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Results for “Norepinephrine”

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PubMed1999

Effect of alterations in extracellular norepinephrine on adrenoceptors: a microdialysis study in freely moving rats.

Chronic electroshock treatment (once daily for 12 days) increases extracellular norepinephrine in the frontal cortex and hippocampus as measured by microdialysis. This chronic treatment produced an elevation of basal norepinephrine overflow into extracellular space while both the first and the twelfth treatments produced a transient increase in norepinephrine overflow of about 40 min. Acutely, desmethylimipramine (10 mg/kg) treatment significantly increased extracellular norepinephrine. While chronic desmethylimipramine (once daily for 10 days) increased basal overflow of norepinephrine in the frontal cortex and hippocampus, the tenth daily administration of desmethylimipramine did not produce a statistically significant increase in extracellular norepinephrine. Both daily electroshock and daily desmethylimipramine produced down regulation of beta-adrenoceptors in the hippocampus and the frontal cortex. Chronic electroshock caused up regulation of alpha-adrenoceptors in the frontal cortex but not in the hippocampus while chronic desmethylimipramine administration did not alter alpha-adrenoceptors in either structure. Depletion of norepinephrine with reserpine or with 6-hydroxydopamine prevented the down regulation of beta-adrenoceptors while depletion of this neurotransmitter did not prevent the electroshock-induced up regulation of alpha-adrenoceptors in the frontal cortex. These data suggest that down regulation of beta-adrenoceptors is mediated through increases in extracellular norepinephrine. In contrast, up regulation of alpha-adrenoceptors appears to be independent of norepinephrine release and does not require the presence of noradrenergic neurons in order to be induced by electroshock.

Adrenergic Uptake Inhibitors↗

PubMed2002

Cardiac response to norepinephrine and sympathetic nerve stimulation following experimental subarachnoid hemorrhage.

This study aimed to investigate the cardiac response to sympathetic stimulation and norepinephrine exposure following subarachnoid hemorrhage (SAH). Cardiac functional response was assessed 3 days following an injection of 300 microl of homologous blood in the cisterna magna using an in situ perfused, innervated rat heart model. Sympathetic nervous activity was indirectly assessed from measurements of arterial plasma and tissue norepinephrine concentration and cardiac beta-receptor density. In in situ perfused hearts, sympathetic nerve stimulation (2, 4 and 8 Hz, 1 min duration) induced a frequency-dependent increase in left ventricular pressure (VP), with the response being more pronounced in the SAH group of animals at the higher frequency (P<0.05). However, the concomitant release of norepinephrine was identical in the two groups of animals. Increasing doses of norepinephrine (10(-9) to 10(-5) M) added to the perfusate induced a dose-dependent increase in VP and its first derivative (dP/dt). Both responses were greater in the SAH animals compared to the sham rats (P<0.01). ECG recordings from SAH animals presented a higher incidence of different types of arrhythmias, both at rest and when submitted to electrical stimulation or norepinephrine exposure. No difference was found between groups in left ventricle norepinephrine content, plasma norepinephrine nor left ventricle beta-receptor density. In conclusion, hearts from animals following acute experimental SAH exhibit enhanced sensitivity to norepinephrine infusion and sympathetic nerve stimulation, and are more prone to develop arrhythmias. However, hypersensitivity of the heart may not be explained by changes in norepinephrine release or by beta-receptor density.

Animals↗

PubMed1996

Dihydroxyphenylglycol in pheochromocytoma: its diagnostic use for norepinephrine dominant tumor.

PURPOSE: To discern whether the 3,4-dihydroxyphenylglycol produced in adrenal medulla is associated with altered urinary excretion, we compared the tissue and urinary levels of this catecholamine metabolite, epinephrine and norepinephrine in 23 patients with pheochromocytoma and 26 subjects with renal cell carcinoma. MATERIALS AND METHODS: Tissue and urine concentrations of dihydroxyphenylglycol, epinephrine and norepinephrine were determined by catechol-O-methyl-transferase-based radioenzymatic method and high performance liquid chromatography with electrochemical detection. RESULTS: Contents of dihydroxyphenylglycol, epinephrine and norepinephrine in pheochromocytomas were higher than those in normal adrenal medullae. Removal of pheochromocytomas lowered urinary excretion of these catecholamines and dihydroxyphenylglycol. Norepinephrine content correlated closely with dihydroxyphenylglycol content in normal adrenal medullae and pheochromocytomas but not with epinephrine content in either tissue. Contents of norepinephrine and dihydroxyphenylglycol correlated significantly with urinary norepinephrine excretion and dihydroxyphenylglycol excretion in patients with pheochromocytoma but not in subjects with renal cell carcinoma. The norepinephrine-to-dihydroxyphenylglycol ratio in a 24-hour preoperative urine collection from patients with pheochromocytoma was higher than that from subjects with renal cell carcinoma, which was almost similar to that of epinephrine dominant pheochromocytomas. CONCLUSIONS: Our study suggests that dihydroxyphenylglycol in urine in subjects with renal cell carcinoma is predominantly of a neuronal origin and urinary dihydroxyphenylglycol in patients with pheochromocytoma is of tumor origin. A high level of norepinephrine-to-dihydroxyphenylglycol ratio in urine can be used to determine the diagnosis of the norepinephrine dominant type pheochromocytoma. Measurement of at least a few markers is preferable for precise biochemical diagnosis of pheochromocytoma.

Adrenal Gland Neoplasms↗

PubMed2003

Differences in norepinephrine clearance in cerebellar slices from low-alcohol-sensitive and high-alcohol-sensitive rats.

High-alcohol-sensitive (HAS) and low-alcohol-sensitive (LAS) rats were bred for sensitivity and insensitivity, respectively, to the sedative/hypnotic effects of ethanol. These rats also display differential sensitivity to the depressant effects of locally applied ethanol on cerebellar Purkinje neurons in vivo. We have found that LAS animals exhibit a greater influence of endogenous beta-adrenergic activity on neuronal responses to gamma-aminobutyric acid (GABA) and ethanol than do HAS animals. In the current study, we investigated the possibility that the regulation of synaptic norepinephrine levels by norepinephrine transporters could contribute to a differential beta-adrenergic influence on GABA and ethanol sensitivity between HAS and LAS rats. We locally applied norepinephrine from a glass micropipette into the various layers of cerebellar brain slices prepared from LAS and HAS rats, and recorded the levels of norepinephrine clearance by using Nafion-coated carbon-fiber microelectrodes. Norepinephrine clearance was significantly faster by approximately 64% in the Purkinje cell layer of HAS rats. No differences in norepinephrine clearance were found in the molecular or the granule layer between LAS and HAS rats. The catecholamine uptake inhibitor nomifensine reduced norepinephrine clearance in both rat lines. These findings support the hypothesis that regulation of synaptic norepinephrine levels by norepinephrine transporter activity in the Purkinje cell layer may contribute to the differential sensitivity of Purkinje neurons to ethanol and GABA in LAS and HAS rats.

Animals↗

PubMed1984

Renal interactions between norepinephrine and calcium antagonists.

The combined action of norepinephrine and calcium antagonists on the glomerular filtration rate (GFR) of isolated rat kidneys perfused at a constant pressure of 105 mm Hg was studied. Norepinephrine, 74 +/- 9 ng/ml (mean +/- SEM), increased the renal vascular resistance (RVR) by 50% and GFR declined by 88% (P less than 0.001). The subsequent addition of either diltiazem or verapamil (5 microM) returned RVR nearly to control and increased the GFR by an average of 86% over control (P = 0.007). Diltiazem or verapamil alone had little effect on RVR or GFR. Norepinephrine (20 ng/ml) did not affect RVR or GFR. In the presence of diltiazem, norepinephrine (20 ng/ml) again did not affect RVR but increased GFR by 58% (P = 0.003). With a low-calcium perfusate containing 0.4 mM total calcium, norepinephrine (90 ng/ml) did not affect RVR or GFR. Increasing perfusate norepinephrine to 236 +/- 8 ng/ml elicited a 50% increase in RVR, and GFR decreased by 95% (P less than 0.001). The subsequent addition of verapamil increased GFR to 2.8 times the original baseline value (P = 0.011) and restored RVR to control levels. These data suggest that diltiazem and verapamil block the vasoconstrictor action of norepinephrine on afferent arterioles selectively. Renal vascular sensitivity to norepinephrine decreases markedly either when the extracellular calcium concentration is reduced or in the presence of a calcium antagonist. However, a low-calcium perfusate does not mimic the property of calcium antagonists to facilitate an increase in GFR in the presence of norepinephrine.

Animals↗

PubMed1996

Mesenteric organ production, hepatic metabolism, and renal elimination of norepinephrine and its metabolites in humans.

This study used regional differences in plasma concentrations of norepinephrine and its metabolites to examine how production of the transmitter by sympathetic nerves, in particular, those innervating mesenteric organs, is integrated with metabolism by the liver and elimination by the kidneys. Higher concentrations of norepinephrine, its glycol metabolites 3,4-dihydroxyphenylglycol and 3-methoxy-4-hydroxyphenylglycol and their sulfate conjugates in portal venous than arterial plasma indicate substantial production of norepinephrine by mesenteric organs (15.5 nmol/min). Much lower concentrations of norepinephrine and its glycol metabolites in plasma leaving than entering the liver indicate their efficient hepatic removal (20 nmol/min). Higher concentrations of vanillylmandelic acid in the hepatic outflow than inflow indicate that this metabolic end product is produced largely from the norepinephrine and glycol metabolites removed by the liver. Renal elimination of vanillylmandelic acid (18-20 nmol/min), produced mainly by the liver (17 nmol/min), and of 3-methoxy-4-hydroxyphenylglycol sulfate (7-9 nmol/min), produced largely by mesenteric organs (7 nmol/min), compromised 86-91% of the total renal elimination of norepinephrine metabolites. The results show that mesenteric organs produce about one-half of the norepinephrine formed in the body. The liver removes substantial amounts of circulating norepinephrine and its glycol metabolites and converts these compounds to vanillylmandelic acid, which is then eliminated from the body by the kidneys. The sulfate conjugates are also metabolic end products eliminated by the kidneys. However, these metabolites are produced by extrahepatic tissues, in particular, mesenteric organs, which represent a significant source of sulfate-conjugated norepinephrine and 3,4-dihydroxyphenylglycol, and the main source of sulfate-conjugated 3-methoxy-4-hydroxyphenylglycol.

Aged↗

PubMed2001

Decreased intracellular calcium mediates the histamine H3-receptor-induced attenuation of norepinephrine exocytosis from cardiac sympathetic nerve endings.

Activation of presynatic histamine H(3) receptors (H(3)R) down-regulates norepinephrine exocytosis from cardiac sympathetic nerve terminals, in both normal and ischemic conditions. Analogous to the effects of alpha(2)-adrenoceptors, which also act prejunctionally to inhibit norepinephrine release, H(3)R-mediated antiexocytotic effects could result from a decreased Ca(2+) influx into nerve endings. We tested this hypothesis in sympathetic nerve terminals isolated from guinea pig heart (cardiac synaptosomes) and in a model human neuronal cell line (SH-SY5Y), which we stably transfected with human H(3)R cDNA (SH-SY5Y-H(3)). We found that reducing Ca(2+) influx in response to membrane depolarization by inhibiting N-type Ca(2+) channels with omega-conotoxin (omega-CTX) greatly attenuated the exocytosis of [(3)H]norepinephrine from both SH-SY5Y and SH-SY5Y-H(3) cells, as well as the exocytosis of endogenous norepinephrine from cardiac synaptosomes. Similar to omega-CTX, activation of H(3)R with the selective H(3)R-agonist imetit also reduced both the rise in intracellular Ca(2+) concentration (Ca(i)) and norepinephrine exocytosis in response to membrane depolarization. The selective H(3)R antagonist thioperamide prevented this effect of imetit. In the parent SH-SY5Y cells lacking H(3)R, imetit affected neither the rise in Ca(i) nor [(3)H]norepinephrine exocytosis, demonstrating that the presence of H(3)R is a prerequisite for a decrease in Ca(i) in response to imetit and that H(3)R activation modulates norepinephrine exocytosis by limiting the magnitude of the increase in Ca(i). Inasmuch as excessive norepinephrine exocytosis is a leading cause of cardiac dysfunction and arrhythmias during acute myocardial ischemia, attenuation of norepinephrine release by H(3)R agonists may offer a novel therapeutic approach to this condition.

Animals↗

PubMed1983

Life changes and urinary norepinephrine in myocardial infarction.

The relationship between norepinephrine and stress caused by life changes was assessed using urinary norepinephrine levels and responses to a 57-item stress questionnaire interview obtained from 21 post-myocardial infarction and 27 healthy control male and female subjects. High correlations between norepinephrine and duration of present stress and duration and severity of life changes, and moderate correlations between norepinephrine and anxiety and depression were found among the post-infarction group. No significant correlations were found in the control group. Post-infarction subjects with elevated norepinephrine had significantly higher scores on duration of present stress and duration and severity of life changes than did post-infarction subjects with normal norepinephrine levels. Control subjects with normal and elevated norepinephrine did not differ significantly on any of the comparison variables. Standard risk factors failed to add significantly to the prediction of norepinephrine in either group. However, 68.3 percent of the variance in norepinephrine was accounted for by a single predictor, the duration of present stress.

Female↗

PubMed2002

Influence of norepinephrine and dopamine on cortical perfusion, EEG activity, extracellular glutamate, and brain edema in rats after controlled cortical impact injury.

Following traumatic brain injury, catecholamines given to ameliorate cerebral perfusion may induce brain damage via cerebral arteriolar constriction and increased neuronal excitation. In the present study the acute effects of norepinephrine and dopamine on pericontusional cortical perfusion (rCBF), electroencephalographic (EEG) activity, extracellular glutamate, and brain edema were investigated in rats following controlled cortical impact injury (CCI). rCBF, cerebral perfusion pressure (CPP), EEG activity, and glutamate were determined before, during, and after infusing norepinephrine or dopamine, increasing MABP to 120 mm Hg for 90 min at 4 h after CCI. Control rats received physiological saline. At 8 h after CCI, hemispheric swelling and water content were determined gravimetrically. Following CCI, rCBF was significantly decreased. In parallel to elevating MABP and CPP, rCBF was significantly increased by norepinephrine and dopamine, being mostly pronounced with norepinephrine (+44% vs. +29%). In controls, rCBF remained diminished (-45%). EEG activity was significantly increased by norepinephrine and dopamine, while pericontusional glutamate was only elevated by norepinephrine (28 +/- 6 vs. 8 +/- 4 microM). Brain edema was not increased compared to control rats. Despite significantly increasing MABP and CPP to the same extent, norepinephrine and dopamine seem to differentially influence pericontusional cortical perfusion and glutamatergic transmission. In addition to the pressure-passive increase in CPP local cerebral effects seem to account for the sustained norepinephrine-induced increase in pericontusional cortical perfusion. The significantly elevated pericontusional glutamate concentrations in conjunction with the increased EEG activity suggest a sustained metabolically driven increase in cortical perfusion during norepinephrine infusion.

Animals↗

PubMed1984

Halothane-induced changes in the release and disposition of norepinephrine at adrenergic nerve endings in dog saphenous vein.

The effect of halothane on the release and metabolism of norepinephrine during resting conditions and in response to electrical stimulation at 2 Hz was studied in isolated superfused segments od dog saphenous vein. Liquid chromatography with electrochemical detection was used to measure endogenous norepinephrine overflowing in response to electrical stimulation and the content of norepinephrine remaining in the tissue after stimulation. In other preparations, norepinephrine stores were labeled with [3H]norepinephrine, and measurements were made of [3H]norepinephrine and its metabolites (separated by column chromatography) in superfusates. Radiolabeled metabolites of norepinephrine produced intraneuronally (3,4-dihydroxyphenylglycol) and extraneuronally (O-methylated) were quantitated by liquid scintillation spectrometry. Electrically stimulated release and overflow of endogenous norepinephrine was decreased 11.9% at 0.75% halothane, 17.7% at 1.5% and 19.2% at 2.5% halothane. At each halothane concentration studied, the per cent of tissue NE content released in response to electrical stimulation was less. Halothane decreased the fraction of radioactivity lost during basal conditions and during stimulation. Less oxidative deamination of norepinephrine occurred in the presence of halothane.

Animals↗

PubMed1996

Nitric oxide synthase inhibition versus norepinephrine for the treatment of hyperdynamic sepsis in sheep.

OBJECTIVES: To investigate the effects of Nomega-mono-methyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthesis, on hemodynamics, oxygen transport, and regional blood flow in an ovine model of hyperdynamic sepsis and to compare these effects with the responses to norepinephrine. DESIGN: Prospective, nonrandomized, controlled experimental study with repeated measures. SETTING: Investigational intensive care unit at a university medical center. SUBJECTS: Twenty-five female, healthy, adult sheep of the Merino breed, divided into three groups: nine control sheep; eight sheep treated with L-NMMA; and eight sheep treated with norepinephrine. INTERVENTIONS: All sheep were chronically instrumented. After a 5-day recovery period, a continuous infusion of live Pseudomonas aeruginosa (2.5 x 10(6) colony-forming units/min) was started and maintained for the remainder of the experiment. After 24 hrs of sepsis, eight sheep received L-NMMA (7 mg/kg/hr), eight sheep received norepinephrine, and nine sheep received the vehicle alone (0.9% saline). The norepinephrine dosage was continuously and individually adjusted to achieve the same increase in blood pressure as was observed in a matched sheep of the L-NMMA group. MEASUREMENTS AND MAIN RESULTS: After 24 hrs of sepsis, all sheep developed a hyperdynamic circulatory state with increased cardiac indices and reduced arterial pressures, and systemic vascular resistances. L-NMMA reversed the hyperdynamic circulation, causing an increase in arterial pressure by peripheral vasoconstriction. Norepinephrine led to an increase in blood pressure by augmenting cardiac indices, leaving the systemic vascular resistance unaffected. The norepinephrine dose needed to keep the blood pressure high had to be continuously increased, reflecting the reduced vascular responsiveness to catecholamines during sepsis. Renal blood flow remained unaffected by all treatment forms. Norepinephrine and L-NMMA led to a dramatic increase in urine production. Blocking the nitric oxide synthase with L-NMMA did not interfere with the host's pulmonary ability to clear bacteria, nor did treatment with norepinephrine. CONCLUSIONS: Blocking nitric oxide synthase had a marked vasoconstrictive effect. Both norepinephrine and L-NMMA increased arterial pressure without reducing renal blood flow, leading to an improved renal function.

Animals↗

PubMed1996

Renal hemodynamics during norepinephrine and low-dose dopamine infusions in man.

OBJECTIVE: To characterize the effects of pressor doses of norepinephrine and low-dose dopamine (3 micrograms/kg/min) on renal hemodynamics in man, as well as to determine the clinical relevance of combining dopamine with norepinephrine. DESIGN: Prospective, single-blind, randomized study. SETTING: Clinical research unit of a tertiary care hospital. SUBJECTS. Six healthy male volunteers ranging in age between 20 and 28 yrs. INTERVENTIONS: The subjects were assigned randomly to four treatments (1 wk apart) in which renal hemodynamics and electrolyte excretion were assessed. Treatments consisted of 180-min infusions of the following: a) 0.9% sodium chloride (control); b) pressor doses of norepinephrine; c) dopamine at 3 micrograms/kg/min; and d) pressor doses of norepinephrine and dopamine at 3 micrograms/kg/min. Pressor doses of norepinephrine was defined as doses required to increase mean arterial pressure (MAP) by 20 mm Hg. MEASUREMENTS AND MAIN RESULTS: Glomerular filtration rate and renal blood flow were derived from inulin and para-aminohippurate clearances, respectively. Urine output and urine solute excretion were also determined. The mean norepinephrine dose required to increase MAP by 22 +/- 2 mm Hg was 118 +/- 30 ng/kg/min (range 76 to 164). After the addition of dopamine, similar doses of norepinephrine resulted in an MAP increase of 15 +/- 4 mm Hg. Glomerular filtration rate and urine output were comparable under all conditions. The infusion of norepinephrine decreased renal blood flow from 1241 +/- 208 to 922 +/- 143 mL/min/1.73 m2 (p = .03). The addition of dopamine returned renal blood flow to baseline values. The clearance of urine sodium increased significantly with the infusion of dopamine alone (p = .03). All subjects completed the four treatment periods. Adverse events, manifested mostly as palpitations and flushing, were rare and self-limiting. CONCLUSIONS: The addition of dopamine (3 micrograms/kg/min) to pressor doses of norepinephrine normalized renal blood flow in healthy volunteers. These hemodynamic changes were not reflected in urine output and glomerular filtration rate; hence, these monitoring parameters may be unreliable indicators of renal function in the setting of vasopressor therapy. In addition, systemic effects were observed with dopamine (3 micrograms/kg/min), as indicated by a decrease in MAP.

Adult↗

PubMed1988

Pressure natriuresis and control of arterial pressure during chronic norepinephrine infusion.

The goal of this study was to quantitate changes in mean arterial pressure (MAP) and renal function during chronic increases in plasma levels of norepinephrine, and to determine the role of the renal pressure natriuresis mechanism in controlling sodium balance in norepinephrine hypertension. In six conscious dogs in which renal artery pressure (RAP) was allowed to increase during 7 days of norepinephrine infusion (0.2 micrograms/kg per min), sodium excretion (UNaV) rose from 66 +/- 3 to 112 +/- 15 mmol/day and MAP increased from 100 +/- 3 to 109 +/- 3 mmHg on the first day. On days 2-7, UNaV returned toward the control level while MAP averaged 108 +/- 2 mmHg. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) did not change significantly, averaging 85.9 +/- 4.0 and 235 +/- 17 ml/min, respectively, during 7 days of norepinephrine, compared to controls of 84.1 +/- 3.9 and 252 +/- 20 ml/min. When RAP was servo-controlled for 7 days during norepinephrine infusion, the natriuresis was abolished; UNaV averaged 76 +/- 8 during control, 77 +/- 13 during the first day of norepinephrine and 65 +/- 4 mmol/day during 7 days of norepinephrine. GFR and ERPF did not change significantly during norepinephrine infusion with RAP held constant. MAP did not reach a plateau but continued to rise from 102 +/- 3 to 137 +/- 3 mmHg after 7 days of norepinephrine and servo-control of RAP.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗

PubMed2000

Differential effects of carvedilol on norepinephrine release in normoxic and ischemic heart.

Carvedilol is a beta-adrenoceptor antagonist with multiple actions, which may contribute to superior cardioprotection in heart failure and myocardial infarction. We hypothesized that carvedilol may modulate presynaptic norepinephrine release in the heart. Therefore, we compared the effects of carvedilol (racemate and both enantiomers) and beta1-selective as well as nonselective beta-adrenoceptor blockers on norepinephrine release in isolated perfused rat hearts under normoxic and brief ischemic conditions. Exocytotic release of endogenous norepinephrine was induced by paired electric field stimulations to compare the release before (S1) and after (S2) beta-adrenoceptor blocker application. Metoprolol, bisoprolol, and pindolol (0.1-10 microM) had essentially no effect on exocytotic norepinephrine release under normoxic and ischemic conditions. In contrast, carvedilol exerted a biphasic concentration-response curve (increase followed by suppression) on norepinephrine release. The increase in norepinephrine release was more pronounced with R-carvedilol than with S-carvedilol, indicating an effect independent from beta-receptor antagonism. During ischemia, the facilitatory effect of carvedilol on norepinephrine release was lost, resulting in a concentration-dependent suppression of the release. These results indicate that carvedilol in contrast to classic beta1-selective and -nonselective beta-adrenoceptor blockers has pronounced effects on cardiac norepinephrine release with a remarkable difference between normoxic and ischemic conditions. Whereas a facilitation of norepinephrine release prevailed in normoxia, we observed a suppression of the release in ischemia. It remains to be established whether this unique action of carvedilol on cardiac sympathetic neurotransmission is of clinical relevance.

Adrenergic beta-Antagonists↗

PubMed2001

Reduction of cardiac norepinephrine improves postischemic heart function in stroke-prone spontaneously hypertensive rats.

Although mammalian ventricle is richly supplied with adrenergic nerves, endogenous norepinephrine is not essential to the intrinsic contractility of the normal heart. However, it is not clear whether acute changes in cardiac norepinephrine could alter heart function in genetically hypertensive rats. The purpose of this study was to examine the effect of cardiac norepinephrine reduction on basal and postischemic heart function in stroke-prone spontaneously hypertensive rats (SHRSPs) using an isolated working heart preparation. Hypertrophied hearts of SHRSPs showed higher cardiac norepinephrine content and impaired heart function at 4 months of age as compared with normal Wistar-Kyoto rats. Poor postischemic recovery of heart function observed in SHRSPs was accompanied by large amounts of coronary norepinephrine overflow. Cardiac norepinephrine reduction or depletion did not affect basal heart function in SHRSPs. Considerable reduction in cardiac norepinephrine with acute reserpine injection (5 mg/kg) in SHRSPs significantly improved postischemic recovery of cardiac output, coronary flow, and rate-pressure product. However, complete norepinephrine depletion with reserpine (10 mg/kg) was detrimental to myocardial automaticity and limited the postischemic recovery of systolic function in the hypertrophied hearts. These results suggest that acute reduction in cardiac norepinephrine may be of potential therapeutic importance to postischemic dysfunction in the hypertrophied hearts.

Animals↗

PubMed2002

Effect of ACE-inhibitor ramiprilat and AT1-receptor antagonist candesartan on cardiac norepinephrine release: comparison between ischemic and nonischemic conditions.

ACE-inhibitors and AT -receptor antagonists may exert part of their pharmacological actions by interference with angiotensin-and/or bradykinin-mediated prejunctional stimulation of cardiac norepinephrine release. As endogenous formation of angiotensin and bradykinin is increased in ischemia, we investigated the effects of the ACE-inhibitor ramiprilat and the AT -receptor antagonist candesartan on cardiac norepinephrine release in isolated perfused rat hearts, under nonischemic and stop-flow conditions. Exocytotic release of endogenous norepinephrine was induced by electrical field stimulation and measured by HPLC. Paired stimulations were applied in each heart to obtain an intraindividual comparison of the effect of the pharmacological agent on norepinephrine release with the release under baseline conditions. The ACE-inhibitor ramiprilat (0.1-10 nM) and the AT -receptor antagonist candesartan (1-100 nM) were studied during normal flow or in the fourth minute of stop-flow. Under nonischemic conditions, the ACE-inhibitor slightly reduced norepinephrine release at the highest concentration, while the AT -receptor antagonist did not influence norepinephrine release in normoxia. Conversely, both substances significantly increased norepinephrine release during ischemia. Augmentation of norepinephrine release in ischemia by ramiprilat and candesartan was blocked by the bradykinin B -receptor antagonist HOE 140 and, in case of candesartan, by the AT -receptor antagonist PD 123319. The ACE-inhibitor ramiprilat and AT -receptor antagonist candesartan enhance cardiac norepinephrine release selectively in ischemia by stimulating presynaptic bradykinin B -receptors. Regarding the AT -receptor antagonist, AT -receptor activation is also involved in bradykinin-mediated prejunctional stimulation.

Angiotensin Receptor Antagonists↗

PubMed2004

Bone marrow norepinephrine mediates development of functionally different macrophages after thermal injury and sepsis.

OBJECTIVE: We sought to determine the influence of thermal (burn) injury with sepsis and norepinephrine on the clonogenic potential and functional cytokine response to lipopolysaccharide (LPS) stimulation in nonmyeloid committed (CD117) and myeloid committed (ER-MP12) bone marrow progenitor cells. SUMMARY AND BACKGROUND DATA: We have previously demonstrated that norepinephrine stimulated myelopoiesis after burn injury and sepsis, but the site of this stimulation in monocyte development is unknown. In the present study the influence of norepinephrine on the developmental hierarchy of bone marrow cells after thermal injury and sepsis was determined by assessing the clonogenic potential and LPS-stimulated cytokine responses of mature macrophages derived from CD117 and ER-MP12 bone marrow progenitor cells. METHODS: Tissue and bone marrow norepinephrine content was ablated by chemical sympathectomy with 6-hydroxydopamine treatment. CD117 and ER-MP12 bone marrow cells were isolated using antibody-linked magnetic microbeads. Clonogenic potential in response to colony-stimulating factors was determined. Both progenitor cell types were differentiated to mature macrophages in vitro and tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 cytokine responses to LPS provocation were determined. RESULTS: The macrophage- and granulocyte-macrophage colony-stimulating factor responsive clonogenic potential was increased with burn sepsis, suggesting an expansion of both progenitor populations. Such increases were greatly reduced with prior depletion of norepinephrine. TNF-alpha and IL-6 cytokine responses to LPS were markedly influenced by the specific progenitor cells involved as well as the injury conditions and the status of norepinephrine prior to injury. In burn sepsis the depletion of norepinephrine resulted in a dramatic decrease in both IL-6 and TNF-alpha production by both progenitor-derived macrophages. CONCLUSIONS: Depletion of norepinephrine attenuated burn and burn sepsis-induced bone marrow progenitor clonal growth in response to macrophage- and granulocyte-macrophage colony-stimulating factor. Functional phenotypes of bone marrow progenitor-derived macrophages are greatly influenced by norepinephrine and the milieu created by thermal injury and sepsis.

Animals↗

PubMed1995

Synergistic effects of Bay K 8644 and bradykinin on norepinephrine release in the hypothalamus of spontaneously hypertensive rats.

1. In the present study, we examined the effects of Bay K 8644, a dihydropyridine (DHP)-sensitive Ca2+ channel agonist, and bradykinin on norepinephrine release in the hypothalamus of spontaneously hypertensive rats (SHR). 2. In the preliminary studies using Sprague-Dawley rats, Bay K 8644 by itself had no significant effects on the stimulation-evoked [3H]-norepinephrine release from hypothalamic slices. Bradykinin increased the stimulation-evoked [3H]-norepinephrine release in a dose-related fashion. The facilitatory effects of bradykinin on norepinephrine release were potentiated by Bay K 8644. 3. In SHR, Bay K 8644 significantly increased the stimulation-evoked norepinephrine release from hypothalamic slices. However, exposure of slices to Bay K 8644 caused no significant effects on norepinephrine release in Wistar-Kyoto (WKY) rats. The effects of Bay K 8644 in combination with bradykinin on the stimulation-evoked norepinephrine release were also greater in SHR than in WKY rats. 4. These results demonstrate that Bay K 8644 significantly potentiated the facilitatory effects of bradykinin on norepinephrine release in rat hypothalamus. The finding indicates a possible interaction of bradykinin with DHP-sensitive Ca2+ channels in the central nervous system. Furthermore, the pronounced effects of Bay K 8644 and bradykinin in SHR suggest that bradykinin-related Ca2+ channels might have a role in the regulation of norepinephrine release in the hypothalamus of SHR.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗