Increase In Plasma Norepinephrine Concentration Research Articles

Biological Response to Stress During Battlefield Trauma Training: Live Tissue Versus High-Fidelity Patient Simulator.

Tactical Combat Casualty Care (TCCC) training imposes psychophysiological stress on medics. It is unclear whether these stress levels vary with the training modalities selected. It is also unclear how stress levels could have an impact on medical performance and skill uptake. We conducted a pilot study to compare the effects of live tissue (LT) with a high-fidelity patient simulator (SIM) on the level of stress elicited, performance, and skill uptake during battlefield trauma training course in an operating room (OR) and in a simulated battlefield scenario (field). In the report, we studied the effects of training modalities and their changes on stress levels by measuring different biomarkers (salivary amylase, plasma catecholamines, and neuropeptide Y) at various time points during the trauma training course. We found that the training resulted in significant psychophysiological stress as indicated by elevated levels of various biomarkers relative to baseline immediately after both OR and field assessment (p < 0.05). Compared with pre-OR levels, the LT training in the OR resulted in significant increases in the plasma levels of epinephrine, norepinephrine, and neuropeptide (p = 0.013, 0.023, 0.004, respectively), whereas the SIM training in the OR resulted in significant increases in the plasma levels of norepinephrine and neuropeptide (p = 0.003 and 0.008). Compared with pre-field levels, we found significant increases in plasma epinephrine concentration in the SIM group (p = 0.016), plasma norepinephrine concentration in the LT group (p = 0.015), and plasma neuropeptide Y concentration in both LT (p = 0.006) and SIM groups (p = 0.029). No differences in the changes of biomarker levels were found between LT and SIM groups in the OR and field. Compared with pre-field levels, the testing on the same modality as that in the OR in the simulated battlefield resulted in significant increases in norepinephrine and neuropeptide levels (p = 0.013 and 0.015), whereas the testing on different modalities resulted in significant increases in amylase, epinephrine, and neuropeptide levels (p = 0.016, 0.05, 0.018, respectively). There was a significantly larger increase in plasma norepinephrine concentration (p = 0.031) and a trend toward a greater increase in the salivary amylase level (p = 0.052) when the field testing involved a different modality than the OR compared with when OR and field testing involved the same modality. Although most of the biomarkers returned to baseline levels after 24 h, plasma norepinephrine levels remained significantly higher regardless of whether field testing occurred on the same or different modality compared with OR (p = 0.040 and 0.002). TCCC training led to significant increase in psychophysiological stress, as indicated by elevated levels of various biomarkers. The training modalities did not result in any differences in stress levels, whereas the switch in training modalities appeared to elicit greater stress as evidenced by changes in specific biomarkers (amylase and norepinephrine). A comparative study with a larger sample size is warranted.

Acute arterial baroreflex-mediated changes in plasma catecholamine concentrations in a chronic rat model of myocardial infarction.

While it may be predictable that plasma norepinephrine (NE) concentration changes with efferent sympathetic nerve activity (SNA) in response to baroreceptor pressure inputs, an exact relationship between SNA and plasma NE concentration remains to be quantified in heart failure. We examined acute baroreflex‐mediated changes in plasma NE and epinephrine (Epi) concentrations in normal control (NC) rats and rats with myocardial infarction (MI) (n = 6 each). Plasma NE concentration correlated linearly with SNA in the NC group (slope: 2.17 ± 0.26 pg mL−1 %−1, intercept: 20.0 ± 18.2 pg mL−1) and also in the MI group (slope: 19.20 ± 6.45 pg mL−1 %−1, intercept: −239.6 ± 200.0 pg mL−1). The slope was approximately nine times higher in the MI than in the NC group (P < 0.01). Plasma Epi concentration positively correlated with SNA in the NC group (slope: 1.65 ± 0.79 pg mL−1 %−1, intercept: 115.0 ± 69.5 pg mL−1) and also in the MI group (slope: 7.74 ± 2.20 pg mL−1 %−1, intercept: 24.7 ± 120.1 pg mL−1). The slope was approximately 4.5 times higher in the MI than in the NC group (P < 0.05). Intravenous administration of desipramine (1 mg kg−1) significantly increased plasma NE concentration but decreased plasma Epi concentration in both groups, suggesting that neuronal NE uptake had contributed to the reduction in plasma NE concentration. These results indicate that high levels of plasma catecholamine in MI rats were still under the influence of baroreflex‐mediated changes in SNA, and may provide additional rationale for applying baroreflex activation therapy in patients with chronic heart failure.

Ageing is a process where the growth effect of neuronal noradrenaline changes progressively in favour of the flow mediated, neurodegenerative and inflammatory effect of plasma noradrenaline

The noradrenaline stimulus has two components, one excitor, the other inhibitory. Neuronal noradrenaline is the excitor component and plasma noradrenaline is the inhibitory. The balance of effect between the two, the noradrenergic balance, is the controlled variable of the sympathetic system and determines the effect of noradrenaline. Neuronal noradrenaline stimulates tissues by diffusion from their sympathetic nerve endings, plasma noradrenaline does so by diffusion from their microcirculations. Changes in microcirculatory flow, by altering the flow mediated effect of plasma noradrenaline, are mainly responsible for altering the noradrenergic balance in the peripheral tissues; changes in CSF flow are speculated to be mainly responsible for doing the same in the brain, by altering the balance between synaptic noradrenaline in the brain and nonsynaptic noradrenaline in the subarachnoid CSF. When plasma noradrenaline alters the noradrenergic balance it triggers afferent sympathetic activity that alerts hypothalamic neurons to the event and they restore the balance and tissue homeostasis, within milliseconds, by adjusting the level of efferent sympathetic activity they project back to the affected tissue. Because the restoration is so rapid the effect of plasma noradrenaline is normally unobservable and dismissed as not having occurred. Because the hypothalamus is not involved with the responses of isolated canine lateral saphenous vein segments to noradrenaline, the effects of plasma noradrenaline in that preparation are not countered by reactive efferent activity and, consequently, are readily apparent in it. Quantitatively, they have been found to be a function of microcirculatory flow and noradrenaline concentration and, qualitatively, to be inhibitory, dilator, pro inflammatory and neurodegenerative. In life, due to a progressive increase in plasma noradrenaline concentration and, more so, in microcirculatory flow, the noradrenergic balance moves progressively in favour of the neurodegenerative and inflammatory effects of plasma noradrenaline. These observations are the basis of an hypothesis that ageing is caused by a genetically programmed shift in balance away from the growth and anti-inflammatory effects of neuronal noradrenaline, early in life, towards the neurodegenerative and pro-inflammatory effects of plasma noradrenalin, later in life. Death is believed to occur when plasma noradrenaline has damaged the structure of the sympathetic system so much that it can no longer create the minimum quantity of neurotransmitter needed to maintain the level of noradrenergic balance and homeostasis necessary for life.

The balance between the pro-inflammatory effect of plasma noradrenaline and the anti-inflammatory effect of neuronal noradrenaline determines the peripheral effects of noradrenaline

Experiments on canine lateral saphenous vein segments have shown that noradrenaline causes potent, flow dependent effects, at a threshold concentration comparable to that of plasma noradrenaline, when it stimulates a segment by diffusion from its microcirculation (vasa vasorum). The effects it causes contrast with those neuronal noradrenaline causes in vivo and that, in the light of the principle that all information is transmitted in patterns that need contrast to be detected – star patterns need darkness, sound patterns, quietness – has generated the hypothesis that plasma noradrenaline provides the obligatory contrast tissues need to detect and respond to the regulatory information encrypted in the diffusion pattern of neuronal noradrenaline. Based on the implications of that hypothesis, the controlled variable of the peripheral noradrenergic system is believed to be the maintenance of a set point balance between the contrasting effects of plasma and neuronal noradrenaline on a tissue. The hypothalamic sympathetic centres are believed to monitor that balance through the level of afferent sympathetic traffic they receive from a tissue and to correct any deviation it detects in the balance by adjusting the level of efferent sympathetic input it projects to the tissue. The failure of the centres to maintain the correct balance is believed to be responsible for inflammatory and genetic disorders. When the failure causes the balance to be polarised in favour of the effect of plasma noradrenaline that is believed to cause inflammatory diseases like dilator cardiac failure, renal hypertension, varicose veins and aneurysms; when it causes it to be polarised in favour of the effect of neuronal noradrenaline that is believed to cause genetic diseases like hypertrophic cardiopathy, pulmonary hypertension and stenoses and when, in pregnancy, a factor causes the polarity to favour plasma noradrenaline in all the maternal tissues except the uterus and conceptus, where it favours neuronal noradrenaline, that is believed to cause preeclampsia. Finally, the shift in the balance caused by the slow physiological increase in plasma noradrenaline concentration in life is believed to be responsible for ageing.

Direct Protective Effects of Dexmedetomidine Against Myocardial Ischemia-Reperfusion Injury in Anesthetized Pigs

Systemic administration of α2-adrenergic agonists has been shown to protect ischemic myocardium, but the direct effects on ischemia-reperfused myocardium have not yet been clarified. This study was carried out to determine the effects of intracoronary dexmedetomidine (DEX) on the myocardial ischemia-reperfusion injury in anesthetized pigs. In open-chest pigs, the left anterior descending coronary artery was perfused through an extracorporeal circuit from the carotid artery. They received intracoronary infusion of DEX at a rate of 1 ng · mL(-1) (group LD, n = 9), 10 ng · mL(-1) (group MD, n = 9), or 100 ng · mL(-1) (group HD, n = 9) of coronary blood flow or vehicle (group C, n = 12) for 30 min before ischemia. Myocardial stunning was produced by 12-min ischemia of the perfused area of left anterior descending coronary artery and 90-min reperfusion. The effect on reperfusion-induced arrhythmias was evaluated using the incidence of ventricular tachycardia or fibrillation after reperfusion. Regional myocardial contractility was evaluated with segment shortening (%SS). Dexmedetomidine significantly reduced the incidence of reperfusion-induced ventricular arrhythmias. Dexmedetomidine significantly improved the recovery of percentage segment shortening at 90 min after reperfusion (32.6% ± 3.1% in group C, 58.2% ± 2.1% in group LD, 61.1% ± 1.8% in group MD, and 72.0% ± 2.0% in group HD). Dexmedetomidine suppressed the increase in plasma norepinephrine concentration after reperfusion. The results indicate that DEX would exert the protective effect against ischemia-reperfusion injury by the direct action on the myocardium, which is not mediated through the central nervous system.

Increased plasma norepinephrine concentration in psychotic depression

We previously found psychotic depression (PSDEP) to have positively correlating plasma norepinephrine (NE) and vasopressin (AVP) concentrations. Since central noradrenergic activity and plasma NE concentration are highly correlated, this suggests an increased noradrenergic activation of the hypothalamus-pituitary-adrenal axis. We hypothesize the increased release of NE in PSDEP to be an associated mechanism. To test this hypothesis we analyzed the relation between plasma NE and PSDEP in a comparison with non-psychotically depressed patients. Potentially confounding variables were, among others, melancholia and two better validated subcategories in the field of melancholia and endogenous depression, three global dimensions of psychopathology - Emotional Dysregulation, Retardation and Anxiety - smoking habit, and different types of psychotropic and particularly antidepressant treatment. The data from nine patients with PSDEP and 69 patients with non-PSDEP were reanalysed. Analysis of covariance controlling for the effects of tricyclic antidepressant treatment (≥100 mg) and smoking habit showed that PSDEP had an increased concentration of plasma NE. The previously found correlation between plasma NE and AVP was still present after correcting for the effects of confounding variables. The results suggest an increased activity of the sympathetic nervous system in PSDEP that may act as a specific mechanism for increased vasopressinergic activation. This supports the view of PSDEP as a distinct subcategory of major depression.

Effects of the α2-Adrenergic Agonist Clonidine on the Pharmacodynamics and Pharmacokinetics of 3,4-Methylenedioxymethamphetamine in Healthy Volunteers

The mechanism of action of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) involves the carrier-mediated and potentially vesicular release of monoamines. We assessed the effects of the sympatholytic α₂-adrenergic receptor agonist clonidine (150 μg p.o.), which inhibits the neuronal vesicular release of norepinephrine, on the cardiovascular and psychotropic response to MDMA (125 mg p.o.) in 16 healthy subjects. The study used a randomized, double-blind, placebo-controlled crossover design with four experimental sessions. The administration of clonidine 1 h before MDMA reduced the MDMA-induced increases in plasma norepinephrine concentrations and blood pressure but only to the extent that clonidine lowered norepinephrine levels and blood pressure compared with placebo. Thus, no interaction was found between the cardiovascular effects of the two drugs. Clonidine did not affect the psychotropic effects or pharmacokinetics of MDMA. The lack of an interaction of the effects of clonidine and MDMA indicates that vesicular release of norepinephrine, which is inhibited by clonidine, does not critically contribute to the effects of MDMA in humans. Although clonidine may be used in the treatment of stimulant-induced hypertensive reactions, the present findings do not support a role for α₂-adrenergic receptor agonists in the prevention of psychostimulant dependence.

Pressor effect of L-threo-3,4-dihydroxyphenylserine in rats.

The pressor effect of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) in rats and its decarboxylation in vivo have been examined. On i.v. administration, it produces a slow-onset and long-lasting pressor response, but no significant change in heart rate or e.c.g. The pressor effect was markedly reduced by inhibition of peripheral decarboxylase and by blockade of alpha-adrenoceptors. The slow-onset and long-acting pressor effect was also evident when the drug was given orally, while intracerebroventricular administration produced a long-lasting decrease in blood pressure. Noradrenaline (NA) concentrations in the plasma were significantly increased by both i.v. and oral administration of L-threo-DOPS. Elevation of plasma NA concentration by L-threo-DOPS given i.v. was suppressed by inhibition of decarboxylase. The plasma concentration of the drug was highest immediately after its i.v. administration. Its pressor effect was enhanced in rats made hypotensive by chemical sympathectomy with 6-hydroxydopamine (6-OHDA), compared with control rats, nevertheless, L-threo-DOPS produced the same increase in plasma NA concentrations in sympathectomized rats as in the controls. These results indicate that L-threo-DOPS is gradually converted to NA by L-aromatic amino acid decarboxylase in vivo. These findings suggest that L-threo-DOPS may be clinically useful as an oral pressor agent for the treatment of certain disorders related to hypotension.

Estimation of cerebral vascular tone during exercise; evaluation by critical closing pressure in humans

The aim of the present study was to calculate critical closing pressure (CCP) of the cerebral vasculature at rest and during exercise to estimate cerebral vascular tone. Five men and two women were seated upright for 15 min and then performed 15 min of right-legged knee extension exercise at 40, 60 and 75% of their maximal workload (WL(max)). Middle cerebral artery blood velocity (MCA V) and blood pressure in the radial artery were recorded. The CCP was calculated by linear extrapolation from 1 min recordings of pairs of systolic and diastolic pressure and MCA V waveforms from both the right and the left MCA. In both arteries, the CCP increased (right MCA, +6.6 +/- 8.5 mmHg, P = 0.023; left MCA, +7.3 +/- 9.1 mmHg, P = 0.016) during 75% WL(max) without changes in resistance-area product, while femoral vascular resistance of the non-exercising leg decreased (from 0.32 +/- 0.07 to 0.18 +/- 0.05 mmHg min ml(1); P < 0.001). There was no significant difference in CCP between the right and left MCA (P = 0.31). These findings suggest an increase in cerebral vascular tone in both the right and the left MCA from rest to exercise despite a decrease in vascular resistance of the systemic vasculature. In addition, the increases in CCP were related to the increases in plasma noradrenaline concentrations (right, P = 0.001; left, P = 0.025) and decreases in the partial pressure of arterial carbon dioxide (right, P = 0.008; left, P = 0.086), but not to changes in mean arterial pressure (right, P = 0.282; left, P = 0.564) or adrenaline concentrations (right, P = 0.138; left, P = 0.108). We consider that an exercise-induced increase in cerebral vascular tone serves to protect the blood-brain barrier from the exercise-induced hypertension.

Norepinephrine-induced nerve growth factor depletion causes cardiac sympathetic denervation in severe heart failure

In severe congestive heart failure (CHF), sympathetic overactivity correlates with the exacerbation of cardiac performance. To test the hypothesis that the cardiac sympathetic nerve density dramatically changes with the acceleration of circulating norepinephrine (NE) concentration, we investigated the temporal association of nerve growth factor (NGF) expression in the heart and cardiac sympathetic nerve density during the development of CHF in the continuous NE-infused rats. The animals were analyzed at 0-, 1-, 3-, 7-, 14-, and 28-day after implantation of osmotic pump at a rate of 0.05 mg/kg/hr. The cardiac performance was temporally facilitated in NE-exposed rats at 3-day in accordance with the sympathetic hyper-innervation induced by the augmentation of NGF mRNA expression in the heart. In NE-treated rats, left ventricular end-diastolic pressure was significantly increased after 7-day and marked left ventricular hypertrophy and systemic fluid retention were observed at 28-day. CHF-induced sympathetic overactivity further increased plasma NE concentration in NE-treated rats and finally reached to 16.1 ± 5.6 ng/ml at 28-day (control level was 0.39 ± 0.1 ng/ml, p < 0.01). In the decompensated CHF rats at 28-day, the NGF mRNA expression was conspicuously reduced concomitant with the obvious nerve fiber loss confirmed by the immunostaining of nerve axonal marker, PGP9.5 and sympathetic neuron marker, tyrosine hydroxylase. This resulted in the attenuated tissue NE contents and the exacerbating cardiac performance. The cardiac sympathetic fiber loss was also confirmed in NE-exposed DBH (dopamine β-hydroxylase)-Cre/Floxed-EGFP (enhanced green fluorescent protein) mice with severe CHF, in which sympathetic nerve could be traced by EGFP. Our results suggest that the cardiac sympathetic nerve density is strictly regulated by the NGF expression in the heart and long-exposure of high plasma NE concentration caused myocardial NGF reduction, following sympathetic fiber loss in severe CHF animals.

Evidence of vasopressinergic-noradrenergic mechanisms in depression with above-normal plasma vasopressin concentration with and without psychotic features

Previous studies in the field of melancholic or endogenous depression have resulted in support for a subcategory of depression with above-normal plasma vasopressin (AVP) concentration (ANA). Since an analogous animal model with increased release of above-normal plasma vasopressin exhibits reduced Sympathetic-Nervous-System activity, the present study investigated the plasma norepinephrine concentration and the correlation between plasma norepinephrine and AVP in this ANA depression. As psychotic-melancholic patients may have increased plasma norepinephrine concentration, and noradrenergic activation may stimulate AVP release, potentially confounding effects of psychotic features were also investigated. The data set of the same depressed patient sample that was used before, but limited to those with complete hormonal data (n = 75), was re-analysed. ANA depression (n = 14) had negatively correlating AVP and norepinephrine concentrations. A very small subcategory of ANA depression with psychotic features (n = 3) had high plasma norepinephrine concentration, suggesting that this could be an independent subcategory. This was supported by the combination of relatively low above-normal plasma AVP concentrations with the highest severity scores for depression in this subcategory, which does not correspond with the positive correlation between AVP concentration and severity in non-psychotic ANA depression. The results further support the validity of ANA depression and the analogy with the High Anxiety Behaviour animal model of depression. Further investigations are needed to replicate these findings and to search for genetic and traumatic factors involved.

Prolonged activation of the baroreflex decreases arterial pressure even during chronic adrenergic blockade.

Previous studies suggest that prolonged electric activation of the baroreflex may reduce arterial pressure more than chronic blockade of alpha(1)- and beta(1,2)-adrenergic receptors. To determine whether central inhibition of sympathetic outflow has appreciable effects to chronically reduce arterial pressure by actions distinct from well-established mechanisms, we hypothesized that chronic baroreflex activation would lower arterial pressure substantially even during complete alpha(1)- and beta(1,2)-adrenergic receptor blockade. This hypothesis was tested in 6 dogs during adrenergic blockade (AB; 18 days) with and without electric activation of the carotid baroreflex (7 days). During chronic AB alone, there was a sustained decrease in the mean arterial pressure of 21+/-2 mm Hg (control: 95+/-4 mm Hg) and an approximately 3-fold increase in plasma norepinephrine concentration (control: 138+/-6 pg/mL), likely attributed to baroreceptor unloading. In comparison, during AB plus prolonged baroreflex activation, plasma norepinephrine concentration decreased to control levels, and mean arterial pressure fell an additional 10+/-1 mm Hg. Because of differences in plasma norepinephrine concentration, we also tested the acute blood pressure-lowering effects of MK-467, a peripherally acting alpha(2)-antagonist. After administration of MK-467, there was a significantly greater fall in arterial pressure during AB (15+/-3 mm Hg) than during AB plus prolonged baroreflex activation (7+/-3 mm Hg). These findings suggest that reflex-induced increases in sympathetic activity attenuate reductions in arterial pressure during chronic AB and that inhibition of central sympathetic outflow by prolonged baroreflex activation lowers arterial pressure further by previously undefined mechanisms, possibly by diminishing attendant activation of postjunctional alpha(2)-adrenergic receptors.

Salt intake and insulin sensitivity in healthy human volunteers

The literature on salt intake and insulin sensitivity presents a mixed picture, as some studies have shown an increase, whereas others have shown a decrease, in insulin action as sodium intake is enhanced. In some cases, this may relate to the study of salt intake in patients with co-morbidities such as hypertension or diabetes. In the present study, we selected healthy normotensive lean volunteers who underwent a euglycaemic clamp following 6 days of a low-salt diet (20 mmol sodium daily) and, subsequently, 6 days of a high-salt diet (200 mmol sodium daily). Our results show an increase in insulin-mediated glucose disposal during euglycaemic clamp conditions that was significantly higher following the high-salt diet compared with the low-salt diet (7.41+/-0.41 compared with 6.11+/-0.40 mg x kg(-1) of body weight x min(-1) respectively; P=0.03). We measured calf blood flow before and during insulin infusion (no significant change after the two dietary salt interventions was detected) and plasma non-esterified fatty acids (also no significant differences were detected). We observed the expected increases in renin concentration and aldosterone activity in subjects on the low-salt diet, and also observed a significantly less increase in plasma noradrenaline concentration during euglycaemic insulin infusion following the high-salt compared with the low-salt diet. We propose that the 4-5-fold increase in serum aldosterone and the greater increase in plasma noradrenaline concentration following the low-salt intervention compared with the high-salt period may have contributed to the differences in insulin sensitivity following the adjustment in dietary sodium intake.

Hemodynamic and Neurohormonal Predictors and Consequences of the Development of Atrial Fibrillation in Dogs With Chronic Heart Failure

Heart failure increases the risk of atrial fibrillation (AF), which frequently results in heart failure progression. This prospective study examined the contribution of hemodynamic and neurohormonal activation to the spontaneous occurrence of AF in heart failure, and assessed the effects of AF on left ventricular (LV) function and neurohormonal activation. Heart failure (LV ejection fraction [LVEF] 25%-30%) was induced in 27 dogs via sequential coronary microembolizations. Hemodynamic and neurohormonal measurements were performed at 1 month (prior to development of AF) and 4 months post-embolization. During the time between measurements, 10 dogs developed spontaneous AF. Plasma norepinephrine concentration (PNE) at 1 month was higher in animals that subsequently developed AF (576 + 101 vs. 425 + 197 pg/mL, P = .03). There were no significant differences between the groups in 1-month LV end-diastolic pressure (LVEDP), pulmonary artery wedge pressure (PAWP), cardiac output, end-diastolic volume (EDV), LVEF, or plasma renin activity (PRA). At 4 months, cardiac output was lower (2.1 + .4 vs. 2.6 + .6 L/h, P = .02) and PNE was higher (1036 + 857 vs. 508 + 288 pg/mL, P = .03) in dogs with AF versus those in sinus rhythm. There were no significant differences between groups in 4-month LVEDP, PAWP, EDV, LVEF, or PRA. Spontaneous AF in heart failure was preceded by a significant increase in PNE. In animals that developed AF, there was a further decline in cardiac output and increase in PNE.

Variations in the alpha2A-adrenergic receptor gene and their functional effects.

The alpha2A-adrenergic receptor (ADRA2A) plays a central role in the regulation of systemic sympathetic activity and hence cardiovascular responses such as heart rate and blood pressure. The objectives of this study were to systematically search for variants in the ADRA2A gene, to define the gene's haplotype structure, and to examine potential functional effects of these variants. We examined 5957 base pairs of contiguous sequence of ADRA2A (promoter, exonic, and 3'-flanking region) using polymerase chain reaction to amplify the genomic target, followed by bidirectional sequencing, in 135 healthy subjects (85 white and 50 black subjects). Haplotypes were inferred by use of an expectation-maximization algorithm. Primary (plasma norepinephrine concentration) and secondary (resting heart rate and blood pressure) phenotypes were compared among subjects grouped by individual polymorphisms and haplotypes. We identified 41 variants, including 24 novel variants. On the basis of 9 optimally selected markers, 11 haplotypes in 5 haplotype groups were inferred, representing approximately 99% of the cohort. Two uncommon variants in complete linkage disequilibrium (G>C at -1903 and C>G at -1607, identified in 3 black subjects) were associated with significantly increased plasma norepinephrine concentrations (376.7 +/- 6.1 pg/mL versus 218.4 +/- 95.0 pg/mL, P = .011). There was no other significant association between genetic variants or any of the haplotypes with phenotypes. We describe novel variants and the haplotype structure of the ADRA2A gene. Common genetic ADRA2A variants are not important determinants of baseline cardiovascular measures (plasma norepinephrine, heart rate, and blood pressure) in healthy volunteers.

Sympathetic Neural Regulation of Heart Rate Is Robust against High Plasma Catecholamines

The sympathetic regulation of heart rate (HR) may be attained by neural and humoral factors. With respect to the humoral factor, plasma noradrenaline (NA) and adrenaline (Adr) can reportedly increase to levels approximately 10 times higher than resting level during severe exercise. Whether such high plasma NA or Adr interfered with the sympathetic neural regulation of HR remained unknown. We estimated the transfer function from cardiac sympathetic nerve stimulation (SNS) to HR in anesthetized and vagotomized rabbits. An intravenous administration of NA (n = 6) at 1 and 10 microg.kg(-1).h(-1) increased plasma NA concentration (pg/ml) from a baseline level of 438 +/- 117 (mean +/- SE) to 974 +/- 106 and 6,830 +/- 917 (P < 0.01), respectively. The dynamic gain (bpm/Hz) of the transfer function did not change significantly (from 7.6 +/- 1.2 to 7.5 +/- 1.1 and 8.1 +/- 1.1), whereas mean HR (in bpm) during SNS slightly increased from 280 +/- 24 to 289 +/- 22 (P < 0.01) and 288 +/- 22 (P < 0.01). The intravenous administration of Adr (n = 6) at 1 and 10 microg.kg(-1).h(-1) increased plasma Adr concentration (pg/ml) from a baseline level of 257 +/- 86 to 659 +/- 172 and 2,760 +/- 590 (P < 0.01), respectively. Neither the dynamic gain (from 8.0 +/- 0.6 to 8.4 +/- 0.8 and 8.2 +/- 1.0) nor the mean HR during SNS (from 274 +/- 13 to 275 +/- 13 and 274 +/- 13) changed significantly. In contrast, the intravenous administration of isoproterenol (n = 6) at 10 microg.kg(-1).h(-1) significantly increased mean HR during SNS (from 278 +/- 11 to 293 +/- 9, P < 0.01) and blunted the transfer gain value at 0.0078 Hz (from 5.9 +/- 1.0 to 1.0 +/- 0.4, P < 0.01). In conclusion, high plasma NA or Adr hardly affected the dynamic sympathetic neural regulation of HR.

Carvedilol Exerts More Potent Antiadrenergic Effect than Metoprolol in Heart Failure

It is still uncertain whether or not there is a difference between metoprolol and carvedilol for the treatment of congestive heart failure. We attempted to determine the difference between the two beta-blockers in terms of their antiadrenergic effect during exercise in patients with heart failure and their efficacy based on the baseline plasma brain natriuretic peptide concentration. Fifty-three patients with mild to moderate heart failure with a radionuclide left ventricular ejection fraction <40% received open label metoprolol or carvedilol in a randomized fashion. The increase in the heart rate normalized to the increase in the plasma norepinephrine concentration during exercise, was calculated as an index of adrenergic responsiveness during exercise. The increase in heart rate normalized by the increase in plasma norepinephrine concentration, decreased after the initiation of beta-blockers in the carvedilol group, but not in the metoprolol group. The change in cardiac function was more favorable for carvedilol than metoprolol in patients who exhibited a higher baseline brain natriuretic peptide concentration. Carvedilol exerts a more potent antiadrenergic effect than metoprolol during stress in patients with mild to moderate heart failure. Carvedilol appears to be more efficacious than metoprolol in patients who exhibit higher baseline brain natriuretic peptide concentrations. These differences should be kept in mind when selecting appropriate pharmacologic agents in the treatment of heart failure.

Serial Alterations of .BETA.-Adrenergic Signaling in Dilated Cardiomyopathic Hamsters-Possible Role of Myocardial Oxidative Stress-

The relationship between enhanced myocardial oxidative stress and impaired beta-adrenergic signaling remains to be characterized during the development of dilated cardiomyopathy. Alterations in myocardial oxidative stress and beta-adrenergic signaling, as well as left ventricular (LV) functional and structural changes, were evaluated during the development of cardiomyopathy in TO-2 hamsters; F1B hamsters served as controls. LV dysfunction was first apparent at 8 weeks of age and deteriorated thereafter in the TO-2 hamsters. At 32 weeks, the animals exhibited heart failure with an increased plasma norepinephrine concentration. Cardiac myolysis, as demonstrated by elevated plasma concentration of cardiac troponin T, peaked at 8 weeks. The glutathione redox ratio revealed increased oxidative stress in the LV myocardium in TO-2 hamsters even at 4 weeks and became manifest after 8 weeks. The hearts of TO-2 hamsters had significantly reduced superoxide dismutase activity from 8 weeks onward compared with control hamsters. However, glutathione peroxidase activity was unchanged at any time point. The LV functional response to isoproterenol was markedly reduced at 8 weeks, without any apparent changes in the amount of beta-adrenergic signaling molecules, and it deteriorated thereafter. Adenylyl cyclase activity was significantly decreased, despite increased amounts of both G(s) alpha mRNA and protein, in the LV myocardium at 18 weeks. Myocardial oxidative stress is actually enhanced in the initial development of LV dysfunction. Both activation of myocardial oxidative stress and impairment of beta-adrenergic signaling become prominent at the stage of severe LV dysfunction. Myocardial oxidative stress may be involved in the development of beta-adrenergic desensitization.

Effects of Nitrous Oxide on Cardiovascular Response to Laryngoscopy and Endotracheal intubation

Background: Endotracheal intubation in patients undergoing general anesthesia often causes hypertension and tachycardia. Nitrous oxide (), which is frequently used during the induction of anesthesia, is known to augment sympathetic nervous activity in humans. The aim of the present study was to investigate whetheraffects cardiovascular response to intubation. Methods: After IRB approval, 100 ASA I patients (aged 35-60 yr) were assigned randomly to receive one of four concentrations (0, 25, 50 or 75%;n = 25 for each) ofin oxygen throughout the study period, beginning 3 min before intubation. Anesthesia was induced with IV thiopental (5-7 mg/kg) and tracheal intubation was faciliated with IV vecuronium (0.12 mg/kg), while patients were ventilated with the designated concentrations ofin oxygen. After intubation, all patients received 2% sevoflurane andin oxygen via a semiclosed anesthesia circuit. Systolic arterial pressure (SAP), heart rate (HR) and rhythm were recorded before and after intubation at intervals for up to 5 min. Plasma concentrations of catecholamines were measured before and 3 min after induction, and 1 and 5 min after intubation. Results: The intubation caused significant increases in SAP and HR in all groups (P ＜ 0.05). Increasing concentrations ofgradually attenuated the pressor response to intubation, without affecting the tachycardiac response. No significant differences were observed between the groups in plasma concentrations of either norepinephrine or epinephrine: norepinephrine concentration increased significantly 1 min after intubation in all -treated groups, while it remained unchanged in the control group. In contrast, the epinephrine concentration remained unaltered in all -treated groups, but increased significantly in the control group. Incidence of tachycardia, bradycardia, and arrhythmia was not different among the groups. Conclusions: These results indicate thatsuppresses the pressor but not the tachycardiac response associated with endotracheal intubation, while it enhances the increases in plasma norepinephrine concentrations.

Association Analysis of Arg16Gly Polymorphism of the β 2 -Adrenergic Receptor Gene in Offspring from Hypertensive and Normotensive Families

Objective: Since g 2 -adrenergic receptors ( g 2 AR) can influence blood pressure not only by vasodilation, but also participate in noradrenaline release from sympathetic nerve endings, we have studied whether Arg16Gly polymorphism of the g 2 AR gene is associated with predisposition to essential hypertension and increased plasma noradrenaline concentration in offspring from normotensive (SN) and hypertensive parents (SH). Design and methods: The study population consisted of 105 young SN and 101 SH subjects matched for age and body mass index. Arg16Gly polymorphism of the g 2 AR gene was determined by polymerase chain reaction (PCR) technique and subsequent incubation with NcoI restriction enzyme. Resulting fragments were separated using electrophoresis on a 4.2% Metaphor agarose gel. Results: SH already had significantly higher systolic BP, and a tendency to higher diastolic BP than the SN group. The frequency of Arg/Arg homozygotes was significantly increased in SH when compared to SN (25% vs 15%). Results of logistic regression analysis showed the highest relative risk for the Arg/Arg genotype and suggested a recessive action of the Arg16 variant. There was an increased diastolic BP in Arg/Arg homozygotes of the SN group ( p = 0.029). This genotype also had a tendency to increased heart rate in both groups ( p = 0.049). There was no relationship of this polymorphism with plasma noradrenaline concentration. Conclusion: Our findings suggest that genetic variability of the g 2 AR gene is implicated in predisposition to essential hypertension. However, the contradictory results between individual studies indicate that the action of the g 2 AR gene is indirect, through multiple intermediate phenotypes and gene interactions.