Increase In Plasma Norepinephrine Concentration Research Articles

Norepinephrine kinetics in dogs with experimentally induced renal vascular hypertension.

To determine norepinephrine (NE) kinetics in dogs with experimentally induced renal vascular hypertension. 4 mixed-breed dogs. The study comprised a control and hypertensive period. The hypertensive period followed induction of renal vascular hypertension achieved by surgical placement of clips on both renal arteries to reduce diameter by approximately 80%. Arterial blood pressure, renal clearance, and NE kinetics were measured during each period while dogs were receiving a low-sodium diet. Measurements of NE kinetics and renal clearance during the hypertensive period were made 5 days after induction of hypertension. Five days after induction of hypertension, arterial blood pressure increased by 15 to 20 mm Hg. Mean (+/- SEM) plasma NE concentration and NE spillover rate increased significantly from 151.5+/-14.1 pg/ml and 8.03+/-0.62 ng/kg/min, respectively, during the control period to 631.4+/-30.5 pg/ml and 54.0+/-5.2 ng/kg/min, respectively, during the hypertensive period. Norepinephrine clearance rate also increased (54.0+/-2.4 vs. 86.0+/-9.3 ml/kg/min). Positive associations between mean arterial pressure (MAP) and NE concentration and spillover rate were detected. However, MAP and NE clearance rate were not associated. Increased blood pressure during the hypertensive period was likely attributable to increased NE spillover rate, which resulted in a significant increase in plasma NE concentration. Analysis of these results suggests that central sympathetic outflow was increased and may be responsible for the pathogenesis of high blood pressure during the acute phase of renal vascular hypertension in dogs.

Renin-angiotensin system and sympathetic nervous system in cardiac pressure-overload hypertrophy.

Angiotensin II and norepinephrine (NE) have been implicated in the neurohumoral response to pressure overload and the development of left ventricular hypertrophy. The purpose of this study was to determine the temporal sequence for activation of the renin-angiotensin and sympathetic nervous systems in the rat after 3-60 days of pressure overload induced by aortic constriction. Initially on pressure overload, there was transient activation of the systemic renin-angiotensin system coinciding with the appearance of left ventricular hypertrophy (day 3). At day 10, there was a marked increase in AT(1) receptor density in the left ventricle, increased plasma NE concentration, and elevated cardiac epinephrine content. Moreover, the inotropic response to isoproterenol was reduced in the isolated, perfused heart at 10 days of pressure overload. The affinity of the beta(2)-adrenergic receptor in the left ventricle was decreased at 60 days. Despite these alterations, there was no decline in resting left ventricular function, beta-adrenergic receptor density, or the relative distribution of beta(1)- and beta(2)-receptor sites in the left ventricle over 60 days of pressure overload. Thus activation of the renin-angiotensin system is an early response to pressure overload and may contribute to the initial development of cardiac hypertrophy and sympathetic activation in the compensated heart.

INCREASED TYROSINE HYDROXYLASE IMMUNOREACTIVITY IN BLADDER TISSUE FROM PATIENTS WITH CLASSIC AND NONULCER INTERSTITIAL CYSTITIS

Interstitial cystitis is a chronic debilitating condition which mainly affects women. Accumulated evidence indicates that interstitial cystitis is a heterogeneous syndrome. The nonulcer subtype appears different than classic interstitial cystitis in regard to symptoms, and endoscopic and histological findings as well as response to various treatments. We further explore the neurogenic nature of this disease using indirect immunofluorescence to evaluate the presence and density of various autonomic and sensory nerve fibers. Specimens from the bladder wall of 6 patients with classic interstitial cystitis, 7 with nonulcer interstitial cystitis and 6 controls were evaluated to determine the presence and density of nerve fibers containing tyrosine hydroxylase, calcitonin gene-related peptide, neuropeptide Y and substance P using specific antibodies, and the general presence of nerve fibers using a mixture of antibodies against nerve filament, neuron specific enolase and S-100 protein. Increased density and number of nerve fibers immunoreactive for tyrosine hydroxylase were noted in interstitial cystitis cases compared to controls. Furthermore, there was a difference between classic and nonulcer disease in the overall density of nerves using the antibody mixture. Our findings indicate an altered peripheral sympathetic innervation in interstitial cystitis cases, which may be an indication of primary neurogenic etiology. The difference in nerve density observed after incubation with the antibody mixture between classic and nonulcer interstitial cystitis supports the hypothesis that the 2 forms represent separate entities.

Association Analysis of Two Tyrosine Hydroxylase Gene Polymorphisms in Normotensive Offspring from Hypertensive Families

Objective: We have studied possible association between predisposition to essential hypertension, plasma noradrenaline level and two polymorphisms of the gene for tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine biosynthesis. Design and Methods: One hundred and one normotensive sons from normotensive parents (SN) and 107 normotensive sons of hypertensive families (SH) were studied. Tetranucleotide TCAT repeat and Val81Met polymorphisms of the TH gene were determined by polymerase chain reaction (PCR) technique. Results: SH had higher systolic BP and plasma noradrenaline concentration than the SN group. No significant difference was found between the allele and genotype frequencies in the SH and SN groups for both polymorphisms. The two polymorphisms were in tight linkage disequilibrium. The CD genotype of the microsatellite marker was associated with increased plasma noradrenaline concentration in both groups. Genotypes AB, AE and BB of the TCAT repeat polymorphism and genotypes VM and MM of the Val81Met polymorphism exhibited the greatest difference in plasma noradrenaline concentration between the SH and SN groups. Conclusion: The studied TH polymorphisms do not appear to be associated with family history of essential hypertension. Nevertheless, some genotypes of TH might be related to disturbance of plasma noradrenaline concentration.

Factors associated with post-operative myocardial ischaemia in elderly patients undergoing major non-cardiac surgery

Forty patients (> 65 years) undergoing hip arthroplasty or peripheral vascular surgery both associated with high risk for post-operative myocardial ischaemia were randomized to receive either spinal or general anaesthesia. Ambulatory ECG recording (Holter) until the third post-operative morning, a daily 12-lead ECG and serum creatine kinase and troponine concentrations were obtained. The number of ischaemic episodes, total duration of ischaemia and ischaemic minutes per hour were noted for each patient perioperatively. Sixteen of the patients (40%) had post-operative myocardial ischaemia. An intra-operative increase in the plasma concentration of norepinephrine but not epinephrine was detected in the patients who later developed post-operative myocardial ischaemia. The increase in plasma norepinephrine concentrations correlated with the decrease in core temperature. The type of anaesthesia had no effect on the incidence of myocardial ischaemia during or after surgery. Our results suggests that intraoperatively decreased core temperature and the increase in plasma concentration of norepinephrine probably caused peripheral vasoconstriction leading to latent cardiac dysfunction. These events should be avoided in the patients at risk of post-operative cardiac ischaemia.

Supine exercise restores arterial blood pressure and skin blood flow despite dehydration and hyperthermia.

We determined whether the deleterious effects of dehydration and hyperthermia on cardiovascular function during upright exercise were attenuated by elevating central blood volume with supine exercise. Seven trained men [maximal oxygen consumption (VO(2 max)) 4.7 +/- 0. 4 l/min (mean +/- SE)] cycled for 30 min in the heat (35 degrees C) in the upright and in the supine positions (VO(2) 2.93 +/- 0.27 l/min) while maintaining euhydration by fluid ingestion or while being dehydrated by 5% of body weight after 2 h of upright exercise. When subjects were euhydrated, esophageal temperature (T(es)) was 37. 8-38.0 degrees C in both body postures. Dehydration caused equal hyperthermia during both upright and supine exercise (T(es) = 38. 7-38.8 degrees C). During upright exercise, dehydration lowered stroke volume (SV), cardiac output, mean arterial pressure (MAP), and cutaneous vascular conductance and increased heart rate and plasma catecholamines [30 +/- 6 ml, 3.0 +/- 0.7 l/min, 6 +/- 2 mmHg, 22 +/- 8%, 14 +/- 2 beats/min, and 50-96%, respectively; all P < 0. 05]. In contrast, during supine exercise, dehydration did not cause significant alterations in MAP, cutaneous vascular conductance, or plasma catecholamines. Furthermore, supine versus upright exercise attenuated the increases in heart rate (7 +/- 2 vs. 9 +/- 1%) and the reductions in SV (13 +/- 4 vs. 21 +/- 3%) and cardiac output (8 +/- 3 vs. 14 +/- 3%) (all P < 0.05). These results suggest that the decline in cutaneous vascular conductance and the increase in plasma norepinephrine concentration, independent of hyperthermia, are associated with a reduction in central blood volume and a lower arterial blood pressure.

Changes of plasma L-arginine levels in spontaneously hypertensive rats under induced hypotension.

Nicardipine, a dihydropyridine type calcium channel blocker, was infused at two flow-rates into spontaneously hypertensive (SH) and control normotensive Wistar-Kyoto (WKY) rats (young, 6-week-old and adult, 23-week-old, n = 5) under pentobarbital anesthesia, to cause hypotension. Mean arterial blood pressure and the concentrations of plasma amino acids and norepinephrine (NE) were measured before infusion and at each step of the infusion. The reduction in blood pressure caused by nicardipine induced a decrease in plasma L-arginine concentration in both young and adult SH rats, this effect being larger in adult rats. There was no significant change in plasma levels of L-arginine in age-matched WKY rats. The concentration of other amino acids did not change in both rat strains. On the contrary, there was an increase in plasma NE concentration in both SH and WKY rats after infusion with nicardipine. Plasma L-arginine concentration showed a good inverse correlation with the logarithm of plasma NE concentration in SH and WKY rats and the correlation was expressed as Y = -alpha log(X) + m (Y, plasma L-arginine concentration (nmol/mL); X, plasma NE concentration (pmol/mL); alpha, a slope; and m, an intercept). alpha, 43.0 and 4.35 for 23-week-old SH and WKY rats, respectively, and 17.0 and 4.0 for 6-week-old SH and WKY rats, respectively. The present data together with previous data suggest a direct noradrenergic stimulation of the synthesis of nitric oxide (NO) from L-arginine. The findings also indicate an impairment of the L-arginine metabolism or pools in SH rats compared with WKY rats. The deficiency of L-arginine increases with the age of SH rats and could be related to the development and maintenance of hypertension due to inefficient production of NO.

Effects of a sympathetic activation by a lower body negative pressure on glucose and lipid metabolism.

The effects of a sympathetic activation elicited by a lower body negative pressure (LBNP) (at -15 mmHg for 75 min) were assessed in 7 healthy subjects on two occasions: (i) in post-absorptive conditions, and (ii) during glucose infusion (22.2 mumol kg-1 min-1). LBNP increased plasma norepinephrine concentration and heart rate. It did not alter whole-body glucose metabolism (measured with [6,6-2H]glucose) and glycerol turnover (measured with [1,1,2,3,3-2H]glycerol). Interstitial glycerol concentrations were monitored with microdialysis in subcutaneous adipose tissue and in skeletal muscle. LBNP increased dialysate glycerol concentrations in muscle by 16% (P < 0.03) but not in adipose tissue in post-absorptive conditions, and by 37% in adipose tissue (P < 0.05) but not in muscle during glucose infusion. These results indicate that an LBNP-induced sympathetic activation (i) does not increase endogenous glucose production, and (ii) induces only a slight stimulation of lipolysis in adipose tissue during glucose infusion.

Nitric oxide modulates sympathetic control of left ventricular contraction in vivo in the dog

Recently, evidence has been presented that nitric oxide (NO) modulates myocardial contraction induced by β-adrenergic stimulation in vitro and in vivo. In this study, we investigated whether inhibition of the l-arginine NO system augments the positive inotropic response of the left ventricle to direct stimulation of the sympathetic nerves in vivo in the dog. Electrical stimulation was applied to the left stellate ganglion (LSG) for 1 min at submaximal (5 V, 2.5, 5 and 10 Hz) and supramaximal intensities (10 V, 10 Hz) in twelve anesthetized and vagotomized dogs. Next, in the same dogs, N ω -nitro l-arginine methylester ( l-NAME) was infused into the left anterior descending (LAD) coronary artery, and LSG stimulation repeated using the same protocol. Finally, l-arginine was infused into the LAD artery, and LSG stimulation repeated. We used the maximum of the first derivative of left ventricular pressure (LV max d P/d t) as an index of the myocardial contractility. Plasma epinephrine and norepinephrine concentrations were measured in the coronary sinus at 5 V, 2.5 Hz before and after l-NAME treatment in five of twelve dogs. l-NAME treatment significantly augmented the inotropic response of the left ventricle (percent change in the LV max d P/d t) to LSG submaximal stimulation trains from 164±13 to.212±21 ( P<0.03), from 187±15 to 234±25 ( P<0.05) and from 220±19 to 280±33% ( P<0.05), respectively. This response was reversed by l-arginine treatment. However, the inotropic response to the supramaximal stimulation train did not change after l-NAME and l-arginine treatment. l-NAME significantly increased plasma norepinephrine concentration from 0.69±0.41 to 1.00±0.52 ng/ml without changing plasma epinephrine concentration in the coronary sinus. It is concluded that the inhibition of the l-arginine NO system augmented the positive inotropic effect on the left ventricle during sympathetic nerve stimulation in normal dogs in vivo.

Circulatory Dysfunction in Asymptomaticin VitroFertilization Patients. Relationship with Hyperestrogenemia and Activity of Endogenous Vasodilators1

Severe ovarian hyperstimulation syndrome (OHSS) is consistently associated with a circulatory dysfunction characterized by arterial hypotension, low peripheral vascular resistance, and increased activity of the renin-aldosterone system. To investigate whether circulatory dysfunction also occurs in asymptomatic patients undergoing controlled gonadotropin ovarian hyperstimulation under pituitary suppression for in vitro fertilization (IVF), 12 women without clinical manifestations of OHSS underwent sequential blood, urine, and hemodynamic measurements at five study points: the 7th day of the menstrual cycle preceding IVF (study point 1 or baseline), the day when pituitary suppression was shown (study point 2), the day of hCG ovulatory injection (study point 3), the day after hCG was injected (study point 4), and 7 days after hCG administration (study point 5). Mean arterial pressure, cardiac output, peripheral vascular resistance, plasma concentrations of estradiol (E2) and aldosterone, and plasma renin activity (PRA) were measured at each study point in all women. Serum levels of nitrite/nitrate, and plasma concentration of atrial natriuretic peptide, norepinephrine, adrenomedullin, and cyclic guanosine 3'5'-monophosphate were measured in samples obtained at study points 1 and 5. Multiple follicular development during ovarian stimulation associated with increased plasma E2 concentration (mean peak plasma E2 level, 2430 +/- 428 pg/mL, range 1630-3840 pg/mL) were observed in each woman. All patients developed a significant increase in cardiac output and decrease in arterial pressure and peripheral vascular resistance, and a marked elevation in PRA and aldosterone, all indicating the development of arteriolar vasodilation. Changes in circulatory measurements were temporarily related with the increase in E2 both being detected at study points 3-5. In contrast, there was a clear chronological dissociation between the increase in plasma E2 concentration and the stimulation of the renin-aldosterone system. PRA and aldosterone only reached abnormal levels at study point 5 in association with a significant increase in plasma norepinephrine concentration. Serum levels of nitrite/nitrate and plasma concentrations of atrial natriuretic peptide, adrenomedullin, and cyclic GMP were similar at study points 1 and 5. It is concluded that the circulatory dysfunction that characterizes severe OHSS is a universal event in patients undergoing controlled ovarian hyperstimulation for IVF. Although the increase in E2 levels during IVF cycles is associated with significant circulatory changes, the circulatory dysfunction that characterizes severe OHSS is clearly unrelated to the onset of hyperestrogenemia. Arteriolar vasodilation during IVF cycles was not associated with an increased activity of the vasodilator substances atrial natriuretic peptide, adrenomedullin, and nitric oxide.

Effects of various beverages on the hormones involved in energy metabolism during exercise in the heat in previously dehydrated subjects.

The objective of our study was to examine the effects of beverage content on hormone responses involved in fuel substrate metabolism (catecholamines, insulin and glucagon) in previously dehydrated subjects exercising at a moderate intensity in the heat. Six healthy men walked for 60-min on five occasions at 50% maximal oxygen uptake in a warm environment (dry bulb temperature 35 +/- 0.2 degrees C, relative humidity 20%). On each occasion, the subjects were dehydrated before exercise (loss of 2% body mass) by passive controlled hyperthermia, which led to a reduction in plasma volume (PV) of about -5% to -9%. In one session, the subjects exercised without rehydration (Dh). In the other sessions, four beverages (650 ml) were given just before the exercise: mineral water (W), a 60 g x l(-1) glucose and 1.2 g x l(-1) NaCl solution (GS), a 60 g x l(-1) maltodextrin solution, and a 60 g x l(-1) maltodextrin and 1.2 g x l(-1) NaCl solution. Compared to Dh and W, carbohydrate supply with or without NaCl induced a higher glycaemia (P < 0.05), a reduced increase in plasma adrenaline concentration (P < 0.05) and a higher plasma insulin concentration (P < 0.05), which lowered plasma free fatty acids and glycerol concentrations (P < 0.05). The lesser increase in plasma noradrenaline concentrations observed during GS compared to Dh and W sessions can be explained by a larger correction in PV which might have induced better haemodynamic conditions. However, the increase in plasma glucagon with carbohydrate supply--compared to Dh and W (P < 0.05)--remains unexplained.

Elevated plasma norepinephrine after in utero exposure to cocaine and marijuana.

To compare plasma catecholamine concentrations between cocaine-exposed and unexposed term newborns and to determine the relationship between plasma catecholamines and newborn behavior. Forty-six newborn infants participating in a prospective study of the neonatal and long-term effects of prenatal cocaine exposure were studied. Based on maternal self-report, maternal urine screening, and infant meconium analysis, 24 infants were classified as cocaine-exposed and 22 as unexposed. Between 24 and 72 hours postpartum, plasma samples for norepinephrine (NE), epinephrine, dopamine, and dihydroxyphenylalanine analysis were obtained. The Neonatal Behavioral Assessment Scale was administered at 1 to 3 days of age and at 2 weeks of age by examiners masked to the drug exposure status of the newborns. The cocaine-exposed newborns had increased plasma NE concentrations when compared to the unexposed infants (geometric mean, 923 pg/mL vs 667 pg/mL). There were no significant differences in plasma epinephrine, dopamine, or dihydroxyphenylalanine concentrations. Analysis for the effect of potential confounding variables revealed that maternal marijuana use was also associated with increased plasma NE, although birth weight, gender, and maternal use of alcohol or cigarettes were not. Geometric mean plasma NE was 1164 pg/mL in those infants with in utero exposure to both cocaine and marijuana compared to 812 pg/mL in those exposed to only cocaine and 667 pg/mL in those exposed to neither. Among the cocaine-exposed infants, plasma NE concentration correlated with an increased score for the depressed cluster (r = .53) and a decreased score for the orientation cluster (r = -.43) of the Neonatal Behavioral Assessment Scale administered at 1 to 3 days of age. Adjusting for marijuana exposure had no effect on these relationships between plasma NE and the depressed and orientation clusters. Plasma NE is increased in newborns exposed to cocaine and marijuana. Increased plasma NE is associated with selected neurobehavioral disturbances among cocaine exposed infants at 1 to 3 days of life but not at 2 weeks.

Captopril does not Blunt the Sympathoadrenal Response to Cigarette Smoking in Normotensive Humans

Ottesen M. M., Worck R and Ibsen H. Captopril does not blunt the sympathoadrenal response to cigarette smoking in normotensive humans.The aim of this study was to assess whether an interaction exists between the renin-angiotensin system and the sympathetic nervous system at the level of the adrenal medulla during smoking in normal humans. Thirteen habitual smoking volunteers were studied in a randomized, single-dose, double-blind, cross-over fashion using 50 mg captopril vs placebo followed by smoking of two high nicotine content cigarettes within 15 min. Blood samples were obtained at frequent intervals before, during and after smoking. We found that the increase in plasma adrenaline concentration during cigarette smoking was modest. There was no difference between captopril treatment as compared to placebo. Thus, the adrenaline response to cigarette smoking was not blunted by acute blockade of angiotensin IT generation. A significant increase in heart rate, and blood pressure was found as well. No increase in plasma noradrenaline concentration was found. Plasma renin concentration increased significantly during captopril treatment, whereas it decreased throughout the study period in the placebo phase. Plasma angiotensin II concentration decreased in both the captopril treatment and the placebo phase throughout the study period, but this was more pronounced during captopril treatment. In conclusion, cigarette smoking-induced activation of the sympathetic nervous system was not blunted by acute ACE-inhibition by captopril. This indicates that angiotensin II does not facilitate smoking-induced activation of sympathoadrenal activity in humans.

Endocrine, osmoregulatory, respiratory and haematological parameters in flounder exposed to the water soluble fraction of crude oil

Flounders Pleuronectes flesus with an implanted vascular catheter were exposed to a 50% dilution of the water soluble fraction (WSF) of Omani crude oil (c. 6ppm total aromatic hydrocarbons) and serial blood samples taken to determine their endocrine status (cortisol, catecholamines and thyroid hormones) and the resultant and/or causal physiological (haematological, ionoregulatory and respiratory) disturbances. This resulted in a progressive increase in plasma cortisol concentrations from 3 h onwards (rising from 18 to 51 ng ml−1 after 48-h exposure), and increased plasma glucose concentrations indicating a generalized stress response. Plasma T3 and T4 concentrations of both control and WSF-exposed groups declined progressively over the experimental period; exposure to the WSF of crude oil further depressed plasma T4 concentrations but not plasma T3 concentrations relative to those of control fish. Plasma osmolality and sodium and chloride concentrations were stable in WSF-exposed fish, however, plasma potassium concentrations were increased significantly at the 24-and 48-h sampling points. The most profound physiological disturbance in WSF-exposed fish was a dramatic decline in blood oxygen content (CvO2) (from 2–8 to 0–8 ml 100 ml−1 after 48-h exposure), which is likely to be the cause of the increased plasma noradrenaline concentrations from 3 h onwards. Increased noradrenaline is likely in turn to have been responsible for the significant increase in blood haematocrit and blood haemoglobin at the 3-h sampling point, although the dominant effect in the longer-term was a significant decline in both of these haematological parameters.

Endocrine, osmoregulatory, respiratory and haematological parameters in flounder exposed to the water soluble fraction of crude oil

Flounders Pleuronectes flesus with an implanted vascular catheter were exposed to a 50% dilution of the water soluble fraction (WSF) of Omani crude oil (c. 6ppm total aromatic hydrocarbons) and serial blood samples taken to determine their endocrine status (cortisol, catecholamines and thyroid hormones) and the resultant and/or causal physiological (haematological, ionoregulatory and respiratory) disturbances. This resulted in a progressive increase in plasma cortisol concentrations from 3 h onwards (rising from 18 to 51 ng ml−1 after 48‐h exposure), and increased plasma glucose concentrations indicating a generalized stress response. Plasma T3 and T4 concentrations of both control and WSF‐exposed groups declined progressively over the experimental period; exposure to the WSF of crude oil further depressed plasma T4 concentrations but not plasma T3 concentrations relative to those of control fish. Plasma osmolality and sodium and chloride concentrations were stable in WSF‐exposed fish, however, plasma potassium concentrations were increased significantly at the 24‐and 48‐h sampling points. The most profound physiological disturbance in WSF‐exposed fish was a dramatic decline in blood oxygen content (CvO2) (from 2–8 to 0–8 ml 100 ml−1 after 48‐h exposure), which is likely to be the cause of the increased plasma noradrenaline concentrations from 3 h onwards. Increased noradrenaline is likely in turn to have been responsible for the significant increase in blood haematocrit and blood haemoglobin at the 3‐h sampling point, although the dominant effect in the longer‐term was a significant decline in both of these haematological parameters.

Norepinephrine-mediated hypoxic stimulation of embryonic red cell carbonic anhydrase and 2,3-DPG synthesis.

Hypoxia is the stimulus for activation of red cell carbonic anhydrase II (CAII) and 2,3-diphosphoglycerate (2,3-DPG) synthesis of chick red blood cells during late embryonic development. We have tested whether plasma catecholamines are involved as hormonal mediators, because hypoxia is a well-known stimulus for catecholamine release in mammalian fetuses. Plasma catecholamines were measured in 8- to 16-day-old chick embryos. Plasma levels of norepinephrine (NE) were initially low, but its concentration increased rapidly from 2.7 nM (day 12) to 13.4 nM at day 13 and 25.5 nM at day 16. Epinephrine (E) was not detectable before day 13. Short-term hypoxic exposure of day 11 embryos (1-h incubation at 13.5% O2) increased plasma NE concentration fivefold compared with the controls but had no effect on E. During 15-h in vitro incubation of red blood cells from day 11, addition of 1 microM NE to the incubation medium increased the red cell 2,3-DPG concentration nearly threefold and CAII activity sixfold compared with the control. The CAII activity and 2,3-DPG concentration were also increased when cells were incubated with plasma from late chick embryos. The activation was induced by beta-adrenergic stimulation of adenylyl cyclase. Atenolol and propranolol blocked the effects of NE and embryonic chick plasma. Analysis of de novo protein synthesis ([35S]methionine incorporation) demonstrated that catecholamines stimulate the synthesis of several proteins besides CAII. The results indicate that developmental changes of plasma NE concentration are instrumental in the adenosine 3',5'-cyclic monophosphate-dependent activation of CAII and 2,3-DPG synthesis of red blood cells from late chick embryos.

Differential neuroendocrine and behavioral responses to cocaine in Lewis and Fischer rats.

Lewis (LEW) and Fischer 344 (F344) rats differ in responsiveness of the hypothalamo-pituitary-adrenocortical (HPA) axis as well as in their behavioral responses to drugs of abuse. The present experiments were conducted to compare hypothalamic corticotropin-releasing factor (CRF), plasma adrenocorticotropic hormone (ACTH) and plasma corticosterone (CS) responses to cocaine (0-60 mg/kg, i.p.) in LEW and F344 rats. Acute administration of cocaine resulted in decreases in CRF and dose-related increases in CS and ACTH with significant differences observed between the strains. Cocaine also increased plasma norepinephrine concentrations. Although the CS response was increased in the F344 compared to LEW rats, the percent change in the CS response was markedly enhanced in LEW rats. Plasma ACTH concentrations as well as the percentage of the control response were dramatically increased at the 40 mg/kg cocaine dose in the LEW compared to F344 rats. Since cocaine-induced changes in HPA axis activity may contribute to behavioral responses to cocaine, another experiment was performed to compare the locomotor responses to novelty and to acute cocaine between LEW and F344 rats. Strain differences were not observed in the locomotor response to novelty or to cocaine. These data indicate that strain differences exist in the neuroendocrine response to acute cocaine exposure.

The glucose clamp procedure activates the sympathetic nervous system even in the absence of hyperinsulinemia.

There is a well established connection between hyperinsulinemia and hypertension, and activation of the sympathetic nervous system (SNS) by insulin has been proposed as one mechanism. In short term infusion studies, hyperinsulinemia during the euglycemic glucose clamp examination is associated with increased norepinephrine concentration. However, many of the studies lack sufficient control groups. The euglycemic glucose clamp examination could possibly, by discomfort from iv cannulas, the use of heating cuffs, and prolonged immobilization, by itself increase SNS activity. To examine this, we included nine controls, who had saline instead of glucose and insulin infused iv, among other healthy young men (n = 50) who underwent the euglycemic hyperinsulinemic glucose clamp. During hyperinsulinemic clamp, the plasma norepinephrine concentration increased from 0.87 +/- 0.06 to 1.06 +/- 0.05 nmol/L; in the control study, it increased from 0.99 +/- 0.14 to 1.21 +/- 0.11 nmol/L, a significant treatment effect (P < 0.001, by repeated measures analysis of variance), but no group x treatment effect (P = 0.17), i.e. there was no difference between the groups. There were no significant changes in systolic or diastolic blood pressure, heart rate, or plasma epinephrine concentration during the clamps, nor any differences between the groups. We conclude that the increase in plasma norepinephrine concentration observed during an euglycemic glucose clamp examination may be attributed to the procedure itself, and that the inclusion of a control group is mandatory when assessing SNS activity.

Serotonin and thermoregulation: Physiologic and pharmacologic aspects of control revealed by intravenous m-CPP in normal human subjects

Meta-chlorophenylpiperazine (m-CPP), a probe of central serotonergic function, elevates core temperature in rodents, nonhuman primates, and humans via serotonin receptor-mediated mechanisms. To further characterize the thermoregulatory aspects of this response, we studied 16 healthy volunteers using multiple core and skin temperature recording sites. Compared to placebo, intravenous m-CPP (0.08 mg/kg) produced statistically significant biphasic changes in rectal temperature, characterized by initial hypothermia (-0.04 degrees C at 12 minutes) followed by progressive hyperthermia (+0.17 degrees C at 90 minutes). m-CPP also produced significant increases in plasma norepinephrine concentrations. Analysis of the skin temperature recordings suggests that the effector mechanism primarily responsible for m-CPP-induced core hyperthermia is increased metabolic thermogenesis. Individual differences in the magnitude of the hyperthermia were independent of m-CPP plasma concentrations but were found to be linearly correlated with the level of the previous night's core rectal temperature minimum and mean. It appears that m-CPP activates a mode of metabolic thermogenesis governed by a nocturnally sensitive proportional control mechanism. The operation of such a proportional controller is characterized by a set point and a gain, and has been implicated in the general economy of mammalian energy balance.

Co-released adrenaline markedly facilitates noradrenaline overflow through prejunctional β2-adrenoceptors during swimming exercise

The effect of intravenously applied (−)-adrenaline, taken up by and released from sympathetic nerves, on swimming exercise-induced noradrenaline overflow in permanently cannulated adrenal demedullated rats was studied. Adrenaline (100 ng/min) was infused for 2 h, during which a plasma concentration of 500 pg/ml (approximately 2.5 nM) was reached. One hour later plasma adrenaline had returned to undetectable levels. During swimming, adrenaline was released into the plasma in concentrations up to 133 pg/ml and the noradrenaline concentration was markedly enhanced as well. The total catecholamine increase amounted to 178% of control (saline infusion) in the first 3 min of swimming and 165% for the whole 20 min. Cocaine (2.5 mg/kg plus 0.05 mg/kg/min), infused together with adrenaline and continued throughout the experiment, prevented the exercise-induced release of adrenaline and no increase in plasma noradrenaline concentration was observed. Yohimbine (0.25 mg/kg) strongly further enhanced the exercise-induced overflow of both noradrenaline and adrenaline. This further increase was completely blocked by the selective β 2-adrenoceptor antagonist ICI 118,551 ((±)-1-[(2,3-dihydro-7-methyl-1 H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol) (1.0 mg/kg). These results demonstrate that adrenaline can be taken up by sympathetic nerve endings through cocaine-sensitive uptake carriers and is released from these nerves during swimming exercise. Neuronally released adrenaline markedly enhances exercise-induced catecholamine overflow through activation of prejunctional β 2-adrenoceptors.