Higher Norepinephrine Research Articles

Defective glucoregulation of brain alpha 2-adrenoceptors in obesity-prone rats.

Only half the male Sprague-Dawley rats fed high-energy diets develop diet-induced obesity (DIO); the rest are diet resistant (DR). It has been established that rats prone to develop DIO have decreased basal brain alpha 2-adrenoceptor levels compared with DR-prone rats and that DIO- but not DR-prone rats show glucose-induced increases in plasma norepinephrine (NE) levels. Because it has also been shown that alpha 2-adrenoceptors modulate ingestive and autonomic functions and are responsive to changes in plasma glucose levels, we tested the hypothesis that DIO- and DR-prone rats would regulate these receptors differently by using hyperinsulinemic clamping to vary plasma glucose levels. Rats with low glucose-induced plasma NE responses (DR-prone) showed significant positive correlations (r = 0.724-0.919) between plasma glucose levels and alpha 2-adrenoceptor ([3H]paraminoclonidine) binding in 5 of 17 brain areas (anterior, ventromedial, and arcuate hypothalamic nucleus; medial and basomedial amygdalar nucleus) assessed by autoradiographic techniques. Near-significant correlations were also seen in the paraventricular nucleus and lateral hypothalamus. High glucose-induced NE responders (DIO-prone) showed such a correlation only in the arcuate nucleus (r = 0.726). There was little glucoregulation of alpha 1-adrenoceptors. The defective ability of DIO-prone rats to alter brain alpha 2-adrenoceptors to changes in plasma glucose levels might underlie their predisposition to become obese on diets high in sucrose.

Plasma neurotransmitters throughout an oral glucose tolerance test in non-depressed essential hypertension patients.

The oral glucose tolerance test (OGTT) with plasma neurotransmitter assays and blood pressure measurements were performed on 68 hypertensive (A and B) and 68 paired normal controls (group C). Those patients who failed to show significant or persistent blood pressure reductions throughout OGTT constitute group A (37 subjects); and those who did show significant and persistent reductions constitute group B (31 subjects). The purpose of this study was to assess if there were any significant differences between those patients whose blood pressure levels normalized throughout OGTT and those who didn't and, further, compare them to their controls. In group A, noradrenaline (NA) was high at the 0' (fasting) period, increasing further at 60' and 90'; however, circulating serotonin (p5HT) did not vary throughout OGTT. Group B, although showing high NA at 0', did not show rises afterwards; whereas, significant and sustained p5HT rises registered throughout postprandial periods. In group C, both p5HT and plasma NA showed significant and sustained increases. Therefore, the NA/p5HT ratio is higher in A, than in B and C. Group A patients were awake and alert throughout. Group B patients were mostly drowsy and many slept light and intermittently. Group C subjects slept throughout, dreaming and showing rapid eye movements. Our findings suggest that the hypertensive syndrome is most severe in those patients who do not show a rise in postprandial circulating serotonin (parasympathetic activity), group A, than those who do exhibit such a rise, group B.

Alterations of binding characteristics of alpha 1-,beta 1-adrenoceptors and Ca2+ binding sites in the myocardium of spontaneously hypertensive rats (SHR) by chronically administered bunazosin, atenolol, ketanserin and verapamil.

The effects of chronic treatment with bunazosin, atenolol, ketanserin and verapamil on the myocardium of the spontaneously hypertensive rat (SHR) were examined by the radioligand binding assay method using [3H]prazosin, [125I]iodocyanopindolol and [3H]nitrendipine binding to alpha 1- and beta 1-adrenergic receptors and Ca2+ binding sites. The norepinephrine concentration in the rat myocardium was also determined. (1) All of these drugs lowered the elevated blood pressure of the SHR. (2) Only ketanserin administration increased the Kd value of the alpha 1-adrenoceptor in the SHR. (3) Administration of atenolol and ketanserin to the SHR decreased the Bmax value of the beta 1-adrenoceptor. (4) Verapamil, bunazosin and atenolol also lowered the Bmax values of the Ca2+ binding sites of SHRs. (5) All drugs except for atenolol lowered the norepinephrine concentration in the myocardium of the SHR. These findings suggest that the SHR has an abnormality of the alpha 1- and beta 1-adrenoceptors and Ca2+ binding site of the myocardium, that the drugs had a beneficial effect on these receptors, that the drugs could also lower the high norepinephrine content in the myocardium of the SHR and that some of these drugs also affected the binding characteristics of other types of membrane receptors.

A histofluorescent study of sympathetic innervation of human palatine tonsils.

The glyoxylic catecholaminergic histofluorescence method was employed on human palatine tonsil specimens in order to study the sympathetic innervation present. One percent neutral red was used as a counterstain. Abundant sympathetic fibers were demonstrable around the blood vessels of the medulla and capsule. However, few sympathetic fibers were found around the vessels of the subepithelial connective tissue and interfollicular septa. In the areas of the follicle and extrafollicle where B and T lymphocytes were located, sympathetic fibers were not found. These findings indicate that if sympathetic innervation can affect T and B cells, it will do so indirectly. Results also show that there is a higher norepinephrine content in focally infected tonsils that is not due to hyperactivity of the sympathetic nerve, but may be due to other mechanisms. Finally surgical dissection at the capsule during tonsillectomy will reduce bleeding, perhaps because vessels there have an abundant sympathetic innervation that leads to good vessel contraction.

Neuroendocrine and behavioral responses during conditioned active and passive behavior in the defensive burying/probe avoidance paradigm: Effects of ipsapirone

Plasma epinephrine (E), norepinephrine (NE), and corticosterone (CORT) concentrations were determined in the rat before, during, and after a 15-min exposure to a nonelectrified probe one day after receiving electric shock (1.5 mA) through a probe mounted on the wall of the home cage. Rats displayed burying (active coping) if sawdust was provided on the floor and immobility (passive coping) if bedding was absent both during training and testing. The conditioned burying was accompanied by high plasma NE but low E and CORT concentrations, whereas immobility was associated with high CORT and low NE levels. A forced switch from the active to passive coping (training with and testing without sawdust) led to the highest rise in E concentration. The 5-HT 1A agonist ipsapirone, with anxiolytic properties, dose-dependently (0.5 and 2.5 mg/kg, IV) reduced defensive burying behavior and increased the amount of time spent on feeding behavior in the presence of bedding material. Both plasma E and CORT levels were further elevated by the higher dose of ipsapirone. In the absence of bedding material, ipsapirone failed to affect immobility behavior, but it dose-dependently elevated the stress-induced increase in E, NE, and CORT concentrations. Accordingly, the behavioral anxiolytic action of the 5-HT 1A agonist ipsapirone was restricted to active coping, whereas neuroendocrine activation by the drug was present in all conditions. It is suggested that the effects of ipsapirone on behavioral coping and neuroendocrine regulation are produced by different populations of 5-HT 1A receptors in the brain.

The role of epinephrine, norepinephrine, and dopamine in blood pressure disturbances in patients with pheochromocytoma.

Fifty-six patients with pheochromocytoma underwent surgery during the 9-year period from 1981 to 1990. These patients were divided into two groups according to whether the dominant plasma concentration was of epinephrine or norepinephrine. Plasma levels of the catecholamines were stratified into three grades at 5 and 10 times the normal upper limit. Pre-operative disturbances of blood pressure, sustained or paroxysmal, and normal blood pressure were highly correlated with the dominantly secreted catecholamine and its plasma concentration. Thirteen patients with high plasma norepinephrine levels (greater than or equal to 10 times normal) had sustained hypertension while 18 patients with moderate to high plasma epinephrine levels (greater than or equal to 5 times normal) had paroxysmal hypertension. In the majority of normotensive patients (12 of 14), plasma catecholamine levels were less than 10 times the upper normal limit. Urinary excretion of dopamine and size of the tumor were analyzed according to these patient groups. In the norepinephrine dominant group, urinary dopamine excretion tended to be proportional to the plasma epinephrine levels and when the patients were normotensive, urinary dopamine excretion decreased. In norepinephrine-secreting patients, urinary dopamine tended to be inversely correlated with the plasma norepinephrine level; however dopamine did not prevent the hypertensive action of norepinephrine. Tumor size showed no correlation with the plasma levels of catecholamine in the moderate to high plasma catecholamine groups. We conclude that the plasma catecholamine type and its level are the most important factors in determining the patterns of blood pressure disturbances of patients with pheochromocytoma.

Plasma catecholamines and social behavior in male vervet monkeys ( Cercopithecus aethiops sabaeus)

Many investigations in humans indicate that epinephrine, norepinephrine and their ratio may correlate with such traits as social competence, academic achievement, and aggression. However, the socioeconomic, dietary, and environmental confounds accompanying most human studies complicate their interpretation. Social status, aggression, and other social behaviors can be reliably assessed in nonhuman primates under conditions controlling for crucial environmental factors. If interpretation of human studies is correct, dominant and subordinate male vervet monkeys should exhibit distinctive patterns of catecholamine secretion. To test this possibility, seventeen adult male monkeys living in six stable social groups were observed for 6 months. Based on their success in agonistic events, subjects were categorized as dominant or subordinate. Alpha scores were calculated from empirically derived factors to provide a noncategorical measure of dominant behavioral style. Plasma epinephrine and norepinephrine samples obtained from anesthetized subjects did not differ between dominant and subordinate males. Alpha scores, however, distinguished high from low norepinephrine/epinephrine ratio groups. These findings are consistent with studies in humans linking high epinephrine, low norepinephrine, and social competence.

Characterization of the norepinephrine uptake system and the role of norepinephrine in the expression of the adrenergic phenotype by quail neural crest cells in clonal culture

This study investigates the role norepinephrine (NE) may play in regulating the differentiation of quail neural crest cells into sympathoadrenal cells. Cues originating from the embryonic microenvironment are thought to play an important role during development. It is conceivable that NE has a positive regulatory function because adrenergic expression by quail neural crest cells in clonal culture can be inhibited by NE uptake inhibitors such as desipramine (DMI). This possibility is further supported by the notion that in the avian embryo presumptive adrenergic neural crest cells are likely to encounter catecholamines shortly after they have acquired the NE uptake mechanism. Our present data indicate that neural crest cells in clonal culture express a high affinity NE uptake system that can be inhibited by desipramine. As in the embryo, it appears before noticeable levels of catecholamines are accumulated by neural crest cells, as judged by formaldehyde-induced catecholamine fluorescence (FIF). A comparison of the time course of appearance of different adrenergic markers suggests that immunoreactivity against the biosynthetic enzyme tyrosine hydroxylase (TH) may appear first, and that it is followed very closely by the appearance of detectable levels of dopamine-β-hydroxylase (DBH) and the NE uptake mechanism. Accumulation of catecholamines (FIF) is observed last. Addition of exogenous NE leads to an increase in adrenergic expression in vitro as judged by an increase in the number of colonies containing FIF-positive cells as well as cells expressing the biosynthetic enzymes TH and DBH. This suggests that exogenous NE can play a positive regulatory role in the differentiation of quail neural crest cells intossympathoadrenal cells.

Influence of ischaemic cardioplegic arrest on the haemodynamic efficacy of the PDE-III inhibitor, enoximone

The haemodynamic support from an enoximone infusion (2 x bolus 0.5 mg.kg-1, infusion 0.5 micrograms.kg-1min-1) in the early postischaemic phase is modified by a transient diminution of the drug's positive inotropic and vasodilatory effect (1 to 4 h). Forty-five min after weaning off cardiopulmonary bypass (CPB) the initial increase in cardiac index (CI) induced by enoximone (+26 +/- 8%) faded and was no longer discernible in the control group. A significant increase in CI was observed again 4-6 h after cardioplegic arrest (ultimate steady state values greater than 10 h; CI +0.71.min-1 x m-2; +21%). This pharmacodynamic fading occurred in the presence of constant plasma concentrations of enoximone (442 +/- 31 ng.ml-1) and elevated high plasma norepinephrine (926 +/- 70 pg.ml-1). Two independent processes might be responsible for the ischaemia-induced complex time dependency of the pharmacodynamic effect: (1) sensitization of the adrenergic receptor pathway and/or activation of sarcolemmal Ca-influx, rapidly reversed during reperfusion, and (2) impaired sarcoplasmic reticulum responses, which are slowly repaired after weaning off CPB.

Pathophysiology of the -adrenoceptor system in chronic heart failure: consequences for treatment with agonists, partial agonists or antagonists?

The human heart contains both beta 1-adrenoceptors and a considerable number of beta 2-adrenoceptors, both of which bring about positive inotropic and chronotropic effects of beta-adrenoceptor agonists in vitro and in vivo. In chronic heart failure, the decrease in beta-adrenoceptor function is related to the severity of the disease. However, both cardiac beta 1- and beta 2-adrenoceptors seem to be differentially affected depending on the type of heart failure and its aetiology. beta 1-adrenoceptor function decreases in all forms of chronic heart failure. beta 2-adrenoceptor function, on the other hand, decreases in mitral valve disease, tetralogy of Fallot and end-stage ischaemic cardiomyopathy, and seems to be unaltered (or only mildly uncoupled) in end-stage dilated cardiomyopathy, and possibly in aortic valve disease. Since the human heart has few spare beta-adrenoceptors and these decline with increasing degree of heart failure, beta-adrenoceptor agonists (but only non-selective full agonists) may be of therapeutic use only if the heart needs acute inotropic support; in long-term treatment they may be not effective, since tolerance develops. On the other hand, for long-term treatment selective beta 1-adrenoceptor antagonists may be beneficial since they protect the heart from the deleterious effects of chronic exposure to high (cardiac derived) noradrenaline and simultaneously may restore the previously reduced beta-adrenoceptor function.

Regulation of glucose metabolism by norepinephrine in conscious dogs

The effects of norepinephrine (NE) at levels present in the circulation and synaptic cleft during stress on glucose metabolism were examined in overnight-fasted conscious dogs with fixed basal levels of insulin and glucagon. Plasma NE rose from 132 +/- 14 to 442 +/- 85 pg/ml and 100 +/- 20 to 3,244 +/- 807 pg/ml during 3 h of low (n = 6) and high (n = 5) NE infusion, respectively. Plasma glucose and glucose production rose only with high NE infusion (from 108 +/- 4 to 159 +/- 15 mg/dl and 2.78 +/- 0.24 to 3.41 +/- 0.38 mg.kg-1.min-1, respectively). NE infusion caused dose-dependent net hepatic lactate consumption, but net hepatic alanine uptake fell only with high NE infusion (31%). Alanine conversion to glucose rose by 67 +/- 13, 136 +/- 20, and 412 +/- 104%, and intrahepatic gluconeogenic efficiency rose by 42 +/- 27, 299 +/- 144, and 212 +/- 21% with saline and with low and high NE infusion, respectively. In conclusion, NE enhances gluconeogenesis by stimulating peripheral precursor release, by increasing substrate movement into the hepatocyte, and by increasing intrahepatic gluconeogenic efficiency. However, only the higher NE levels affected glucose metabolism profoundly enough to stimulate glucose production and to elevate the glucose level.

Haemodynamic and neurohormonal responsiveness to different stress tests in mitral valve prolapse

In this study the blood pressure, heart rate, plasma noradrenaline and plasma adrenaline responses to various forms of sympatho-neural stress were evaluated in patients with mitral valve prolapse (MVP). Sympathetic reactivity in different subgroups of MVP were related to the degree of ventricular arrhythmia. Thirty-eight patients with mitral valve prolapse and 17 healthy controls were studied. All underwent 24-h ECG recording, 2-D echocardiography, head-up tilt to 60 degrees, pressor tests (sustained handgrip, mental arithmetic, cold pressor) and psychological assessment. The blood pressure, noradrenaline and adrenaline response to stress in patients without premature ventricular contraction were similar to those of the controls. In patients with unifocal premature ventricular contraction (PVC) less than 300/h, responses were similar to normal but were associated with higher plasma noradrenaline levels in the basal state and a diminished response to isometric stress. In patients with more than 300/h unifocal premature ventricular contraction, pairs of premature ventricular contraction, or runs of ventricular tachycardia there were lower blood pressure values in the basal state with reduced blood pressure, heart rate and plasma noradrenaline and adrenaline responses to head-up tilt and sustained handgrip, but marked increases in blood pressure, heart rate and plasma noradrenaline levels during the cold pressor test. Our data suggest different degrees of autonomic involvement in mitral valve prolapse which may be related to the various degrees of arrhythmia which seem to contribute to their symptoms.

Responses of atrium and ventricle to sustained sympathetic nerve stimulation

To determine whether chronotropic and atrial inotropic responses to sympathetic nerve stimulation are maintained longer than ventricular inotropic response, the present study was performed with control and acute reserpinized dogs. We stimulated the right stellate ganglion of both groups supramaximally for 60 min and compared right atrial responses (chronotropism and inotropism) with left ventricular (LV) dP/dtmax. In the control group, heart rate (HR) immediately increased and was only slightly attenuated with 60 min of stimulation, and right atrial (RA) inotropic response was less attenuated than was LV response (7% in HR, 33% in RA dP/dtmax, 50% in LV dP/dtmax, P less than 0.01, from the peak value of each response). RA and LV norepinephrine (NE) content was decreased by the stimulation but remained higher than the LV control value. In the reserpinized group, NE content in the RA was low before the stimulation and was further decreased by the stimulation. In this group, HR response was attenuated (27% in HR, P less than 0.01) as was LV dP/dtmax, and the difference in contractile responsiveness between atrium and ventricle disappeared (58% in RA dP/dtmax vs. 61% in LV dP/dtmax, NS). The results indicate that the chronotropic response was only slightly attenuated and that the atrial contractile response was attenuated less than the ventricular response, with sustained sympathetic nerve stimulation in the normal heart. This can be ascribed to the much higher NE content in the RA than that in the LV.

The effects of noradrenergic neurotoxin, DSP-4, on the performance of young and aged rats in spatial navigation task

The present study investigated whether an overactive noradrenergic system is related to the impairment in learning/memory in aged subjects. The effects of partial noradrenaline depletion (using the noradrenergic neurotoxin DSP-4) on the acquisition of a water maze task was investigated in young and aged rats, and hippocampal noradrenaline content was correlated with spatial learning performance in similar rats. DSP-4 treatment impaired markedly the acquisition of the water maze task in aged rats, but improved it slightly in young rats. DSP-4 treatment decreased swimming speed, and this effect tended to be more marked in young rats. In the group of control rats, hippocampal noradrenaline tended to correlate positively with spatial bias in aged rats (the rats with the highest noradrenaline content in the hippocampus tended to have the best spatial learning/memory), but negatively in young rats. These results do not support the hypothesis that spatial learning/memory impairment is due to an overactive noradrenergic system in aged rats. Further studies are needed to clarify the reasons of the marked age-related difference in the effects of DSP-4 on the performance of water maze task in rats.

Cardiovascular responses to graded reductions in leg perfusion in exercising humans

Our objective was to determine whether the chemoreflex from human muscle is elicited by small graded reductions in muscle blood flow (MBF) during mild exercise or whether this reflex has an obvious threshold associated with large changes in femoral venous lactate and H+ levels (i.e., as in dogs with high muscle oxidative capacity). Seven subjects exercised supine at 40, 87, and 142 W; lower body positive pressure (LBPP) was applied in 3-min steps at 25, 35, 45, and 50-60 mmHg with the lower body and the cycle ergometer in a sealed box. Estimated MBF (Fick) fell by 5.3 +/- 4.3 to 19.9 +/- 3.8% at four levels of LBPP over three work rates. Mean arterial pressure (MAP), heart rate (HR), and plasma norepinephrine (NE) concentration rose with increasing LBPP. MAP was significantly correlated with femoral venous pH, lactate, O2 tension, and O2 content during moderate and heavy exercise, without an apparent threshold. Percentage decreases in muscle vascular conductance exceeded the decreases in MBF twofold, indicating significant opposition to reduction in MBF by the chemoreflex. Approximately 50% of the correction of MBF back toward control (i.e., at 0 LBPP) could be explained by increased cardiac output, calculated from the rise in HR; the remaining correction could be attributed to both sympathetic vasoconstriction (indicated by high NE levels) and to mechanical effects of partial occlusion. Results suggest that in humans stepwise reductions in MBF gradually elicit muscle chemoreflexes with no apparent threshold at these levels of exercise.

Altered function and structure of the heart in dogs with chronic elevation in plasma norepinephrine.

We have previously shown that chronic elevation of plasma norepinephrine leads to a functional independent increase in left ventricular weight. The goals of the present study were to determine quantitatively the component of the myocardium that accounted for the observed structural changes and to determine the function of the hypertrophied myocardium. Mongrel dogs were chronically instrumented for measurement of arterial and left ventricular pressures, left ventricular internal diameter, and left ventricular wall thickness. Subcutaneous osmotic pumps were implanted to release norepinephrine continuously for 28 days. Hemodynamics were measured with dogs in the quietly resting state and during infusions of isoproterenol at 0.1 and 0.5 micrograms/kg/min before and on days 14 and 28 during the infusion of norepinephrine. The hemodynamic response to 10 micrograms/kg phenylephrine, given as a bolus, was also assessed before norepinephrine and 28 days during the infusion of norepinephrine, and the end-systolic pressure-diameter or wall-stress-diameter relations were calculated. On day 28, hearts were arrested in diastole and perfusion fixed in situ. Tissue samples were prepared for electron microscopy and morphometry. Hemodynamic studies showed that isoproterenol (0.5 micrograms/kg/min) reduced mean arterial pressure (MAP) to the same point on each experimental day, and the increases in indexes of contractility were reduced during norepinephrine infusion. Left ventricular dP/dtmax increased 131 +/- 24% on control day, only 67 +/- 20% on day 14, and 55 +/- 18% on day 28. Similar changes were observed in dP/dt/DP40 and dP/dt/end-diastolic circumference. However, Emax, the slope of the end-systolic pressure-diameter or wall stress diameter relations, was unchanged, suggesting that inotropic state was not altered. Morphometric studies showed that the cross-sectional area of myocytes increased by 55%, but myocyte and capillary densities decreased by 34% and 29%, respectively (p less than 0.05) in dogs with high norepinephrine levels. There were no differences in volume fractions of myocytes, capillary lumen, or interstitium or capillary-to-myocyte ratio. The myocardium of dogs with high norepinephrine levels shows reduced inotropic response to beta-adrenergic stimulation despite the increases in left ventricular mass and left ventricular wall thickness, which are a result of growth of the cardiac myocytes and characteristic of concentric hypertrophy. These data suggest that chronic adrenergic stimulation of the heart reduces the beta-receptor coupling to the contractile response without importantly compromising left ventricular function.

Regulation of lipolysis and ketogenesis by norepinephrine in conscious dogs

The lipolytic and ketogenic effects of norepinephrine (NE) at levels present in the circulation or the synaptic cleft during stress were examined in the overnight-fasted conscious dog. Insulin and glucagon were maintained at basal levels while NE, at a rate of either 0.04 (n = 6) or 0.32 micrograms.kg-1.min-1 (n = 5), or saline (n = 6) was infused for 3 h. NE rose from 129 +/- 17 to 442 +/- 85 pg/ml (P less than 0.05) and 100 +/- 24 to 3,244 +/- 807 pg/ml (P less than 0.05) with the low and high infusion rates, respectively (unchanged with saline infusion). There were no significant changes in lipolysis or ketogenesis with saline infusion. Both low and high NE infusion produced sustained increases in glycerol (from 72 +/- 20 to 119 +/- 24 microM and 59 +/- 19 to 248 +/- 32 microM, respectively, both P less than 0.05), while nonesterified fatty acids (NEFA) rose from 609 +/- 85 to 952 +/- 100 and 767 +/- 140 to 2,054 +/- 199 microM (both P less than 0.05). Ketone levels and net hepatic production rose significantly only with the high NE infusion (from 88 +/- 10 to 266 +/- 46 microM and 1.30 +/- 0.26 to 7.62 +/- 1.48 mumol.kg-1.min-1, respectively, both P less than 0.05). The ratio of net hepatic ketone production to NEFA uptake rose 54% with high NE infusion. In conclusion, at circulating levels seen during stress, NE stimulates lipolysis but does not directly influence ketogenesis. At circulating levels projected to exist in the synaptic cleft during stress, NE has a potent lipolytic effect and stimulates ketogenesis.

Impaired suppression of plasma norepinephrine during head-down tilt in patients with congestive heart failure

Neurohumoral activation is present in congestive heart failure and may contribute to vasoconstriction in this syndrome. The mechanisms leading to and maintaining neurohumoral activation in long-standing congestive heart failure are as yet undefined. The present study addresses the possibility that baroreceptor-mediated suppression of plasma norepinephrine may be abnormal in patients with long-standing congestive heart failure. Eight normal subjects and 12 patients with long-standing congestive heart failure were studied during 15 minutes of 30° head-down tilt. There were no significant changes in heart rate or arterial blood pressure in either group during these maneuvers. In normal subjects, plasma norepinephrine declined from 257 ± 38 pg/ml at control to 208 ± 39 pg/ml during head-down tilt ( p < 0.005). Plasma norepinephrine was elevated in the patients with congestive heart failure, 475 ± 189 pg/ml, and did not change during head-down tilt. These observations suggest that baroreflex loading maneuvers, which in this study included increased central blood volume and hydrostatic effects on the sinoaortic baroreceptor, do not suppress increased plasma norepinephrine in patients with long-standing congestive heart failure. Impaired baroreflex responsiveness could therefore contribute to either the generation or maintenance of high plasma norepinephrine in this syndrome.

Effect of elevated plasma norepinephrine on electrocardiographic changes in subarachnoid hemorrhage.

We compared electrocardiographic abnormalities and plasma norepinephrine concentrations in 40 patients with subarachnoid hemorrhage within the first 24 hours, at 72 hours, and after 1 week. In 20 patients with high plasma norepinephrine concentrations within the first 24 hours, sinus tachycardia (p less than 0.02) and negative T waves (p less than 0.01) were more frequent than in the 20 patients with normal plasma norepinephrine concentrations. After 72 hours, only sinus tachycardia (p less than 0.03) was found with increased frequency in the 26 patients with high plasma norepinephrine concentrations. Although 24 patients had high plasma norepinephrine concentrations after 1 week, we found no differences in the frequency of electrocardiographic abnormalities compared to patients with normal plasma norepinephrine. However, QTc prolongation, U waves, ST depression, and arrhythmias were found with similar frequency in patients with both high and normal plasma norepinephrine concentrations. We conclude that, with the exception of sinus tachycardia and negative T waves, electrocardiographic changes in patients with subarachnoid hemorrhage do not depend on elevated plasma norepinephrine concentrations.

Carotid baroreceptor function in dogs with chronic norepinephrine infusion.

Carotid baroreceptor function, the compliance of the carotid sinus wall, and the structure of the carotid artery were examined in dogs with elevated plasma norepinephrine (2,000-4,000 pg/ml) for 28 days. The dogs with high norepinephrine were normotensive (100 +/- 4.0 versus 98 +/- 4.0 mm Hg; p greater than 0.05) with bradycardia (65 +/- 4.0 versus 87 +/- 16 beats/min; p less than 0.05) compared with normal dogs in the conscious state. However, after pentobarbital anesthesia blood pressure was significantly higher in dogs with chronic norepinephrine infusion (165 +/- 6 mm Hg) compared with normal dogs (132 +/- 6 mm Hg). To assess baroreceptor sensitivity, multiunit carotid baroreceptor activity was recorded from the right carotid sinus nerve, and the carotid sinus wall compliance (sonomicrometers) was measured during nitroglycerin and phenylephrine injections. The threshold and saturation pressures increased from 96 +/- 3.9 to 117 +/- 4.2 mm Hg and from 145 +/- 4.3 to 171 +/- 5.7 mm Hg, respectively, in the normal dogs compared with the high norepinephrine dogs. The most striking differences were the marked increases in sensitivity of carotid baroreceptors (0.47 +/- 0.05 versus 1.99 +/- 0.45 spikes.sec-1.mm Hg-1; p less than 0.01) and maximum firing frequency of the baroreceptors (24 +/- 3.1 versus 48 +/- 4.4 spikes/sec; p less than 0.01), whereas the carotid sinus wall compliance was unchanged (0.014 +/- 0.003 versus 0.012 +/- 0.002 mm/mm Hg; p greater than 0.05). Similar alterations were observed using single fiber recordings, that is, an increase in threshold and saturation pressures and slope of baroreceptor units in dogs with elevated norepinephrine. The wall thickness and area of the carotid artery were determined. Both increased significantly (0.77 +/- 0.06 versus 1.30 +/- 0.12 mm and 9.0 +/- 0.8 versus 11.9 +/- 0.9 mm2; p less than 0.05) in dogs chronically infused with norepinephrine while the dry weight-to-wet weight ratio of left carotid artery tissue also increased from 26.0 +/- 0.73% to 29.0 +/- 0.57%. These studies indicate that 1) one of the possible mechanisms responsible for bradycardia in the conscious dogs with high norepinephrine is enhanced sensitivity of carotid baroreceptors; 2) the enhanced sensitivity of carotid baroreceptors is not due to a change in compliance of the carotid sinus wall; and 3) chronic elevation of norepinephrine causes hypertrophy or hyperplasia of the wall of the common carotid artery.