norepinephrine, and epinephrine were studied. It was found that the level of tyramine in plasma, CSF, and selected brain regions increased steadily after the construction of the shunts. These elevations became more pronounced when the dogs manifested symptoms of hepatic encephalopathy. In postshunted dogs with stage II and III hepatic encephalopathy, tyramine concentration in corpus striatum (1,312 +/- 371), hypothalamus (400 +/- 67.0), and midbrain (660 +/- 78.7 ng/g) was significantly (P less than 0.05) higher than the level in dogs with stage 0 and I hepatic encephalopathy and sham-operated dogs serving as controls (corpus striatum, 831 +/- 140; hypothalamus, 167 +/- 40.0; and midbrain, 132 +/- 37.4 ng/g). This was followed by a concomitant depletion of dopamine and norepinephrine in these brain regions (postshunt: dopamine 104 +/- 20.0, 3,697 +/- 977, and 105 +/- 14.1; norepinephrine 521 +/- 71.6, 81.6 +/- 13.7, and 218 +/- 31.7 ng/g; vs. sham group: dopamine 532 +/- 83.1, 8,210 +/- 1,126, and 192 +/- 35.0; norepinephrine 1,338 +/- 425, 124 +/- 21.3, and 449 +/- 89.7 ng/g) of encephalopathic dogs with portacaval shunt. Furthermore, tyramine, tyrosine, dopamine, and norepinephrine levels in plasma and CSF increased markedly as clinical features in the dogs' behavior characteristic of hepatic encephalopathy occurred, including hypersalivation, ataxia, flapping tremor, somnolence, and coma. Cerebral hypertyraminemia and a defect in sympathetic neurotransmission may contribute to the development of hepatic encephalopathy of liver disease.     

Effect of exercise training on plasma catecholamines and haemodynamics of adolescent hypertensives during rest,submaximal exercise and orthostatic stress

Summary. Twelve adolescents with essential hypertension were studied to determine the effect of exercise training on plasma catecholamine concentrations, blood pressure and cardiovascular haemodynamics at rest and during submaximal exercise and orthostatic stress. Maximal oxygen consumption (V?O₂max) increased 13% with training while body weight and body fat did not change. Resting systolic and diastolic blood pressures decreased significantly with training, while plasma norepinephrine and epinephrine levels were unchanged. The increase in systolic blood pressure in response to standing was significantly lower after training, while the plasma catecholamine response was not significantly different. At the same absolute work rate after training, the subjects' systolic and diastolic blood pressures, heart rates, and plasma norepinephrine and epinephrine levels were significantly lower than before training. At the same relative work rate after training, the blood pressure response was the same as before training despite significantly higher plasma norepinephrine levels. Thus, the training-induced changes in resting blood pressures and blood pressure responses to orthostatic and submaximal exercise stress cannot be attributed to decreases in plasma catecholamine levels.     

Turnover of free and conjugated serum catecholamines during hemodialysis

The response of the catecholaminergic system was evaluated in uremic patients maintained on a chronic outpatient hemodialysis (HD) program. Serum concns of free and conjugated catecholamines (CA) were measured prior to and following HD and in response to upright posture, and were compared to values obtained in a normal group of individuals submitted to the same stimuli. Before HD, the level of free plasma dopamine (DA) (155 +/- 58 pg ml-1) was comparable to that of normal individuals (38 +/- 12 pg ml-1) due to the large number of individuals of the 2 groups having undetectable serum levels. Free norepinephrine (NE) and epinephrine (E) serum levels were higher, before HD, in uremic patients (301 +/- 31 and 139 +/- 43 pg ml-1) than in normal individuals (206 +/- 14 and 34 +/- 4 pg ml-1). Serum concns of the 3 forms of conjugated CA, before HD, in uremic patients were markedly elevated (35,800, 9644 and 1374 pg ml-1 for DA, NE and EPI, respectively), compared to those in normal individuals (1885, 1374 and 65 pg ml-1). Only the serum level of free NE was elevated (from 301 to 600 pg ml-1) due to the rapid fluid loss that occurs during HD. On the other hand, a drastic decrease in the serum level of conjugated DA (16,020 vs 35,794 pg ml-1), NE (4282 vs 10,596 pg ml-1) and E (688 vs 1294 pg ml-1) occurred during HD. It is suggested that uremic patients lose their normal catecholaminergic response to upright posture at the end of HD treatment as a result of a progressive depletion of their free CA storage that cannot be supplemented from the large quantity of conjugated CA still available in the serum under such circumstances.     

Interactions between glucagon and other counterregulatory hormones during normoglycemic and hypoglycemic exercise in dogs.

Somatostatin (ST)-induced glucagon suppression results in hypoglycemia during rest and exercise. To further delineate the role of glucagon and interactions between glucagon and the catecholamines during exercise, we compensated for the counterregulatory responses to hypoglycemia with glucose replacement. Five dogs were run (100 m/min, 12 degrees) during exercise alone, exercise plus ST infusion (0.5 micrograms/kg-min), or exercise plus. ST plus glucose replacement (3.5 mg/kg-min) to maintain euglycemia. During exercise alone there was a maximum increase in immunoreactive glucagon (IRG), epinephrine (E), norepinephrine (NE), FFA, and lactate (L) of 306 +/- 147 pg/ml, 360 +/- 80 pg/ml, 443 +/- 140 pg/ml, 541 +/- 173 mu eq/liter, and 6.3 +/- 0.7 mg/dl, respectively. Immunoreactive insulin (IRI) decreased by 10.2 +/- 4 micro/ml and cortisol (C) increased only slightly (2.1 +/- 0.3 micrograms/dl). The rates of glucose production (Ra) and glucose uptake (Rd) rose markedly by 6.6 +/- 2.2 mg/kg-min and 6.2 +/- 1.5 mg/kg-min. In contrast, when ST was given during exercise, IRG fell transiently by 130 +/- 20 pg/ml, Ra rose by only 3.6 +/- 0.5 mg/kg-min, and plasma glucose decreased by 29 +/- 6 mg/dl. The decrease in IRI was no different than with exercise alone (10.2 +/- 2.0 microU/ml). As plasma glucose fell, C, FFA, and L rose excessively to peaks of 5.4 +/- 1.3 micrograms/dl, 1,166 +/- 182 mu eq/liter and 15.5 +/- 7.0 mg/dl. The peak increment in E (765 +/- 287 pg/ml) coincided with the nadir in plasma glucose and was four times greater than during normoglycemic exercise. Hypoglycemia did not affect the rise in NE. The increase in Rd was attenuated and reached a peak of only 3.7 +/- 0.8 mg/kg-min. During glucose replacement, IRG decreased by 109 +/- 30 pg/ml and the IRI response did not differ from the response to normal exercise. Ra rose minimally by 1.5 +/- 0.3 mg/kg-min. The changes in E, C, Rd, and L were restored to normal, whereas the FFA response remained excessive. In all protocols increments in Ra were directly correlated to the IRG/IRI molar ratio while no correlation could be demonstrated between epinephrine or norepinephrine and Ra. In conclusion, (a) glucagon controlled approximately 70% of the increase of Ra during exercise. This became evident when counterregulatory responses to hypoglycemia (E and C) were obviated by glucose replacement; (b) increments in Ra were strongly correlated to the IRG/IRI molar ratio but not the plasma catecholamine concentration; (c) the main role of E in hypoglycemia was to limit glucose uptake by the muscle; (d) with glucagon suppression, glucose production was deficient but a further decline of glucose was prevented through the peripheral effects of E, (e) the hypoglycemic stimulus for E secretion was facilitated by exercise; and (f) we hypothesize that an important role of glucagons during exercise could be to spare muscle glycogen by stimulating glucose production by the liver.     

Response of sympathetic nervous system activity to exercise in patients with congestive heart failure

To investigate the serial sympathetic nervous system response to exercise, plasma norepinephrine (NE) and epinephrine (E) concentrations were measured at rest, during each stage of treadmill exercise, and immediately and 5 minutes after exercise in 68 congestive heart failure (CHF) patients (NYHA functional class I 24, II 25, III 19) and 30 normal subjects. Circulatory responses of NYHA class II patients increased at early stages of exercise. Systolic blood pressure and double product at peak exercise were significantly lower in NYHA class III patients. Plasma NE response of NYHA class I patients was similar to that of normal subjects. However, plasma NE at rest, and during and after exercise were significantly higher in NYHA classes II and III patients than in normal subjects and NYHA class I patients (peak NE (pg ml-1); Normals: 547 +/- 37, I: 535 +/- 53, II: 867 +/- 87, III: 1033 +/- 157). There was no significant difference in plasma E levels among the four groups. NE response to exercise was augmented according to the severity of heart failure, which suggested compensatory activation of sympathetic nervous system activity. Circulatory responses were reduced in NYHA class III patients despite the exaggerated compensatory activation of the sympathetic nervous system. Blunted circulatory responses to increased NE concentration in NYHA class III patients might relate to a decreased cardiac responsiveness to sympathetic activity in severe CHF patients.     

Effects of pressure overload, left ventricular hypertrophy on beta-adrenergic receptors, and responsiveness to catecholamines.

Pressure overload left ventricular (LV) hypertrophy was produced by banding the ascending aorta of puppies and allowing them to grow to adulthood. LV free wall weight per body weight increased by 87% from a normal value of 3.23 +/- 0.19 g/kg. Hemodynamic studies of conscious dogs with LV hypertrophy and of normal, conscious dogs without LV hypertrophy showed similar base-line values for mean arterial pressure, heart rate, and LV end-diastolic pressure and diameter. LV systolic pressure was significantly greater, P less than 0.01, and LV stroke shortening was significantly lss, P less than 0.01, in the LV hypertrophy group. In both normal and LV hypertrophy groups, increasing bolus doses of norepinephrine or isoproterenol produced equivalent changes in LV dP/dt. beta-adrenergic receptor binding studies with [3H]-dihydroalprenolol ( [3H]DHA) indicated that the density of binding sites was significantly elevated, P less than 0.01, in the hypertrophied LV plasma membranes (111 +/- 8.8, n = 8), as compared with normal LV (61 +/- 5.6 fmol/mg protein, n = 11). The receptor affinity decreased, i.e., disassociation constant (KD) increased, selectively in the LV of the hypertrophy group; the KD in the normal LV was 6.8 +/- 0.7 nM compared with 10.7 +/- 1.8 nM in the hypertrophied LV. These effects were observed only in the LV of the LV hypertrophy group and not in the right ventricles from the same dogs. The plasma membrane marker, 5' -nucleotidase activity, was slightly lower per milligram protein in the LV hypertrophy group, indicating that the differences in beta-adrenergic receptor binding and affinity were not due to an increase in plasma membrane protein in the LV hypertrophy group. The EC50 for isoproterenol-stimulated adenylate cyclase activity was similar in both the right and left ventricles and in the two groups. However, maximal-stimulated adenylate cyclase was lower in the hypertrophied left ventricle. Plasma catecholamines were similar in the normal and hypertrophied groups, but myocardial norepinephrine was depressed in the dogs with LV hypertrophy (163 +/- 48 pg/mg) compared with normal dogs (835 +/- 166 pg/mg). Thus, severe, but compensated LV hypertrophy, induced by aortic banding in puppies, is characterized by essentially normal hemodynamics in adult dogs studied at rest and in response to catecholamines in the conscious state. At the cellular level, reduced affinity and increased beta-adrenergic receptor number characterized the LV hypertrophy group, while the EC50 for isoproterenol-stimulated adenylate cyclase activity was normal. By these mechanisms, adequate responsiveness to catecholamines is retained in conscious dogs with severe LV hypertrophy.     

Effects of dibutyryl cyclic AMP on hemodynamics and plasma catecholamine concentrations during ammonium chloride-induced metabolic acidosis in anesthetized dogs

We investigated, using anesthetized dogs, the effect of dibutyryl cyclic AMP (db-cAMP), a derivative of cyclic AMP (cAMP), on cardiovascular variants and plasma catecholamines during metabolic acidosis. These effects were also compared with those of dopamine. The db-cAMP and dopamine were infused at 200 and 20 micrograms/kg.min, respectively. Metabolic acidosis (pH 7.00, PaCO2 40 torr) was induced by the iv infusion of 1-M ammonium chloride solution (NH4Cl). In the normal acid-base state, both db-cAMP and dopamine significantly increased cardiac output and decreased systemic vascular resistance (SVR). During metabolic acidosis, db-cAMP increased cardiac output by 69 +/- 14% and decreased SVR by 36 +/- 2%, while dopamine did not produce changes in cardiac output and increased SVR. Dopamine caused an elevation of epinephrine and norepinephrine in the normal acid-base state, but db-cAMP did not. During metabolic acidosis, dopamine significantly increased the plasma concentration of epinephrine and norepinephrine, while db-cAMP significantly decreased epinephrine concentration. These results suggest that db-cAMP may have a more beneficial effect on hemodynamics compared with dopamine when therapeutic support is needed during circulatory insufficiency with severe metabolic acidosis.     

Differential effects of carvedilol and metoprolol succinate on plasma norepinephrine release and peak exercise heart rate in subjects with chronic heart failure

Dosing equivalency of carvedilol and metoprolol remains a debate. Degree of beta 1-blockade is best assessed by blunting of the exercise-induced heart rate. Accordingly, the authors have investigated dosing equivalency by examining baseline and peak exercise heart rates and norepinephrine levels in subjects with chronic heart failure treated with carvedilol or metoprolol. Thirty-seven subjects treated with carvedilol (32.9 +/- 3.5 mg; n = 23) or metoprolol succinate (XL) (96.4 +/- 15.9 mg; n = 14) referred for cardiopulmonary exercise testing were studied prospectively. Carvedilol versus metoprolol XL subjects did not differ with respect to baseline heart rate (73 +/- 2 vs 70 +/- 3 bpm), or baseline plasma norepinephrine levels (597.5 +/- 78.3 vs 602.1 +/- 69.6 pg/mL), P = NS. However, despite similar peak exercise norepinephrine levels (2735.8 +/- 320.1 vs 2403.1 +/- 371.6 pg/mL), heart rate at peak exercise was higher in subjects receiving carvedilol (135 +/- 4 bpm) than those receiving metoprolol XL (117 +/- 6 bpm), P = 0.02. Similar norepinephrine release and more complete beta 1-blockade is observed in well-matched subjects with chronic heart failure treated with a mean daily dose of metoprolol XL 96.4 mg compared with carvedilol 32.9 mg.     

Quantitative analysis of the contribution of pulmonary and hind limb circulation to the clearance of exogenous catecholamines

The contribution of pulmonary and hind limb circulation to the clearance of exogenous catecholamines was analyzed quantitatively. During infusion of clinical doses of norepinephrine, epinephrine and dopamine in dogs, the plasma level of catecholamine and the plasma flow were measured simultaneously. Percentage of contribution was calculated from the following equation; transorgan difference of plasma catecholamine (nanograms per milliliter) X plasma flow (milliliters per minute) X 100/dose (nanograms per minute). This value means the percentage of the amount of catecholamine cleared by an organ to the amount of catecholamine administered into the body. Small but significant transpulmonary gradients of plasma levels of norepinephrine, epinephrine and dopamine and large translimb gradients of plasma levels of these catecholamines were observed. The plasma flow of pulmonary circulation was increased by infusion of epinephrine and dopamine, whereas it remained unchanged by infusion of norepinephrine. The plasma flow of hind limb circulation showed no significant change by infusion of catecholamines. The calculated contribution values indicate that pulmonary circulation clears 35.7% of norepinephrine (at 0.2 ng X kg-1 X min-1), 27.1% of epinephrine (0.2 ng X kg-1 X min-1) and 21.5% of dopamine (10 micrograms X kg-1 X min-1) administered exogenously, and that the corresponding figures for hind limb circulation are 8.2, 7.8 and 4.5%.     

Evaluation of a new method for the analysis of free catecholamines in plasma using automated sample trace enrichment with dialysis and HPLC

BACKGROUND: Analysis of urinary free catecholamines was automated recently, but analysis of plasma samples posed special difficulties. The present study was undertaken to evaluate a new method for the automated analysis of plasma catecholamines. METHODS: The procedure is based on an improved sample handling system that includes dialysis and sample clean-up on a strong cation trace-enrichment cartridge. The catecholamines norepinephrine, epinephrine, and dopamine are then separated by reversed-phase ion-pair chromatography and quantified by electrochemical detection. RESULTS: Use of a 740- microL sample is required to give the catecholamine detection limit of 0.05 nmol/L and analytical imprecision (CV) between 1.1% and 9.3%. The assay can be run unattended, although >12 h of analysis time is not recommended without cooling of the autosampler rack. Comparison (n = 68) of the automated cation-exchange clean-up with the well-established manual alumina procedure gave excellent agreement (mean, 3.78 +/- 2.76 and 3.8 +/- 2.89 nmol/L for norepinephrine and 0.99 +/- 1.72 and 1.08 +/- 1.78 nmol/L for epinephrine). Hemodialysis had no clear effect on plasma norepinephrine. Epinephrine concentrations were similar (0.05 < P < 0.1) in chronic renal failure patients (0.24 +/- 0.3 nmol/L; n = 15) and healthy controls (0.5 +/- 0.24 nmol/L; n = 31). Dopamine was not quantified, being usually <0.2 nmol/L. CONCLUSION: The availability of such a fully automated procedure should encourage the more widespread use of plasma catecholamine estimation, e.g., after dialysis, exercise, or trauma/surgery and in the investigation of catecholamine-secreting tumors, particularly in the anuric patient.