Showing papers on "Norepinephrine (medication) published in 1997"
TL;DR: Paracentesis-induced circulatory dysfunction is predominantly caused by an accentuation of the arteriolar vasodilation already present in untreated cirrhotic patients with ascites, and the homeostatic activation of endogenous vasoactive systems may account for the increased intrahepatic vascular resistance associated with this condition.
277 citations
TL;DR: If other vascular beds respond in the same way as the hand, the gestational increase in vasoconstrictor response to L-NMMA that is observed implicates increased generation of nitric oxide in the fall of peripheral vascular resistance during healthy human pregnancy.
Abstract: The maternal circulation vasodilates during pregnancy. We investigated the contribution of nitric oxide to this vasodilatation. Using venous occlusion plethysmography, we measured the effect of nitric oxide synthase inhibition on hand blood flow during human pregnancy. We compared the response to a brachial artery infusion of the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) with the response to norepinephrine in three groups of women: nonpregnant, early pregnant (9-15 wk), and late pregnant (36-41 wk). Basal hand blood flow increased significantly during late pregnancy compared with nonpregnant and early pregnant subjects (P = 0.007). L-NMMA produced a greater reduction in hand blood flow in both pregnant groups compared with nonpregnant controls (P = 0.0003). Norepinephrine produced an attenuated response in late pregnancy compared with nonpregnant and early pregnant women (P = 0.0029). If other vascular beds respond in the same way as the hand, the gestational increase in vasoconstrictor response to L-NMMA that we observed implicates increased generation of nitric oxide in the fall of peripheral vascular resistance during healthy human pregnancy.
213 citations
TL;DR: Brief ischemia of an extremity protects against reperfusion tachyarrhythmia and one of the humoral mediators involved in this response appears to be NE; others remain to be identified.
Abstract: We investigated the hypothesis that a cardioprotective, antiarrhythmic effect might be obtained by brief ischemia of a remote part of the body before ischemia of the heart. Regional ischemia (RI) w...
196 citations
TL;DR: It is suggested that mild hypothermia induced by isolated core cooling is associated with an adrenergic response characterized by peripheral sympathetic nervous system activation without a significant adrenocortical or adrenomedullary response.
Abstract: The adrenergic, respiratory, and cardiovascular responses to isolated core cooling were assessed in awake human subjects. Mild core hypothermia was induced by intravenous infusion of 30 or 40 ml/kg of cold saline (4 degrees C) on 2 separate days. A warm intravenous infusion (30 ml/kg, 37 degrees C) was given on a third day as a control treatment. Mean norepinephrine concentration increased 400% and total body oxygen consumption increased 30% when core temperature decreased 0.7 degrees C. Mean norepinephrine concentration increased 700% and total body oxygen consumption increased 112% when core temperature decreased 1.3 degrees C. Core cooling was associated with peripheral vasoconstriction and increased mean arterial blood pressure, whereas heart rate was unchanged. Plasma epinephrine and cortisol concentrations were unchanged during core cooling. There were no changes in any measured parameter with the warm infusion. These findings suggest that mild hypothermia induced by isolated core cooling is associated with an adrenergic response characterized by peripheral sympathetic nervous system activation without a significant adrenocortical or adrenomedullary response. The respiratory and cardiovascular responses to core cooling are characterized by a shivering-induced increase in metabolic rate, norepinephrine-mediated peripheral vasoconstriction, and increased arterial blood pressure.
170 citations
TL;DR: The use of epinephrine after cardiopulmonary bypass precipitates the development of lactic acidosis in some patients, and this phenomenon is presumably a beta-mediated effect, and is associated with an increase in whole-body and lower limb blood flow and a decrease in whole the body and transfemoral oxygen extraction.
Abstract: OBJECTIVE To determine if lactic acidosis occurring after cardiopulmonary bypass could be attributed to the metabolic or other effects of epinephrine administration. DESIGN Prospective, randomized study. SETTING Postsurgical cardiothoracic intensive therapy unit. PATIENTS Thirty-six adult patients, without acidosis, requiring vasoconstrictors for the management of hypotension after cardiopulmonary bypass. INTERVENTIONS Randomized administration of either epinephrine or norepinephrine by infusion. MEASUREMENTS AND MAIN RESULTS Hemodynamic and metabolic data were collected before commencement of vasoconstrictor therapy (time 0) and then 1 hr (time 1), 6 to 10 hrs (time 2), and 22 to 30 hrs (time 3) later. Six of the 19 patients who received epinephrine developed lactic acidosis. None of the 17 patients receiving norepinephrine developed lactic acidosis. In the epinephrine group, but not in the norepinephrine group, lactate concentration increased significantly at times 1 and 2 (p = .01), while pH and base excess decreased (p < or = .01). Blood glucose concentration was higher in the epinephrine group at time 2 (p = .02), while the cardiac index (p < .03) and the mixed venous Po2 (p = .04) were higher at time 1. compared with the norepinephrine group, the patients receiving epinephrine had higher femoral venous lactate concentrations (p = .03), increased lower limb blood flow (p = .05), and increased femoral venous oxygen saturations (p = .04). CONCLUSIONS The use of epinephrine after cardiopulmonary bypass precipitates the development of lactic acidosis in some patients. This phenomenon is presumably a beta-mediated effect, and is associated with an increase in whole-body and lower limb blood flow and a decrease in whole-body and transfemoral oxygen extraction. The phenomenon does not appear to be related to reduced tissue perfusion and does not have the poor outlook of lactic acidosis associated with shock.
147 citations
TL;DR: Estrogen supplementation in perimenopausal women selectively attenuates vasoconstrictor responses to norepinephrine and reduces total body norpinephrine spillover, which is an index of sympathetic neural activity.
Abstract: Estrogens are reported to provide protection against the development of cardiovascular disease in women, but the mechanisms underlying these effects are not well defined. We hypothesized that estrogen might reduce neural cardiovascular tone. We therefore studied responses to exogenous norepinephrine and norepinephrine spillover in 12 perimenopausal women randomized to 8 weeks of estrogen supplementation (estradiol valerate, 2 mg daily, n=7) or placebo (n=5). Forearm blood flow was measured by venous occlusion plethysmography, and vasoactive agents were infused through a brachial artery cannula in doses that did not influence blood pressure or heart rate. Total body and forearm norepinephrine spillover were measured by radiotracer methodology. Forearm vasoconstrictor responses to norepinephrine (25, 50, and 100 ng/min) were attenuated after estrogen supplementation ( P =.002). Vasoconstrictor responses to angiotensin II (8, 16, and 32 ng/min) were unchanged postestrogen. There was a significant reduction in total body spillover of norepinephrine after estrogen supplementation (pre-estrogen, 700±152; postestrogen, 439±150 ng/min; P
145 citations
TL;DR: Low-dose dopamine has a potential beneficial effect on splanchnic blood flow and oxygen consumption in patients with septic shock, provided the fractional splan Schnic flow is not already high before treatment.
Abstract: Objective: To assess the effects of low-dose dopamine on splanchnic blood flow and splanchnic oxygen uptake in patients with septic shock. Design: Prospective, controlled trial. Setting: University hospital intensive care unit Patients: 11 patients with septic shock, diagnosed according the criteria of the 1992 American College of Chest Physicians/Society of Critical Care Medicine consensus conference, who required treatment with norepinephrine. Measurements and main results: Systemic and splanchnic hemodynamics and oxygen transport were measured before and during addition of low-dose dopamine (3 μg/kg per min). Low-dose dopamine had a marked effect on total body hemodynamics and oxygen transport. The fractional splanchnic flow at baseline ranged from 0.15 to 0.57. In 7 patients with a fractional splanchnic flow less than 0.30, low-dose dopamine increased splanchnic flow and splanchnic oxygen delivery and oxygen consumption. In 4 patients with a fractional splanchnic flow above 0.30, low-dose dopamine did not appear to change splanchnic blood flow. Conclusion: Low-dose dopamine has a potential beneficial effect on splanchnic blood flow and oxygen consumption in patients with septic shock, provided the fractional splanchnic flow is not already high before treatment.
120 citations
TL;DR: Despite the loss of locus ceruleus neurons in Alzheimer's disease, the aging-associated high concentration of CSF norepinephrine is retained in the earlier stages of Alzheimer’s disease and increases further as the disease progresses.
Abstract: Objective: Although loss of noradrenergic neurons in the locus ceruleus has been consistently demonstrated postmortem in Alzheimer’s disease, several small studies suggest that indices of central noradrenergic activity increase with the severity of Alzheimer’s disease in living patients. The authors estimated the effect of Alzheimer’s disease severity on central noradrenergic activity by comparing the CSF norepinephrine concentrations of subjects with Alzheimer’s disease in earlier and advanced stages. The effect of normal aging on CSF norepinephrine also was determined. Method: Lumbar punctures were performed in 49 subjects with Alzheimer’s disease of mild or moderate severity, 25 subjects with advanced Alzheimer’s disease, 42 normal older subjects, and 54 normal young subjects. Advanced Alzheimer’s disease was defined prospectively by a Mini-Mental State score of less than 12. Norepinephrine was measured by radioenzymatic assay. Results: CSF norepinephrine concentration was significantly higher in the patients with advanced Alzheimer’s disease (mean=279 pg/ml, SD=122) than in those with mild to moderate severity (mean=198 pg/ml, SD=89), normal older subjects (mean=219 pg/ml, SD=88), or normal young subjects (mean=154 pg/ml, SD=53). CSF and plasma norepinephrine levels and mean arterial blood pressure all were higher in the older subjects than in the young subjects. Conclusions: Despite the loss of locus ceruleus neurons in Alzheimer’s disease, the aging-associated high concentration of CSF norepinephrine is retained in the earlier stages of Alzheimer’s disease and increases further as the disease progresses. Increased brain noradrenergic activity may contribute to the agitated behaviors or cognitive deficits of patients with advanced Alzheimer’s disease. (Am J Psychiatry 1997; 154:25‐30)
116 citations
TL;DR: Results indicate that addition of norepinephrine affects both ETEC growth and expression of a specific virulence factor.
110 citations
TL;DR: The increase in SNS activity in the posterior hypothalamic nuclei and in the locus coeruleus of CRF rats is partially mitigated by increased local expression of NOS m-RNA, suggesting endogenous NO may partially inhibit the activity of the SNS in brain nuclei involved in the neurogenic regulation of blood pressure.
Abstract: Increased sympathetic nervous system (SNS) activity plays a role in the genesis of hypertension in rats with chronic renal failure (CRF). Because nitric oxide (NO) modulates the activity of the SNS, a deficit of NO synthesis could be responsible for the increased SNS activity in these animals. In the present study, we evaluated the effects of L-arginine and L-NAME on blood pressure and SNS activity-in Sprague Dawley 5/6 nephrectomized or sham-operated rats. SNS activity was determined by measuring norepinephrine turnover rate in several brain nuclei involved in the regulation of blood pressure. In the same brain nuclei, we measured NO content and nitric oxide synthase (NOS) gene expression by semiquantitative measurements of NOS mRNA reverse transcription polymerase chain reaction. In CRF rats, norepinephrine turnover rate was increased in the posterior hypothalamic nuclei, locus coeruleus, paraventricular nuclei, and the rostral ventral medulla, whereas NOS mRNA gene expression and NO2/NO3 content were increased in all brain nuclei tested. L-NAME increased blood pressure and NE turnover rate in several brain nuclei of both control and 5/6 nephrectomized rats. In CRF rats, a significant relationship was present between the percent increment in NOS mRNA gene expression related to the renal failure, and the percent increase in norepinephrine turnover rate caused by L-NAME. This suggests that endogenous NO may partially inhibit the activity of the SNS in brain nuclei involved in the neurogenic regulation of blood pressure, and this inhibition is enhanced in CRF rats. In summary, the increase in SNS activity in the posterior hypothalamic nuclei and in the locus coeruleus of CRF rats is partially mitigated by increased local expression of NOS m-RNA.
109 citations
TL;DR: These data are consistent with previous experiments measuring acetylcholine concentrations in cerebrospinal fluid and support analgesia from alpha2 ‐adrenergic agonists mediated in part by cholinergic activation and suggest stimulation of norepinephrine release by this agent.
Abstract: Background Intrathecal injection of clonidine and dexmedetomidine produce behavioral analgesia by an alpha 2-adrenergic mechanism. Functional and anatomic studies suggest that this analgesia is mediated by cholinergic activation. This hypothesis was directly tested by measuring extracellular acetylcholine concentrations in spinal cord interstitial fluid by means of microdialysis after intrathecal injection of these alpha 2-adrenergic agonists in sheep. Methods Twelve sheep with chronically implanted thoracic intrathecal catheters were anesthetized with halothane. Multiple 200-micron-diameter dialysis fibers were inserted surgically at a mid-thoracic level through the dorsal horn and perfused with artificial cerebrospinal fluid. After baseline sampling, either clonidine (100 micrograms), dexmedetomidine (100 micrograms), or saline were injected intrathecally. Microdialysis samples were analyzed by high-pressure liquid chromatography for acetylcholine and norepinephrine. Results Both alpha 2-adrenergic agonists increased acetylcholine in microdialysate, whereas intrathecal saline had no effect. Analysis of the raw data showed that all groups differed significantly, with greater levels of acetylcholine following administration of dexmedetomidine than clonidine or saline. Unexpectedly, intrathecal clonidine also increased microdialysate norepinephrine levels. Conclusions These data are consistent with previous experiments measuring acetylcholine concentrations in cerebrospinal fluid and support analgesia from alpha 2-adrenergic agonists mediated in part by cholinergic activation. In addition, the increase in norepinephrine concentrations after intrathecal administration of clonidine suggest stimulation of norepinephrine release by this agent.
TL;DR: The relationship between cAMP levels and thermogenesis was investigated in brown fat cells from Syrian hamsters and it was concluded that the thermogenic response to norepinephrine involves two interacting parts, one mediated via β-receptor and cAMP and the other via α1-receptors and increases in cytosolic Ca2+ levels.
TL;DR: This is the first report of a local kallikrein-kinin system in adrenergic nerve endings capable of generating enough bradykinin to activate B2-receptors in an autocrine/paracrine fashion and thus enhance norepinephrine exocytosis.
Abstract: We determined whether local bradykinin production modulates cardiac adrenergic activity. Depolarization of guinea pig heart sympathetic nerve endings (synaptosomes) with 1 to 100 mmol/L K + caused the release of endogenous norepinephrine (10% to 50% above basal level). This release was exocytotic, because it depended on extracellular Ca 2+ , was inhibited by the N-type Ca 2+ -channel blocker ω-conotoxin and the protein kinase C inhibitor Ro31-8220, and was potentiated by the neuronal uptake-1 inhibitor desipramine. Typical of adrenergic terminals, norepinephrine exocytosis was enhanced by activation of prejunctional angiotensin AT 1 -receptors and attenuated by adrenergic α 2 -receptors, adenosine A 1 -receptors, and histamine H 3 -receptors. Exogenous bradykinin enhanced norepinephrine exocytosis by 7% to 35% (EC 50 , 17 nmol/L), without inhibiting uptake 1. B 2 -receptor, but not B 1 -receptor, blockade antagonized this effect. The kininase II/angiotensin-converting enzyme inhibitor enalaprilat and the addition of kininogen or kallikrein enhanced norepinephrine exocytosis by ≈6% to 40% (EC 50 , 20 nmol/L) and ≈25% to 60%, respectively. This potentiation was prevented by serine protease inhibitors and was antagonized by B 2 -receptor blockade. Therefore, norepinephrine exocytosis is augmented when bradykinin synthesis is increased or when its breakdown is inhibited. This is the first report of a local kallikrein-kinin system in adrenergic nerve endings capable of generating enough bradykinin to activate B 2 -receptors in an autocrine/paracrine fashion and thus enhance norepinephrine exocytosis. This amplification process may operate in disease states, such as myocardial ischemia, associated with severalfold increases in local kinin concentrations.
Journal Article•
TL;DR: It is concluded that norepinephrine evokes an alpha-1 adrenoceptor-mediated inotropic effect comparable to that evoked through the beta adrenoceptors in failing human ventricular myocardium, and that this alpha- 1 adreno receptor-mediatedInotropic effect may be of functional importance.
Abstract: The purpose of our study was to investigate the inotropic response to the endogenous agonist norepinephrine mediated through alpha-1 adrenoceptors and to compare this response to that mediated through beta-adrenoceptors in failing human ventricular myocardium. We studied ex vivo the inotropic effect of norepinephrine in isometrically contracting trabecular myocardium from both ventricles of explanted hearts. By studying influence of appropriate adrenoceptor blockers, qualitative characteristics of the inotropic response and sensitivity of the inotropic response to cholinergic stimulation, it was revealed that norepinephrine evoked both alpha-1 and beta adrenoceptor-mediated inotropic effects in failing human ventricle myocardium. Quantitatively the inotropic responses to norepinephrine varied markedly between preparations, but the mean responses elicited through the respective adrenoceptor systems were of comparable magnitude. Concomitant stimulation of alpha-1 and beta adrenoceptors by norepinephrine alone revealed a contribution of an alpha-1 adrenoceptor-mediated component to the final and unopposed inotropic response. Differential sensitivity of the two adrenoceptor systems to norepinephrine depending on etiology of heart failure and possibly also thyroid status was observed. It is concluded that norepinephrine evokes an alpha-1 adrenoceptor-mediated inotropic effect comparable to that evoked through the beta adrenoceptors in failing human ventricular myocardium, and that this alpha-1 adrenoceptor-mediated inotropic effect may be of functional importance.
TL;DR: The decrease in norepinephrine turnover during fasting is completely reversed by 1 day of refeeding, consistent with suppression of centrally mediated sympathetic activity in the fasted state.
Abstract: Two days of fasting in rats significantly reduces the turnover of norepinephrine in the heart. In contrast to the effects of ganglionic blockade in fed controls, similar blockade in fasted animals is without significant effect on [3H]-norepinephrine retention or endogenous norepinephrine in the heart. These data are consistent with suppression of centrally mediated sympathetic activity in the fasted state. The decrease in norepinephrine turnover during fasting is completely reversed by 1 day of refeeding.
TL;DR: Given the abundant adrenergic innervation in the small intestine, these in vitro results suggest that the neurohumoral environment of the host may play a role in bacterial growth and expression of virulence factors.
Abstract: The small intestine is richly innervated by the sympathetic nervous system. High concentrations of monoamines, most notably norepinephrine, are found throughout the various intestinal layers. In order to determine whether norepinephrine is capable of influencing bacterial pathogenesis, the growth and production of virulence factors in ETEC and EHEC were examined in a physiologically relevant medium utilizing very low initial bacterial inoculums to more closely mimic in vivo conditions. The growth of ETEC strain B44 and the production of the K99 pilus adhesin on a protein equivalent basis was greatly increased in the presence of norepinephrine. Growth of EHEC 0157:H7 was also increased in norepinephrine containing medium as well as production of SLT-I and SLT-II. The ability of norepinephrine to increase both bacterial growth and expression of virulence factors was shown to be non-nutritional in nature. Given the abundant adrenergic innervation in the small intestine, these in vitro results suggest that the neurohumoral environment of the host may play a role in bacterial growth and expression of virulence factors.
TL;DR: The intrinsic ultradian fluctuations of plasma catecholamines appear not to be involved in the control of cardiovascular parameters during recumbency, and the increase in blood pressure and heart rate in the morning appears to be controlled by direct sympathetic neural input to the heart and vasculature in response to changes in activity and posture.
Abstract: Diurnal and ultradian rhythms of plasma norepinephrine and epinephrine and their role in the regulation of cardiovascular parameters were investigated over 24 h of recumbency in a group of five men. Catecholamines were measured at 10 min intervals, and blood pressure and heart rate were recorded continuously. Norepinephrine and epinephrine rapidly fluctuated in each subject, with no obvious diurnal rhythm. Spectral analysis suggested two ultradian rhythms with periods of around 12 h and 50‐100 min for both catecholamines. The pulse detection programs PULSAR and CLUSTER revealed 20‐30 pulses/24 h for norepinephrine and epinephrine, with a significant correlation between the two rhythms (r=0·63‐0.80, P<0·001). Neither the frequency nor the amplitude of these rapid fluctuations differed between day and night. Arousal in the morning caused a small increase in plasma catecholamines and getting out of bed a large increase. Thus changes in posture and activity are the main influences on the diurnal variations of plasma catecholamines reported previously, while the ultradian rhythms of sympathoadrenomedullary activity appear to be of intrinsic origin. Blood pressure and heart rate exhibited a diurnal rhythm with a nightly decrease. Arousal and rising from bed increased blood pressure and heart rate significantly. Although the amplitude of the rapid fluctuations of plasma catecholamines at times exceeded those caused by postural changes in the morning, when both plasma norepinephrine and epinephrine levels correlated highly with all cardiovascular parameters, correlations were not significant during recumbency. Thus the intrinsic ultradian fluctuations of plasma catecholamines appear not to be involved in the control of cardiovascular parameters during recumbency, and the increase in blood pressure and heart rate in the morning appears to be controlled by direct sympathetic neural input to the heart and vasculature in response to changes in activity and posture rather than by an endogenous surge of plasma catecholamines.
TL;DR: It is concluded that during endotoxic shock in dogs, norepinephrine hardly influences blood flow distribution and could even increase hepatic artery blood flow, and it can also improve whole body and liver oxygen extraction capabilities.
Abstract: We explored the effects of norepinephrine on blood flow distribution and oxygen extraction capabilities during hyperdynamic endotoxic shock. Twelve anesthetized and mechanically ventilated dogs received 2 mg/kg of Escherichia coli endotoxin followed by a general saline infusion and were then randomly divided into two groups: six received norepinephrine (1 microg/kg/min), and six served as control subjects. The norepinephrine group maintained higher mean arterial pressure, cardiac index, left ventricular stroke work index, and hepatic arterial blood flow without altering blood flow to portal, mesenteric, and renal beds. When cardiac tamponade was induced to study tissue oxygen extraction capabilities, the norepinephrine group had a lower critical oxygen delivery in whole body (11.5 +/- 5.2 versus 14.3 +/- 1.4 ml/kg/min, p < 0.05) and in liver (25.0 +/- 11.3 versus 38.0 +/- 9.0 ml/min, p = NS) and a higher critical oxygen extraction ratio in whole body (53.8 +/- 17.7 versus 32.0 +/- 6.1%, p < 0.05), and in ...
TL;DR: The results of this study indicate that the anti-ischaemic effect of spinal cord stimulation is not due to reduced cardiac sympathetic activity, however, spinal Cord stimulation decreases overall sympathetic activity which may benefit the heart, possibly by reducing oxygen demand.
Abstract: Aims Spinal cord stimulation has been used in the treatment of intractable angina pectoris since the beginning of the 1980s. This study was designed to investigate whether the documented anti-ischaemic effects of spinal cord stimulation are mediated through a decrease in sympathetic activity.
Methods and Results Ten patients with a spinal cord stimulator implanted as anti-anginal treatment were included in the study. Atrial pacing until the patient experienced moderate angina was performed and after 50 min rest the procedure was repeated during spinal cord stimulation. Total body and cardiac norepinephrine spillover was calculated and the former was found to have increased during pacing (47%, P =0·02). When spinal cord stimulation was applied, total body norepinephrine spillover decreased at a comparable pacing rate (18%, P =0·02). Cardiac norepinephrine spillover was not affected during the procedure.
Conclusion The results of this study indicate that the anti-ischaemic effect of spinal cord stimulation is not due to reduced cardiac sympathetic activity. However, spinal cord stimulation decreases overall sympathetic activity which may benefit the heart, possibly by reducing oxygen demand.
TL;DR: Degree of insulin sensitivity and acetylcholine sensitivity explain a small portion of the variability of the clamp-induced vasodilatation in hypertensive patients.
Abstract: Background Insulin resistance and vascular abnormalities have both been described in patients with essential hypertension. Whether these defects are associated with one another in the same individual has not been established. Methods and Results Whole-body insulin sensitivity (by the insulin clamp technique), forearm minimal vascular resistances, and the dose-response curve to acetylcholine, sodium-nitroprusside, and norepinephrine were measured in a group of 29 male patients with untreated essential hypertension. When the patients were divided into tertiles according to their level of insulin sensitivity, resistant and sensitive hypertensives were matched on several potential confounders of insulin action and vascular function. These subgroups showed similar minimal vascular resistances (2.5±0.2 versus 3.2±0.6 mm Hg per mL · min−1 · dL−1) and superimposable responses to graded intraarterial infusions of acetylcholine, sodium-nitroprusside, and norepinephrine. No correlation was found between the vascular...
TL;DR: It is demonstrated that nicardipine and papaverine seem to be pharmacologic tools able to increase the blood flow in anastomotic arteries, and the use of 2% lidocaine as a spasmolytic agent should be re‐evaluated, since this substance may act as a partial agonist.
Abstract: Extreme arterial vasoconstriction (vasospasm) is a common problem encountered in microvascular surgery. An ideal pharmacologic tool able to counteract ischemia during microsurgery should be easy to apply and exert its action both locally and distally in the microcirculation of the flap. We have compared in vitro and in vivo vascular properties of nicardipine, papaverine, and lidocaine in the rabbit carotid artery. In vitro, rings from the rabbit carotid artery (n = 7) were bathed in Krebs-Ringers solution and stretched progressively to an optimal tension of 3.7 to 4.2 g. The specimens were contracted with norepinephrine (1 microM), and a cumulative dose response curve was established. In vivo, microvascular anastomoses were performed bilaterally in the rabbit carotid artery in 35 animals using 9-0 nylon suture and standard microsurgical techniques. During and after the anastomoses, nicardipine (0.1, 0.01 mg topical, or 0.1 mg/hour IV), papaverine (30 mg/cc topical), and lidocaine (2% with and without epinephrine) were applied (blinded) at the anastomotic site in five rabbits each. Heparinized sodium chloride was used as topical irrigation for control and to clean the anastomosis. Blood flow changes were monitored continuously with the transonic Doppler for 30 minutes after the procedure. The systemic blood pressure was also monitored in a group of pilot experiments. A documented decrease in blood flow was noted in all animals after the microvascular anastomosis. Nicardipine and papaverine evoked a concentration-dependent relaxation to precontracted rings to norepinephrine. Nicardipine was greater than papaverine in inducing relaxation. Lidocaine demonstrated a biphasic response with low concentrations potentiating contraction. Systemic nicardipine and papaverine significantly increased the blood flow in the rabbit carotid artery. Topical application of nicardipine and lidocaine did not significantly alter the blood flow; however, the application of nicardipine demonstrates a trend toward increased flow. Lidocaine with epinephrine significantly decreased the blood flow. No drug was found to alter the blood pressure of the animals. Our results demonstrate that nicardipine and papaverine seem to be pharmacologic tools able to increase the blood flow in anastomotic arteries. In contrast, the use of 2% lidocaine as a spasmolytic agent should be re-evaluated, since this substance may act as a partial agonist.
TL;DR: Cardiac dialysis with local administration of a pharmacological tool offers a new, concise approach to assessment of neuronal NE release, uptake, vesicle uptake, and storage capacity by cardiac sympathetic nerve terminals.
Abstract: We applied a dialysis technique to the hearts of anesthetized cats and examined whether the concentration of dialysate norepinephrine (NE) reflected NE disposition at the cardiac sympathetic nerve terminals. Dialysis probes were implanted in the left ventricular wall, and dialysate NE concentrations were measured as an index of myocardial interstitial NE levels. Stimulation of stellate ganglia significantly increased dialysate NE responses that were suppressed by local administration of an NE-releasing inhibitor (omega-conotoxin GVIA, 10 microM). Increments in basal dialysate NE levels were correlated with concentrations of a locally administered neuronal uptake blocker (desipramine; 1, 10, and 100 microM). Desipramine (100 microM) augmented stimulation-induced dialysate NE responses. Local administration of a neuronal vesicle uptake blocker (reserpine, 1 and 10 microM) did not alter dialysate NE levels but increased dialysate dihydroxyphenylglycol levels. An NE-releasing amine (tyramine, 100 microg/ml) was locally administered to examine NE storage capacity at the nerve terminal. The tyramine-induced NE-releasing response was completely abolished by pretreatment with reserpine (1 mg/kg i.p.). Thus cardiac dialysis with local administration of a pharmacological tool offers a new, concise approach to assessment of neuronal NE release, uptake, vesicle uptake, and storage capacity by cardiac sympathetic nerve terminals.
TL;DR: Fluoxetine's action leading to an increase in extracellular norepinephrine was not occurring in the terminal areas of the hypothalamus but elsewhere in the brain, possibly cell bodies in the locus coeruleus.
Abstract: The selective serotonin uptake inhibitor fluoxetine (10mg/kg i.p.) increased tissue levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol sulfate (MHPG-SO4) in rat hypothalamus, indicating an increased release of norepinephrine. Microdialysis studies in conscious rats showed that fluoxetine (10 mg/kg i.p.) increased extracellular concentrations of norepinephrine as well as serotonin in the hypothalamus. In contrast, desipramine (10mg/kg i.p.) increased extracellular concentration of norepinephrine but not serotonin in the hypothalamus. Consistent with its mechanism of being a selective serotonin uptake inhibitor, local perfusion of fluoxetine (10μM) caused a 7-fold increase in hypothalamic extracellular serotonin and a small non-significant increase in extracellular norepinephrine. The subsequent systemic injection of fluoxetine (10mg/kg s.c.) after local perfusion caused a 3-fold increase in extracellular norepinephrine, indicating that fluoxetine's action leading to an increase in extracellular norepinephrine was not occurring in the terminal areas of the hypothalamus but elsewhere in the brain, possibly cell bodies in the locus coeruleus.
TL;DR: The possibilities that adolescents development brings about a change in alpha 2-adrenoceptor subtype and that juveniles may have a greater NE reuptake capacity than adults are discussed are discussed.
TL;DR: The rise in epinephrine exerts potent stimulatory effects on glucose production principally by enhancing hepatic glycogenolysis, although the rise in circulating norepinephrine has minimal effects during chronic SHI.
Abstract: The role of epinephrine and norepinephrine in contributing to the alterations in hepatic glucose metabolism during a 70-h stress hormone infusion (SHI) was investigated in four groups of chronicall...
TL;DR: It is concluded that in conscious humans the primary effect of intranasal cocaine is to increase sympathetic nerve discharge to the skeletal muscle bed and sinoaortic baroreflexes play a pivotal role in modulating the cocaine-induced sympathetic excitation.
Abstract: Cocaine-induced cardiovascular emergencies are mediated by excessive adrenergic stimulation. Animal studies suggest that cocaine not only blocks norepinephrine reuptake peripherally but also inhibits the baroreceptors, thereby reflexively increasing sympathetic nerve discharge. However, the effect of cocaine on sympathetic nerve discharge in humans is unknown. In 12 healthy volunteers, we recorded blood pressure and sympathetic nerve discharge to the skeletal muscle vasculature using intraneural microelectrodes (peroneal nerve) during intranasal cocaine (2 mg/kg, n = 8) or lidocaine (2%, n = 4), an internal local anesthetic control, or intravenous phenylephrine (0.5-2.0 microg/kg, n = 4), an internal sympathomimetic control. Experiments were repeated while minimizing the cocaine-induced rise in blood pressure with intravenous nitroprusside to negate sinoaortic baroreceptor stimulation. After lidocaine, blood pressure and sympathetic nerve discharge were unchanged. After cocaine, blood pressure increased abruptly and remained elevated for 60 min while sympathetic nerve discharge initially was unchanged and then decreased progressively over 60 min to a nadir that was only 2+/-1% of baseline (P < 0.05); however, plasma venous norepinephrine concentrations (n = 5) were unchanged up to 60 min after cocaine. Sympathetic nerve discharge fell more rapidly but to the same nadir when blood pressure was increased similarly with phenylephrine. When the cocaine-induced increase in blood pressure was minimized (nitroprusside), sympathetic nerve discharge did not decrease but rather increased by 2.9 times over baseline (P < 0.05). Baroreflex gain was comparable before and after cocaine. We conclude that in conscious humans the primary effect of intranasal cocaine is to increase sympathetic nerve discharge to the skeletal muscle bed. Furthermore, sinoaortic baroreflexes play a pivotal role in modulating the cocaine-induced sympathetic excitation. The interplay between these excitatory and inhibitory neural influences determines the net effect of cocaine on sympathetic discharge targeted to the human skeletal muscle circulation.
TL;DR: Investigation of 2 months of streptozotocin-induced diabetes mellitus in rats suggests that diabetes causes a deficit in nitric oxide mediated endothelium-dependent relaxation of vasa nervorum, resulting in increased vasoconstrictor sensitivity which is likely to impair perfusion and contribute to the pathogenesis of neuropathy.
Abstract: The aim was to investigate the effects of 2 months of streptozotocin-induced diabetes mellitus in rats on the responses of sciatic vasa nervorum to vasoactive drugs. Changes in perineurial blood flow were monitored by laser-Doppler flowmetry during drug superfusion in vivo. Laser-Doppler flux was reduced by 53.3% after 2 months of diabetes. A 38-fold increase in norepinephrine sensitivity was found in diabetic compared to nondiabetic rats. Co-superfusion of norepinephrine and a high dose (100 μM) of the nitric oxide synthase inhibitor, N G -nitro-L-arginine, resulted in 116-fold and 3.6-fold increases in norepinephrine sensitivity in nondiabetic and diabetic rats, respectively, such that dose-response curves for changes in vascular conductance were superimposed. This suggests that the increased norepinephrine sensitivity in diabetes was caused by defective endothelial nitric oxide production or action. After norepinephrine preconstriction, acetylcholine caused dose-dependent increases in vascular conductance, sensitivity being 8.1-fold greater in nondiabetic than diabetic rats. In contrast, endothelium-independent responses to the nitrovasodilator, glyceryl trinitrate, were relatively unaffected by diabetes. Thus, diabetes causes a deficit in nitric oxide mediated endothelium-dependent relaxation of vasa nervorum, resulting in increased vasoconstrictor sensitivity which is likely to impair perfusion and contribute to the pathogenesis of neuropathy.
TL;DR: The results suggest that vasopressin, in addition to its direct vasoconstrictor effect, strongly potentiates the responses to adrenergic stimulation and KCl depolarization.
Abstract: Vasopressin not only acts directly on blood vessels through V1-receptor stimulation but also may modulate adrenergic-mediated responses in animal experiments in vitro and in vivo. The aim of the present study was to investigate whether subpressor concentrations of vasopressin could modify the constrictor responses to norepinephrine and electrical stimulation of the perivascular nerves in human mesenteric arteries. Human mesenteric artery rings (3-3.5 mm long, 0.8-1.2 mm OD) were obtained from 38 patients undergoing abdominal operations. The arterial rings were suspended in organ bath chambers for isometric recording of tension. Vasopressin (3 x 10(-11) M) enhanced the contractions elicited by electrical stimulation at 2, 4, and 8 Hz (by 100, 100, and 72%, respectively) and produced a leftward shift of the concentration-response curves to norepinephrine (half-maximal effective concentration decreased from 2.2 x 10(-6) to 5.0 x 10(-7) M; P < 0.05) without any alteration in maximal contractions. Vasopressin also potentiated KCl- and calcium-induced contractions. The V1-receptor antagonist 1-[beta-mercapto-beta,beta-cyclopentamethylenepropionic acid-2-O-methyl-tyrosine, 8-arginine]vasopressin (10(-6) M) prevented the potentiation evoked by vasopressin in all cases. The calcium antagonist nifedipine (10(-6) M) did not affect the potentiation of electrical stimulation and norepinephrine induced by vasopressin but abolished KCl-induced contractions. The results suggest that vasopressin, in addition to its direct vasoconstrictor effect, strongly potentiates the responses to adrenergic stimulation and KCl depolarization. Both the direct and indirect effects of vasopressin appear to be mediated by V1-receptor stimulation. The amplifying effect of vasopressin on constrictor responses may be relevant in those clinical situations characterized by increased plasma vasopressin levels.
TL;DR: Glibenclamide therapy is accompanied by greater systolic BP responses to norepinephrine and angiotensin II and higher plasma norpinephrine levels than those that occur on metformin therapy, which suggests that glibenClamide may have negative chronotropic effects.
Abstract: OBJECTIVE To compare the effects of chronic glibenclamide and metformin therapy on blood pressure (BP) and cardiovascular responsiveness in patients with NIDDM. RESEARCH DESIGN AND METHODS Fourteen patients with NIDDM received metformin or glibenclamide for 1 month in a double-blind, randomized crossover study. At the end of each treatment period, patients were tested for forearm vascular responsiveness to intrabrachial arterial infusion of diazoxide (an ATP-sensitive potassium channel opener), acetylcholine, sodium nitroprusside, and norepinephrine, BP responses to intravenous infusions of NE and angiotensin II, BP responses to cold pressor testing and isometric exercise, and 24-h ambulatory BP monitoring. RESULTS Metformin and glibenclamide produced similar glycemic control. Mean 24-h BPs did not differ between the two groups, but mean 24-h heart rates were significantly lower (75 ± 6 bpm vs. 80 ± 6 bpm) on glibenclamide therapy than on metformin. Plasma norepinephrine levels were significantly higher on glibenclamide (6.41 ± 1.77 vs. 4.26 ± 1.54 mmol/l, P CONCLUSIONS Glibenclamide therapy is accompanied by greater systolic BP responses to norepinephrine and angiotensin II and higher plasma norepinephrine levels than those that occur on metformin therapy. Lower heart rates on glibenclamide therapy despite evidence of greater sympathetic activity suggests that glibenclamide may have negative chronotropic effects.
TL;DR: It is suggested that cilnidipine can suppress norepinephrine release from the renal nerve endings and thereby interfere with the neural control of renal functions.