Age differences in plasma norepinephrine kinetics in humans

To determine if the increased plasma norepinephrine (NE) of older individuals is due to greater plasma NE appearance rate and/or decreased NE clearance, arterialized plasma NE kinetics were measured in 25 healthy young (27 +/- 6 yr, M +/- SD) and 18 healthy older volunteers (68 +/- 5 yr) using a tritium-labeled NE isotope dilution technique. Basal NE levels were 54% greater in the older participants (282 +/- 24 vs. 183 +/- 11 pg/ml, M +/- SEM, p less than .001). The mean plasma NE appearance rate was 32% higher (0.33 +/- 0.03 vs. 0.25 +/- 0.02 microgram/m2/min, p less than .016) and NE clearance was 19% lower (1.21 +/- 0.08 vs. 1.49 +/- 0.06 L/min/m2, p less than .006) in the older participants. There was a close correlation between NE appearance rate and NE levels (r = .76, p less than .001, N = 43), but only modest inverse correlation between NE clearance and NE levels (r = -.37, p less than .01, N = 43). Stepwise multiple linear regression analysis revealed that NE appearance rate and clearance explained 80% of the variance in NE levels and that 57% of the variance was attributable to NE appearance, F (1,41) = 54.8, p less than .001, compared with only 14% by NE clearance, F (1, 41) = 6.5, p = .01. We conclude that the principal factor accounting for the higher plasma NE levels of older individuals is an increase in plasma NE appearance rate.     

Age differences in the plasma clearance mechanisms for epinephrine and norepinephrine in humans

There is an age-related increase in plasma norepinephrine (NE) in humans that is due to both an increase in NE appearance into plasma and a decrease in plasma NE clearance. However, previous studies demonstrated no difference in plasma epinephrine (EPI) in young and old subjects, and the effect of aging on plasma EPI appearance and clearance is unclear. To study age differences in basal NE and EPI metabolism we infused eight young (aged 19-26 yr) and eight old (aged 64-74 yr) normal subjects with [3H]NE or [3H]EPI (15 microCi/m2 bolus dose plus 0.35 microCi/m2/min for 50 min) to achieve steady state conditions on separate days. The old subjects had higher arterialized plasma NE levels [mean, 217 +/- 13 (+/- SE) vs. 149 +/- 12 pg/mL; P less than 0.005] and plasma NE appearance. In contrast, neither plasma EPI levels (98 +/- 8 vs. 104 +/- 10 pg/mL; P = NS) nor EPI appearance rates were different in the old and young subjects. The plasma clearance rates of EPI and NE were nearly identical in the young subjects (1.63 +/- 0.14 vs. 166 +/- 0.09 L/min X m2; P = NS). Plasma NE clearance was lower in the old compared to the young subjects (1.38 +/- 0.06 vs. 1.64 +/- 0.10 L/min X m2; P less than 0.05) and was lower than EPI plasma clearance in the same subjects. Although NE and EPI can be removed by both neuronal and nonneuronal uptake mechanisms, and mean plasma clearance values for NE and EPI are the same in the young, the age-related decline in catecholamine clearance is specific for NE. This finding implies a differential effect of age on a catecholamine removal mechanism that is specific for NE.     

Failure of plasma norepinephrine to consistently reflect sympathetic activity in humans

To determine whether venous plasma norepinephrine concentrations consistently reflect changes in sympathetic nervous activity, the influence of mental arithmetic, static handgrip, and submaximal bicycle exercise on intra-arterial blood pressure, heart rate, and plasma norepinephrine was studied in 51 subjects with untreated essential hypertension (mean age, 46 years; range, 16-69 years). At rest, plasma norepinephrine was unrelated to age or blood pressure. Mental arithmetic increased mean arterial pressure from 108 +/- 18 to 127 +/- 18 mm Hg (mean +/- S.D.; p less than 0.001) and heart rate from 69 +/- 7 to 93 +/- 13 beats/min (p less than 0.001) but not plasma norepinephrine (547 +/- 297 to 518 +/- 250 pg/ml). Isometric exercise raised mean arterial pressure from 115 +/- 18 to 148 +/- 21 mm Hg (p less than 0.001) and heart rate from 76 +/- 9 to 95 +/- 13 beats/min (p less than 0.001) but not plasma norepinephrine (683 +/- 253 to 741 +/- 253 pg/ml). Bicycle exercise increased mean arterial pressure from 114 +/- 20 to 146 +/- 26 mm Hg (p less than 0.001), heart rate from 77 +/- 9 to 128 +/- 19 beats/min (p less than 0.001), and plasma norepinephrine from 645 +/- 228 to 1151 +/- 462 pg/ml (p less than 0.001). Both the maximum mean arterial pressure and the peak heart rate attained during bicycle exercise were related to the exercise plasma norepinephrine level (r = 0.33, p less than 0.02 and r = 0.28, p less than 0.03, respectively). Increases in plasma norepinephrine with exercise were not greater in older or more hypertensive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Human secretin. Biologic effects and plasma kinetics in humans

The action of synthetic human secretin, which differs in two amino acid residues from porcine secretin, was compared with synthetic porcine secretin in 6 healthy volunteers. Pancreatic secretion was assessed by a marker perfusion technique and plasma secretin concentrations were assessed by a specific radioimmunoassay. Increasing doses of either human or porcine secretin produced increasing bicarbonate output (p less than 0.01), whereas trypsin and lipase were not stimulated over basal. The highest doses of secretin induced a significant increase in pancreatic amylase secretion. The two secretin preparations were found to be equipotent with respect to pancreatic secretion and plasma kinetics. Significant increases of plasma secretin were observed after a steak meal in 15 volunteers (p less than 0.001). When human secretin was infused at postprandial concentrations, significant increases in pancreatic bicarbonate output were observed (p less than 0.05). We conclude (a) that the substitution of two amino acids in human secretin does not affect biologic activity and plasma metabolism of the compound; (b) secretin does not stimulate pancreatic enzyme secretion at physiologic concentrations; and (c) the stimulatory effects of secretin on pancreatic amylase remain to be elucidated. The study suggests that human secretin is a true hormone.     

Yohimbine increases cerebrospinal fluid and plasma norepinephrine but not arginine vasopressin in humans

Previous studies have demonstrated alpha 2-inhibitory regulation of central nervous system (CNS) noradrenergic and arginine vasopressinergic systems. We tested the hypothesis that alpha 2-inhibition of CNS noradrenergic and vasopressinergic systems is tonic in nature by measuring the response of cerebrospinal fluid (CSF) norepinephrine (NE) and arginine vasopressin (AVP) to the alpha 2-antagonist yohimbine in 7 young normal male human subjects. We also evaluated the tonic nature of alpha 2-inhibition of the sympathetic nervous system (SNS) and of AVP release into plasma by measuring the response of plasma NE and plasma AVP to yohimbine. CSF NE was significantly higher following yohimbine as compared to placebo. In contrast CSF AVP did not differ between yohimbine and placebo conditions. Similarly, plasma NE was significantly higher following yohimbine as compared to placebo, while plasma AVP was unchanged. These results support a tonic alpha 2-inhibitory regulatory mechanism for both CNS noradrenergic systems and sympathetic outflow. Such tonic alpha 2-inhibition could not be demonstrated for regulation of AVP levels in CSF or plasma in humans.     

Presynaptic alpha-2 receptors inhibit norepinephrine release in tracheal smooth muscle

The presence of inhibitory presynaptic alpha-2 adrenergic receptors and their ability to modulate nerve-mediated relaxation responses was examined in strips of canine tracheal smooth muscle (TSM). TSM strips were incubated with 3H-labelled norepinephrine (NE), rinsed, and mounted in superfusion chambers for electrical stimulation (ES) of the intramural adrenergic neurons. Yohimbine, an alpha-2 receptor antagonist, increased the release of [3H]NE into the superfusate during ES and decreased the amount of [3H]NE remaining in TSM strips after ES, indicating the presence of presynaptic alpha-2 receptors. Whether these alpha-2 receptors were functional in atropine-treated TSM was determined by comparing the inhibitory effect of ES on TSM contractions induced by histamine in the absence and presence of yohimbine. Relaxation of TSM strips at stimulus frequencies of 1-20 Hz was significantly greater in the presence of yohimbine. Moreover, the stimulus frequency required to produce a 50% relaxation, was 5.1 +/- 0.9 Hz in control strips, but only 2.1 +/- 0.4 in TSM strips pretreated with yohimbine. We conclude that presynaptic alpha-2 receptors serve a functional role in regulating NE release in canine TSM.     

Regulation of glucose kinetics during intense exercise in humans: effects of alpha- and beta-adrenergic blockade

This study examined the effect of combined alpha- and beta-adrenergic blockade on glucose kinetics during intense exercise. Six endurance-trained men exercised for 20 minutes at approximately 78% of their peak oxygen consumption (Vo(2)) following ingestion of a placebo (CON) or combined alpha- (prazosin hydrochloride) and beta- (timolol maleate) adrenoceptor antagonists (BLK). Plasma glucose increased during exercise in CON (0 minutes: 5.5 +/- 0.1; 20 minutes: 6.5 +/- 0.3 mmol. L(-1), P <.05). In BLK, the exercise-induced increase in plasma glucose was abolished (0 minutes: 5.7 +/- 0.3; 20 minutes: 5.7 +/- 0.1 mmol. L(-1)). Glucose kinetics were measured using a primed, continuous infusion of [6,6-(2)H] glucose. Glucose production was not different between trials; on average these values were 25.3 +/- 3.9 and 30.9 +/- 4.4 micromol. kg(-1). min(-1) in CON and BLK, respectively. Glucose uptake during exercise was greater (P <.05) in BLK (30.6 +/- 4.6 micromol. kg(-1). min(-1)) compared with CON (18.4 +/- 2.5 micromol. kg(-1). min(-1)). In BLK, plasma insulin and catecholamines were higher (P <.05), while plasma glucagon was unchanged from CON. Free fatty acids (FFA) and glycerol were lower (P <.05) in BLK. These findings demonstrate that adrenergic blockade during intense exercise results in a blunted plasma glucose response that is due to enhanced glucose uptake, with no significant change in glucose production.     

Role of adrenergic alpha-2-receptors on feeding behavior in layer-type chicks

The present study was designed to investigate the role of brain adrenergic alpha-2-receptors on feeding regulation of layer-type chicks. Intracerebroventricular injection of the adrenergic alpha-2-receptor agonist, clonidine, stimulated food intake. This effect was blocked by co-injection of the alpha-2-receptor antagonist, yohimbine, demonstrating that the alpha-2-receptor is related to stimulation of feeding in layer-type chicks. Stimulation of food intake caused by neuropeptide Y and beta-endorphin was attenuated by co-injection with yohimbine. However, yohimbine did not block prolactin-releasing peptide stimulation of food intake. It is therefore likely that brain adrenergic alpha-2-receptors mediate the orexigenic effects of neuropeptide Y and beta-endorphin in layer-type chicks.     

Alpha-2 adrenergic transmission and human baroreflex regulation

We observed earlier that central alpha-2 adrenoceptor stimulation in mice greatly augments parasympathetic tone. To test the effects in humans, we assessed autonomic vasomotor tone and baroreflex regulation in 9 normal young adults on 2 occasions, once with and once without clonidine. We determined heart rate (HR), beat-by-beat blood pressure (BP), and muscle sympathetic nerve activity. HR variability was analyzed in the time and frequency domain. Pharmacological baroreflex slopes were determined using incremental phenylephrine and nitroprusside infusions. Clonidine lowered resting BP (122+/-4/73+/-3 versus 100+/-7/55+/-3 mm Hg, P<0.01), muscle sympathetic nerve activity (18+/-3 versus 4+/-2 bursts/min, P<0.01), and HR (62+/-3 versus 56+/-3 bpm, P<0.05). The baroreflex heart rate curve was reset to much lower HR values and showed no saturation at low HR. HR variability profoundly increased during clonidine plus phenylephrine (total power: 3224+/-843 versus 8943+/-2329 ms2, P<0.05). High-frequency power was 1451+/-520 at baseline and 6720+/-2475 ms2 during baroreceptor loading (P<0.05). The low-frequency/high-frequency ratio decreased (1.94+/-0.41 versus 0.69+/-0.10, P<0.05). In contrast, clonidine reduced resting sympathetic vasomotor tone and shifted the operating point of the sympathetic baroreflex to a flat part of the sympathetic baroreflex curve. The shift decreased the ability of the baroreflex to withdraw sympathetic vasomotor tone during baroreflex loading. These baroreflex changes were associated with a moderate increase in phenylephrine responsiveness. We conclude that alpha-2 adrenoceptor stimulation has a differential effect on baroreflex HR and vasomotor regulation. alpha-2 Adrenoceptor stimulation greatly augments baroreflex-mediated bradycardia, most likely by parasympathetic activation.     

Age effects on alpha-1-acid glycoprotein concentration and imipramine plasma protein binding

Alpha-1-acid glycoprotein concentration and imipramine binding to plasma proteins were determined in a cohort of 69 subjects, aged 20-97 years. No subject had evidence of acute or chronic inflammatory disease or malignancy, or was receiving tricyclic antidepressant therapy. Alpha-1-acid glycoprotein concentration increased significantly with increasing age (r = 0.28; P less than 0.02). Imipramine percentage not bound to plasma proteins was negatively related to alpha-1-acid glycoprotein concentration (r = -0.30; P less than 0.01); however, there was no relationship between subject age and percentage imipramine unbound. Though alpha-1-acid glycoprotein concentration increases with advancing age, because only a small proportion of the variability is explained by age, with other undefined factors being more important, drugs predominantly bound to alpha-1-acid glycoprotein such as imipramine may not have a clinically or statistically significant change in protein binding with increasing age in the absence of overt clinical illness.     

Impaired endothelial alpha-2 adrenergic receptor-mediated vascular relaxation in the fructose-fed rat.

To investigate the vascular endothelial dysfunction in the insulin resistance syndrome, muscarinic and alpha2-adrenergic mediated relaxations were studied in the fructose-fed rat. Male Sprague-Dawley rats were fed either fructose-rich chow (FFR, n=14) or normal chow (CNT, n=13) for 8 weeks. Systolic blood pressure (SBP) was measured by the tail-cuff method. A 3 mm segment of mesenteric artery was cannulated and pressurized, pretreated with prazosin (10(-6) mol/l) and propranolol (3x10(-6) mol/l), then pre-contracted with serotonin (10(-6) mol/l). Endothelium-dependent relaxation was induced by addition of acetylcholine (ACh, 10(-9)-10(-4) mol/l) or a selective alpha2-agonist, B-HT 920 (10(-9)-10(-5) mol/l), with or without the nitric oxide (NO) synthase inhibitor, L-NAME (10(-4) mol/l). SBP was significantly elevated in FFR but not in CNT. Plasma triglyceride in FFT (241+/-115 mg/dl) was significantly (p<0.01) higher than in CNT (84+/-34 mg/dl). Insulin and insulin/glucose ratio were higher but not significantly. Plasma glucose was not different between the two groups. In the dose-response curves to ACh, maximum relaxation and ED50 were similar between FFR and CNT. Moreover, L-NAME shifted the dose-response curves similarly to the right in both groups. Dose-response curves to B-HT 920, however, showed less relaxation in FFR than in CNT (p<0.05). B-HT 920-induced relaxations were mostly abolished by L-NAME. It is concluded that endothelial alpha2-adrenergic relaxation, predominantly mediated by NO, is likely more sensitive to the development of insulin resistance than muscarinic receptor relaxation in this 8-weeks FFR model. This early impairment of endothelial alpha2-adrenergic relaxation may contribute to the development of hypertension and insulin resistance in the FFR.     

Effects of dietary potassium on the hemodynamics and plasma norepinephrine kinetics in patients with essential hypertension

The effects of dietary potassium on the hemodynamics and plasma norepinephrine (NE) kinetics were studied in 10 patients with borderline hypertension. Potassium supplement (96 mEq daily for 5-7 days) induced a significant (p less than 0.05) fall in blood pressure and a slight decrease in cardiac output. Both urine volume and urinary sodium excretion increased significantly (p less than 0.05) for a first few days following the potassium supplement. The baseline values of the half-time of the rapid NE removal from plasma was significantly delayed in the hypertensive patients (1.05 +/- 0.06 min, p less than 0.05) when compared with those (0.88 +/- 0.04) in normal controls. Potassium supplement induced a significant rise in both plasma NE levels and NE outflow rate (p less than 0.01) in the hypertensive patients, while their half-times were significantly shortened (0.89 +/- 0.07 min, p less than 0.01). The pressor responsiveness to exogenously infused NE tended to diminish during the potassium supplement. These findings indicate that a high potassium intake might accelerate the slowed neuronal NE uptake in the hypertensive patients, while a potassium-induced fall in blood pressure might exert a baroreflex stimulation of NE release. As a net result, an increased NE outflow into the circulation has been confirmed. It is likely that a natriuresis-induced volume contraction might be a predominant factor responsible for the early reduction of blood pressure during the high potassium intake.     

Estimation of intrasynaptic norepinephrine concentrations in humans

Levels of synaptic cleft norepinephrine associated with pressor responses were estimated in humans by measuring blood pressure and arterial plasma norepinephrine during norepinephrine infusion and during yohimbine-induced release of endogenous norepinephrine. Linear pressor response-log norepinephrine concentration relationships were observed during the infusions. At a pressor response of 20 mm Hg, arterial norepinephrine averaged 3647 pg/ml. The pressor-log norepinephrine relationship was shifted more than fivefold to the left during combined ganglionic, alpha 2-adrenergic receptor, and Uptake1 (neuronal norepinephrine uptake) blockade: arterial norepinephrine averaged 684 pg/ml at a 20 mm Hg pressor response. During yohimbine-induced release of endogenous norepinephrine in desipramine-pretreated subjects, arterial norepinephrine averaged 467 pg/ml at a 20 mm Hg pressor response. Since the norepinephrine concentration in the synaptic clefts must have been between the values for plasma norepinephrine during its infusion and during its endogenous release, we estimated that in healthy people, a 20 mm Hg sympathetically mediated pressor response is associated with about a 560 pg/ml (3.3 nM) concentration of norepinephrine in the average neuroeffector junction.     

Cardiac norepinephrine kinetics in hypertrophic cardiomyopathy

We examined the uptake and release of norepinephrine in the cardiac circulation and other regional vascular beds in 11 patients with hypertrophic cardiomyopathy (HCM) and in 10 control subjects during simultaneous infusion of tracer-labeled norepinephrine and isoproterenol. Cardiac neuronal uptake of norepinephrine was assessed by comparing regional removal of tracer-labeled norepinephrine with that of tracer-labeled isoproterenol (which is not a substrate for neuronal uptake) and by the relation between production of dihydroxyphenylglycol (DHPG), an exclusively intraneuronal metabolite of norepinephrine, and regional spillover of norepinephrine. Cardiac extraction of norepinephrine averaged 59 +/- 17% in the patients with HCM, significantly less than in the control subjects (79 +/- 13%, p less than 0.05), whereas cardiac extraction of isoproterenol was similar in the two groups (13 +/- 23% versus 13 +/- 14%), indicating that neuronal uptake of norepinephrine was decreased in the patients with HCM. The cardiac arteriovenous difference in norepinephrine was significantly larger in the patients with HCM than in the control subjects (73 +/- 77 versus 13 +/- 50 pg/ml, p less than 0.05), as was the product of the arteriovenous difference in norepinephrine and coronary blood flow (7.3 +/- 7.3 versus 0.8 +/- 3.0 ng/min, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Interactive alpha- and beta-adrenergic actions of norepinephrine in rat cardiac myocytes

We investigated the effects of the physiological neurotransmitter norepinephrine on the contractile properties and Ca2+ dynamics of isolated cardiac myocytes, with particular emphasis on possible interactions between alpha- and beta-adrenergic effects. Individual rat ventricular myocytes were electrically stimulated at a frequency of 1 Hz. Norepinephrine (10(-9) to 10(-5) M) increased extent and velocity of shortening and decreased the contraction duration. beta-Adrenergic activation gave a greater enhancement of extent and velocity of shortening than did norepinephrine alone (i.e. alpha plus beta). Neither alpha 1 nor alpha 2 adrenergic activation individually produced a significant impact upon contraction. Using suspensions of myocytes loaded with Quin-2, we also studied resting levels of cytosolic Ca2+ ([ Ca2+]c), the increase of [Ca2+]c due to caffeine-addition (as an index of sarcoplasmic reticulum Ca2+ content) and the subsequent increase in [Ca2+]c due to depolarization with 30 mM K+ (as an index of sarcolemmal voltage-dependent Ca2+ channel activity). Norepinephrine decreased resting [Ca2+]c, increased sarcoplasmic reticulum Ca2+ content and increased Ca2+ channel activity. beta-Adrenergic activation produced the same effect on resting [Ca2+]c and sarcoplasmic reticulum content, but gave significantly greater activation of sarcolemmal Ca2+ channel activity, than did norepinephrine (alpha plus beta). By contrast, alpha-adrenergic stimulation had no effect on resting [Ca2+]c or sarcoplasmic reticulum Ca2+ content. We conclude that beta-mediated effects predominate in the action of the physiological agonist norepinephrine on cardiac myocytes. However, alpha (specifically alpha 1)-adrenergic effects are significant in diminishing the potentiation of the extent and velocity of shortening, and of depolarization-induced entry of Ca2+ into the cell, which is seen on beta-stimulation alone. Thus, there may be an intrinsic feedback effect in the actions of norepinephrine on the cardiac myocyte.     

The role of protein kinase C and calcium in the regulation of norepinephrine release from the vascular adrenergic neurons in hypertension

This study was designed to investigate the role of protein kinase C and calcium in vascular adrenergic transmission in hypertension. In perfused mesenteric vasculatures of spontaneously hypertensive rats (SHR, 7 to 10 weeks old) and age-matched Wistar-Kyoto rats (WKY), we have examined the effects of the protein kinase C inhibitor H-7 on endogenous norepinephrine release and vascular responsiveness during nerve stimulation. Endogenous norepinephrine release and pressor responses during periarterial nerve stimulation were significantly greater in SHR than in WKY. The protein kinase C inhibitor H-7 inhibited the stimulation-induced norepinephrine release and pressor responses in a dose-dependent manner. The magnitude of these suppressive responses were more pronounced in SHR than in WKY. Calcium removal from extracellular fluid also reduced the norepinephrine release more strongly in SHR than in WKY. These results demonstrate that the regulation of norepinephrine release might be more dependent on protein kinase C and calcium in the blood vessels of SHR, which could contribute, at least partially, to the pathogenesis of this form of hypertension.     

The effect of diet or exercise on plasma norepinephrine kinetics in moderately obese young men

An increase in sympathetic nervous system (SNS) activity in the obese has been described by some but not all investigators. It is possible that an increase in SNS tone may play a role in the predisposition to atherosclerotic cardiovascular disease noted in the obese. The effect of dietary weight loss or exercise training on resting SNS activity in moderately obese subjects has not been extensively studied and the results of previous studies are conflicting. Therefore, we prospectively evaluated resting SNS activity in healthy moderately obese subjects randomized to either a three month dietary weight loss (n = 13) or endurance exercise training (n = 18). All subjects were weight stabilized on a constant composition diet for 10 days prior to study both before and after the interventions. Although both groups lost weight, weight loss was greater in the diet group (-13.6 +/- 6.7 vs -2.3 +/- 3.4 kg, P less than 0.001). The composition of weight loss was also different with 32 percent of total weight loss as fat free mass (FFM) in the dieters compared to no significant change in FFM in the exercisers. The caloric requirement for weight stabilization declined after the diet but increased following exercise training (-247 vs + 202 kcal/day, P less than 0.001). No significant changes in blood pressure occurred in either group, and neither group had a significant change in resting plasma norepinephrine concentration. Plasma epinephrine concentrations were also unchanged. However, SNS activity as reflected by arterialized plasma NE kinetics revealed that NE appearance rate declined by 17 percent after dietary weight loss (P less than 0.01), but was not significantly changed after exercise training. These results suggest that dietary weight loss is more effective than exercise training in reducing overall resting SNS activity in normotensive subjects. Since exercise training is known to reduce the SNS response to a given submaximal workload, a combination of diet plus exercise might be the most effective way to reduce overall SNS activity and its possible role in the premature atherosclerosis associated with obesity.     

Neuropeptide Y, orthosympathetic nervous system, hypertension and alpha-2 adrenergic receptors]

Neuropeptide Y (NPY) is coreleased with noradrenaline (NA) from sympathetic nerve endings. In vitro data suggest that NPY is coreleased during high stimulation frequencies. The present study investigates plasma levels of catecholamines and neuropeptide Y (NPY) during changes in sympathetic nervous activity in conscious dogs. Increase in sympathetic tone: arterial hypertension elicited by sinoaortic denervation induced an increase (X 2) in plasma noradrenaline (NA) but no change in NPY levels. High (0.5 mg/kg i.v.) but not low (0.05 mg/kg i.v.) doses of yohimbine rose plasma NPY concentrations. Decrease in sympathetic tone: clonidine (10 micrograms/kg i.v.) but not beta-blocking agents (propranolol or atenolol: 1 mg/kg i.v.) reduced plasma NPY levels. These results show that NPY is correleased in vivo from sympathetic nerve endings during marked and rapid increases in sympathetic tone. They suggest a lack of relationship between NA and NPY release. Alpha 2-adrenoceptors are involved in the presynaptic control of NPY release from sympathetic tone. Finally, some antihypertensive drugs (clonidine but not beta-blocking agents) are able to decrease plasma NPY levels.     

Abnormal norepinephrine clearance and adrenergic receptor sensitivity in idiopathic orthostatic intolerance

BACKGROUND: Chronic orthostatic intolerance (OI) is characterized by symptoms of inadequate cerebral perfusion with standing, in the absence of significant orthostatic hypotension. A heart rate increase of >/=30 bpm is typical. Possible underlying pathophysiologies include hypovolemia, partial dysautonomia, or a primary hyperadrenergic state. We tested the hypothesis that patients with OI have functional abnormalities in autonomic neurons regulating cardiovascular responses. METHODS AND RESULTS: Thirteen patients with chronic OI and 10 control subjects underwent a battery of autonomic tests. Systemic norepinephrine (NE) kinetics were determined with the patients supine and standing before and after tyramine administration. In addition, baroreflex sensitivity, hemodynamic responses to bolus injections of adrenergic agonists, and intrinsic heart rate were determined. Resting supine NE spillover and clearance were similar in both groups. With standing, patients had a greater decrease in NE clearance than control subjects (55+/-5% versus 30+/-7%, P<0.02). After tyramine, NE spillover did not change significantly in patients but increased 50+/-10% in control subjects (P<0.001). The dose of isoproterenol required to increase heart rate 25 bpm was lower in patients than in control subjects (0.5+/-0.05 versus 1.0+/-0.1 microg, P<0.005), and the dose of phenylephrine required to increase systolic blood pressure 25 mm Hg was lower in patients than control subjects (105+/-11 versus 210+/-12 microg, P<0.001). Baroreflex sensitivity was lower in patients (12+/-1 versus 18+/-2 ms/mm Hg, P<0.02), but the intrinsic heart rate was similar in both groups. CONCLUSIONS: The decreased NE clearance with standing, resistance to the NE-releasing effect of tyramine, and increased sensitivity to adrenergic agonists demonstrate dramatically disordered sympathetic cardiovascular regulation in patients with chronic OI.