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Results for “Norepinephrine”

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PubMed1983

Regulation of choline acetyltransferase in primary cell cultures of spinal cord by neurotransmitter L-norepinephrine.

Neurotransmitter L-norepinephrine increased up to 8-fold the activity of choline acetyltransferase (CAT), the enzyme responsible for the synthesis of acetylcholine, in mouse spinal cord cells in culture grown for several days. The increase of CAT activity by L-norepinephrine was mediated by a beta-adrenergic receptor in the same manner as the response of intracellular cyclic AMP. Derivatives of cyclic AMP caused an increase of CAT activity to the level similar to that of L-norepinephrine. A cyclic AMP phosphodiesterase inhibitor, 3-isobutyl-1-methyl xanthine (IBMX), enhanced the elevation of CAT activity by L-norepinephrine. These results indicate that L-norepinephrine stimulated the synthesis of CAT molecules via the action of cyclic AMP. The pretreatment of cells with 5-fluoro-2'-deoxyuridine (FdU) markedly diminished the numbers of satellite cells and, in parallel, the responses of CAT activity to L-norepinephrine. The increase of cyclic AMP by L-norepinephrine was also reduced by pretreatment of the cells with FdU. In contrast, co-cultures of spinal cord with heart muscle markedly (30-fold) stimulated CAT activity both with and without pretreatment of FdU. The addition of L-norepinephrine and co-cultures with heart muscle showed an additive effect. These observations indicate that the stimulatory effect of L-norepinephrine on CAT activity is mostly, if not only, mediated via the interaction with satellite cells, and that the increase of CAT activity by L-norepinephrine is based on a mechanism different from that of co-cultures with heart muscle cells.

Animals↗

PubMed1979

Stereospecific (--)-[3H]norepinephrine binding to bovine hypothalamus. Possible identification of the catecholamine uptake site in synaptic vesicles.

A (--)-[3H]norepinephrine binding site was identified in a crude synaptosomal fraction isolated from bovine hypothalamus which bound norepinephrine rapidly, reversibly, and stereospecificially. The results were most consistent with binding of (-)-[H]norepinephrine to the carrier molecule used to translocate biogenic amines into synaptic vesicles. The binding studies indicated that specific binding of (--)-[3H]norepinephrine to the crude synaptosomal fraction was greatly enhanced by 4 mM MgCl2 pand 1 mM ATP. The increased binding of (--)-[3H5norepinephrine also occurred in the presence of MgCl2 and GTP, but AMP, adenosine and adenyl-5'-yl imidodiphosphate would not substitute for ATP. Neither CaCl2 nor ZnSO4 could be substituted for the MgCl2. In the presence of MgCl2 and ATP, the dissociation constant for (--)-[3H]norepinephrine was 280 nM with a specific binding site density of 4.8 pmol/mg protein. Binding was stereospecific with ratios of 15, 4, and 6.5 for the affinities of (--)-isomers to (+)-isomers for norepinephrine, epinephrine and isoproterenol, respectively. Drug competition studies, conducted in the presence of Mg2+ and ATP, indicated that (--)-epinephrine, (--)-norepinephrine, dopamine and serotonin had inhibitory constants ranging from 0.25 to 0.8 micron with (--)-isoproterenol and tyramine having inhibitory constants around 2 micron. Reserpine was the most potent inhibitor having an inhibition constant of 8.6 +/- 0.3 nM. The binding data were not consistent with the specific site being the alpha- or beta-receptors for norepinephrine, the Uptake1 Site for norepinephrine into synaptosomes or the metabolizing enzymes for norepinephrine.

Adenine Nucleotides↗

PubMed1983

Mechanism of negative feed-back inhibition of norepinephrine release by alpha-adrenergic agonists.

The mechanism of alpha-adrenergic receptor-mediated feedback regulation of [3H]norepinephrine release was studied in the guinea-pig heart. The overflow of [3H]norepinephrine evoked by stimulation (1 Hz for 60 s) was inhibited up to 90% in a dose-dependent manner by norepinephrine (58.5 and 177 nM) and epinephrine (54 and 164 nM). These inhibitory effects were antagonized by 20 mM tetraethylammonium. The overflow of [3H]norepinephrine was near normal when the calcium concentration of the perfusion medium was reduced from a control value of 2.5 to 0.25 mM in the presence of 20 mM tetraethylammonium. Norepinephrine exerted its typical inhibitory effect on the overflow induced in low [Ca2+] and high [tetraethylammonium] solution. Similarly, the inhibitory effects of epinephrine became evident in the presence of 20 mM tetraethylammonium and 0.25 mM calcium ions. Another K-channel blocker, 4-aminopyridine, was also effective in antagonizing the presynaptic actions of norepinephrine; the effect was more pronounced at lower than higher concentrations of norepinephrine. However, after reduction of the calcium ion concentration to 0.2 mM in the presence of 1 mM 4-aminopyridine, all concentrations of norepinephrine significantly reduced the overflow of [3H]norepinephrine. We conclude that the alpha-adrenergic agonists directly influence the availability of calcium ions needed for the transmitter release, and that this effect is brought about without altering the electrical properties (i.e. nerve conduction, action potential size, resting membrane potential of the nerves, etc.). This is in contrast to the actions of acetylcholine and adenosine which, in an earlier study, were shown to inhibit [3H]norepinephrine release primarily by modifying the electrical properties of the nerves.

4-Aminopyridine↗

PubMed1995

Norepinephrine modulates excitability of neonatal rat optic nerves through calcium-mediated mechanisms.

We report that norepinephrine markedly increases excitability of neonatal rat optic nerves. To investigate the mechanisms of the norepinephrine-induced excitability increase, we studied isolated optic nerves from 42 neonatal (< three days old) and five adult (> three months old) Long-Evan's hooded rats. Norepinephrine (10(-6), 10(-5) and 10(-4) M) rapidly and reversibly increased the amplitude (mean +/- S.D.: 3.5 +/- 1.7%, 12.1 +/- 2.8% and 35.6 +/- 8.4%) of compound action potentials elicited by submaximal stimulation of neonatal optic nerves. The beta-1 adrenoceptor antagonist atenolol (10(-5) M) blocked the norepinephrine-induced increase in excitability but the alpha antagonist phentolamine (10(-5) M) did not. The beta agonist isoproterenol (10(-5) and 10(-4) M) increased response amplitudes (8.7 +/- 4.1% and 25.8 +/- 4.6%) but the alpha-1 agonist methoxamine and alpha-2 agonist clonidine did not. The beta antagonist propranolol blocked the isoproterenol effect. Replacing Ca2+ with Mg2+ or adding 0.8 mM of Cd2+ reversibly blocked the norepinephrine effects. Extracellular K+ concentrations did not change in optic nerves during norepinephrine application. Blockade of K+ channels with apamin (10(-6) M) or tetraethylammonium (10(-3) M) did not prevent the excitatory effects of norepinephrine. Adult rat optic nerves were insensitive to both norepinephrine (10(-4) M) and isoproterenol (10(-4) M). Our results indicate that norepinephrine increases neonatal optic axonal excitability through Ca(2+)-dependent mechanisms. The data suggest that the adrenoceptors are situated on the axons, that the excitability changes are not due to changes in extracellular K+ concentration or K+ channels sensitive to apamin or tetraethylammonium. The sensitivity of rat optic nerves to norepinephrine declined with age. Axonal adrenoceptors may play a role in optic axonal development and injury.

Adrenergic Agonists↗

PubMed1994

Transmural heterogeneity of norepinephrine uptake in failing human hearts.

OBJECTIVES: The aim of this study was to determine whether regional heterogeneity in myocardial sympathetic neural function measured by the uptake of norepinephrine could account for the spatial heterogeneity of beta-adrenergic receptor down-regulation that occurs in the failing human heart. BACKGROUND: Myocardial beta-adrenergic receptor density and function are diminished in patients with chronic heart failure. Down-regulation occurs predominantly in the subendocardium, suggesting that local rather than systemic alterations in sympathetic neural function may be responsible. Although some studies have implicated hypofunction of cardiac sympathetic nerves with defective norepinephrine uptake, others suggest increased cardiac sympathetic nerve activity with unimpaired uptake. METHODS: We measured norepinephrine uptake by incubating transmural slices of the left ventricle from 19 patients who had chronic heart failure and three nonfailing control hearts with [3H]norepinephrine with or without desipramine, a neuronal uptake blocker. The density of uptake sites was measured in subepicardial and subendocardial myocyte regions with light microscopic autoradiography. RESULTS: Although the amount of [3H]norepinephrine uptake varied considerably in failing ventricles, uptake was directly proportional (r = 0.46, p < 0.05) to beta 1-adrenergic receptor density measured in additional slices with radioligand binding assays. In addition, marked transmural heterogeneity in [3H] norepinephrine uptake was consistently observed in failing ventricles. Uptake in subendocardial myocyte regions was significantly less than in subepicardial regions (mean [ +/- SD] subepicardial/subendocardial uptake ratio 4.7 +/- 4.8, p < 0.01). The extent of transmural heterogeneity in norepinephrine uptake was similar in patients with idiopathic and ischemic cardiomyopathy. In contrast, nonfailing hearts exhibited more uniform transmural [3H]norepinephrine uptake (subepicardial/subendocardial uptake ratio 1.8 +/- 1.2, p = NS). CONCLUSIONS: Specific [3H]norepinephrine accumulation is approximately fivefold lower in subendocardial regions of failing left ventricles than in subepicardial regions. These findings support the hypothesis that a subendocardial defect in norepinephrine uptake may chronically elevate local interstitial catecholamine levels and thereby down-regulate beta-adrenergic receptors in a spatially heterogeneous distribution.

Adult↗

PubMed1995

Sodium ions attenuate the inhibitory effects of neuropeptide Y on norepinephrine release in rat hypothalamus.

Neuropeptide Y (NPY) has a wide and specific distribution both in the central and peripheral nervous systems. In the present study, we have investigated the effects of NPY on norepinephrine release in rat hypothalamus, and further examined the interaction of NPY with alpha 2-adrenergic receptors, as well as the influence of sodium ions on the modulation of norepinephrine release. In an in vitro study, NPY significantly inhibited the stimulation-evoked norepinephrine release from hypothalamic slices in a dose-dependent manner. The alpha 2-adrenergic receptor agonist, UK 14,304, also reduced the stimulation-evoked norepinephrine release. A low concentration of NPY, which had no effects on its own, significantly potentiated the inhibitory effect of UK 14,304 on the stimulation-evoked [3H]norepinephrine release. The blockade of alpha 2-adrenergic receptors by RX 781094 diminished the inhibitory effects of NPY on norepinephrine release. Pretreatment of slices with pertussis toxin (a potent inhibitor of the Gi-proteins) significantly attenuated the suppressive effects of NPY and UK 14,304 on norepinephrine release. When the sodium concentration of the perfusion medium was increased, the inhibitory effects of NPY and UK 14,304 on norepinephrine release were significantly reduced. These results show that NPY might inhibit norepinephrine release that is partially mediated by alpha 2-adrenergic receptors and the pertussis toxin-sensitive Gi-proteins in rat hypothalamus. Moreover, less suppressive effects of NPY and UK 14,304 on norepinephrine release in the presence of excess sodium ions suggest that sodium ions might actively participate in regulating the NPY and alpha 2-adrenergic receptor mediated functions in the central nervous system.

Adrenergic alpha-Agonists↗

PubMed2003

Mechanisms underlying the hydrogen peroxide-induced, endothelium-independent relaxation of the norepinephrine-contraction in guinea-pig aorta.

The mechanisms underlying the hydrogen peroxide-induced relaxation of the norepinephrine-contraction were studied by measuring isometric force, myosin light chain (MLC(20)) phosphorylation and cyclic GMP in endothelium-denuded muscle from the guinea-pig aorta. Norepinephrine (5.2+/-1.3 microM) produced a phasic, followed by a tonic contraction. Hydrogen peroxide (10 and 100 microM), glyceryl trinitrate (30 and 300 nM) and 8-bromo cyclic GMP (30 and 100 microM) did not change the basal tone, but reduced the norepinephrine-induced contraction. Phosphorylation of MLC(20) (percentage of phosphorylated to total MLC(20)) was increased 1 min (5.9+/-1.0% vs. 35.9+/-4.9%) and, to a lesser extent, 20 min (3.7+/-1.7% vs. 13.9+/-1.6%) after the addition of norepinephrine. Hydrogen peroxide (100 microM) did not modify basal MLC(20) phosphorylation, but reduced the increase in MLC(20) phosphorylation induced by 1-min exposure to norepinephrine (20.9+/-4.1%). Its effect was abolished by catalase. When the tissue was incubated for 20 min with norepinephrine in the presence of hydrogen peroxide, norepinephrine-induced MLC(20) phosphorylation was not changed (13.6+/-1.5%), as compared to that in the absence of hydrogen peroxide. Hydrogen peroxide relaxed norepinephrine-stimulated aortas in a concentration-dependent fashion with EC(50) values of 5.9+/-0.2 microM. The relaxation was inhibited by soluble guanylate cyclase inhibitors and increased by an inhibitor of cyclic GMP-selective phosphodiesterase. In aorta precontracted with norepinephrine, hydrogen peroxide (100 microM) relaxed the tissue by 89+/-11% and almost doubled tissue concentrations of cyclic GMP, whereas sodium nitroprusside (1 microM) relaxed the tissue by 100% and increased cyclic GMP concentrations 30-fold. It is suggested that the inhibitory effects of hydrogen peroxide on the norepinephrine-induced phasic and sustained contractions are explained by a decrease in MLC(20) phosphorylation and by an alteration in MLC(20) phosphorylation-independent mechanisms, respectively. The effects of hydrogen peroxide were in part mediated by cyclic GMP.

Animals↗

PubMed1996

Differential effects of physiological versus pathophysiological plasma concentrations of epinephrine and norepinephrine on ketone body metabolism and hepatic portal blood flow in man.

Few studies that have examined the effects of catecholamines on ketogenesis have considered the effects of catecholamines on hepatic portal blood flow. Since hepatic blood flow is a major determinant of hepatic ketogenesis (via modification of free fatty acid availability), interpretation of these studies is difficult. To better define the relative contributions of these variables, we studied the effects of physiological and pathophysiological plasma concentrations of epinephrine and norepinephrine on plasma ketone body concentrations and hepatic portal blood flow in controlled paired studies in young healthy male volunteers. To assess the effects of physiological catecholamine concentrations, each of eight subjects received 60-minute sequential infusions of epinephrine (10 ng/kg/min) and norepinephrine (32.5 ng/kg/min) together with a control infusion of heparin (0.4 U/kg/min) separated by 60-minute washout periods. Similar increments in plasma nonesterified fatty acid ([NEFA] to approximately 1 mmol/L) were observed during each infusion. The ketotic ratios, calculated as the ratio of plasma ketone bodies to fatty acids integrated above baseline for 90 and 120 minutes, respectively, for epinephrine and norepinephrine infusions were both significantly greater (P < .005 for each) than for the heparin control infusion. To assess the effects of pathophysiological plasma catecholamine concentrations, each of eight subjects also received sequential 60-minute infusions of epinephrine 60 ng/kg/min, norepinephrine 80 ng/kg/min (plus heparin 0.1 U/kg/min), and a separate control infusion of heparin with or without Intralipid (KabiVitrum, Alameda, CA). Whereas integrated plasma fatty acid levels were approximately twofold greater than those observed in the physiological protocol, the absolute integrated ketone body response to the pathophysiological concentration of epinephrine was significantly lower than that observed for the physiological dose of the hormone (P < .05). In contrast, the ketotic ratio for norepinephrine was significantly greater (P < .005) than for both epinephrine and the control infusion of heparin with or without Intralipid. Significant (P < .01) increases above baseline fasting levels were observed in plasma glucose and immunoreactive insulin concentrations during infusion of pathophysiological concentrations of epinephrine. Because of the technical difficulties of simultaneously measuring portal blood and sampling blood frequently, studies were repeated in six additional subjects using noninvasive image-guided flowmetry to measure percentage changes in hepatic portal blood flow during catecholamine infusion. Norepinephrine reduced hepatic portal blood flow significantly at the low-physiological concentration by 12% (P < .05) and at the pathophysiological concentration by 18% (P < .05). In summary, (1) both epinephrine and norepinephrine were associated with significant ketotic effects at physiological plasma concentrations; and (2) when infused at pathophysiological concentrations, only norepinephrine exerted a significant additional ketotic effect. Since norepinephrine has a significant simultaneous effect of reducing hepatic portal blood flow, we conclude that previous studies may have underestimated the effect of norepinephrine on hepatic ketogenesis.

Adult↗

PubMed1999

Norepinephrine induced alpha-adrenoceptor mediated increase in rat brain Na-K ATPase activity is dependent on calcium ion.

It has been reported that norepinephrine increases Na-K ATPase activity by acting on alpha-1 adrenoceptors. The mechanism of such an increase was investigated. The norepinephrine induced increase in synaptosomal Na-K ATPase activity was prevented by pretreating the rat brain homogenate with either EDTA, a divalent cation chelator or prazosin, an alpha-1 adrenoceptor blocker. The norepinephrine and EGTA increased the Na-K ATPase activity in the synaptosome prepared from rat brain homogenate untreated with EDTA. The EGTA was ineffective in stimulating the enzyme activity if the synaptosome was prepared from homogenate treated with norepinephrine. However, the EGTA was effective in increasing the enzyme activity if the synaptosome was prepared from the homogenate treated with norepinephrine in the presence of prazosin. Thus, norepinephrine did not increase the Na-K ATPase activity in the presence of EDTA or alpha-1 adrenoceptor blocker. Similarly, the Ca++ chelator, EGTA, could not increase the enzyme activity if the homogenate was pretreated with norepinephrine alone. However, if norepinephrine action was blocked by alpha-1 antagonist prazosin, EGTA increased the enzyme activity possibly by chelation of Ca++. Further, chlorotetracycline fluorescence study showed that norepinephrine removes membrane bound Ca++. Thus, it is likely that norepinephrine acts on adrenoceptors and removes membrane bound Ca++ and thereby increases the Na-K ATPase activity in the synaptosome.

Animals↗

PubMed1991

Genetic aspects of variability in superficial vein responsiveness to norepinephrine.

Venoconstriction of the dorsal hand vein by local norepinephrine infusion was measured by the linear variable differential transformer method in 15 healthy unrelated subjects and eight pairs of monozygotic and six pairs of dizygotic twins. Incremental norepinephrine infusion produced dose-related venoconstriction. In unrelated subjects the doses of norepinephrine constricting basal vein diameter by 50% (ED50) ranged from 3.9 to 120.5 ng/min. There was a positive linear relationship between doses of norepinephrine infused and local steady-state plasma concentrations of norepinephrine achieved in each subject. The reciprocals of the slopes of these dose-concentration relationships, which reflect local norepinephrine clearance (disposition) in the vein, ranged from 0.47 to 1.86 ml/min. Plasma concentrations of norepinephrine associated with reduction of basal vein diameter by 50% (EC50) ranged from 1.4 to 110.2 ng/ml, with variability similar to that of ED50. There was a very high level of concordance in ED50, EC50, and clearance of norepinephrine within pairs of monozygotic twins but not within dizygotic twins. Differences in pharmacokinetics of infused norepinephrine exert a minor impact on overall intersubject variability. Genetic aspects of "tissue responsiveness" (i.e., vascular alpha-adrenoceptor response, smooth muscle contractility, and endothelial function) appear to be largely responsible for the wide intersubject variability in venoconstrictor responsiveness to norepinephrine.

Adult↗

PubMed2002

Somatosensory stimuli evoke norepinephrine release in the anterior ventromedial hypothalamus of sexually receptive female rats.

We used in vivo brain microdialysis to determine the role of specific copulatory stimuli in mating-induced release of norepinephrine in the lateral ventromedial hypothalamus (VMH) of hormone-treated, sexually receptive female rats. Ovariectomized rats implanted with a unilateral guide cannula aimed at the ventrolateral VMH received systemic injections of estradiol benzoate daily for 2 days before and progesterone 4 h before the initiation of a 1-h behavioural test. Dialysis probes were lowered immediately after progesterone administration, and 20-min dialysis samples were collected until 1 h after the termination of behavioural testing. Norepinephrine content of dialysates was quantified by high performance liquid chromatography with electrochemical detection. During mating tests with male rats, dialysate levels of norepinephrine increased significantly over baseline in sexually receptive females with probe placements in the anterior but not posterior VMH. Norepinephrine levels were unchanged if rats were nonreceptive, even if males mounted vigorously and probes were located in the anterior VMH. Hormone-treated females that were placed on male-soiled bedding for 1 h showed no changes in dialysate levels of norepinephrine. Similarly, females in which vaginocervical stimulation was prevented by a vaginal mask failed to show increased levels of norepinephrine in dialysates collected from the anterior VMH, even if they displayed high levels of lordosis behaviour. Thus, the release of norepinephrine is not a result of executing the lordosis posture. The findings suggest that mating-induced increases in norepinephrine release in hormone-treated, sexually receptive rats are confined to the anterior VMH and that somatosensory rather than chemosensory stimuli evoke norepinephrine release. Moreover, experiments with vaginal masks indicate that vaginocervical stimulation is necessary for mating-evoked norepinephrine release in the anterior VMH.

Animals↗

PubMed1990

The effect of halothane on norepinephrine responsiveness in rabbit small mesenteric veins.

The effect of halothane on the response of small isolated mesenteric capacitance veins to exogenous norepinephrine and electrically induced endogenous norepinephrine release was studied. The role of extra- and intracellular Ca2+ in norepinephrine-induced contractions was also examined. Two-millimeter-long segments from the second-order branch of the mesenteric vein were stretched to twice their resting diameter, and the generated tension was measured with a force transducer. Dose-dependent effects of norepinephrine on generated tension were examined before and after exposure to 0.75 and 1.5% halothane. (These concentrations produced perfusate halothane concentrations of 0.31 and 0.49 mM respectively.) Norepinephrine produced an increase in the basal vessel tension along with a superimposed rhythmic oscillation in tension. Although the magnitude of the tension increase was not affected by either concentration of halothane, the amplitude of the oscillations was reduced. Ryanodine (a blocker of Ca2+ release from the sarcoplasmic reticulum), like halothane, decreased the amplitude of the oscillations, but did not affect overall tension development. In the Ca2(+)-free medium the contractile response to norepinephrine was greatly attenuated as compared to control, whereas the oscillatory behavior was completely abolished. Norepinephrine release was examined indirectly by measuring the increase in tension during electric field stimulation. Response to endogenously released norepinephrine was significantly decreased by exposure to halothane 1.5% (0.49 mM) and blocked by pretreating the vessel with phentolamine. At concentrations used clinically, halothane did not affect overall developed tension in response to exogenously applied norepinephrine. However, 1.5% (0.49 mM) halothane decreased both sarcoplasmic-reticulum-dependent oscillations in tension and electrically induced release of endogenous norepinephrine.

Animals↗

PubMed2001

Possible involvement of cyclic adenosine monophosphate-independent mechanism in the positive chronotropic effect of norepinephrine in the isolated guinea pig right atrium.

BACKGROUND: Although both positive chronotropic and inotropic effects of beta-adrenergic stimulation are thought to be mediated by cyclic adenosine 3'5'-monophosphate, phosphodiesterase III inhibitors such as amrinone and milrinone potentiate the positive inotropic effect of catecholamines with minimum influence on the heart rate in clinical setting. The aim of the current study was to compare the positive chronotropic effect of norepinephrine with that of forskolin to elucidate whether cyclic adenosine monophosphate is relevant to the chronotropic effect of norepinephrine. METHODS: Concentration-response curves for the positive chronotropic effects of norepinephrine and forskolin on the spontaneously beating right atria of guinea pigs were determined in the absence and presence of phosphodiesterase inhibitors or ion channel inhibitors. In some experiments, the left atria driven electrically were used to determine the positive inotropic effect of norepinephrine. RESULTS: Norepinephrine and forskolin increased the beating rate in a concentration-dependent manner. The positive chronotropic effect of forskolin was potentiated by amrinone and 3-isobutyl-1-methylxanthine, whereas the positive chronotropic effect of norepinephrine was not potentiated by the phosphodiesterase inhibitors. In contrast, the positive inotropic effect of norepinephrine was potentiated by amrinone. The hyperpolarization-activated inward current inhibitor cesium chloride and L-type voltage-dependent Ca2+ current inhibitor verapamil suppressed the chronotropic effect of norepinephrine, whereas these inhibitors did not affect the chronotropic effect of forskolin. CONCLUSION: Norepinephrine increases the spontaneously beating rate by a different mechanism from that of forskolin, suggesting that cyclic adenosine monophosphate is causally unrelated to the positive chronotropic effect of norepinephrine in the guinea pig heart.

Adrenergic alpha-Agonists↗

PubMed2004

Activation of the ATP-dependent potassium channel attenuates norepinephrine-induced vasoconstriction in the human forearm.

Sepsis-induced vasodilation is characterized by an attenuated sensitivity to vasoconstrictor substances such as norepinephrine, possibly mediated by activation of vascular potassium channels. We determined whether vasodilation associated with potassium channel activation resulted in an attenuated vasoconstrictive response to norepinephrine in humans and whether the vasodilation associated with potassium channel activation could be inhibited by pharmacological potassium channel blockers. In 30 volunteers, the brachial artery was cannulated for infusion of drugs. Forearm blood flow (FBF) was measured in both arms using strain-gauge venous occlusion plethysmography. Forearm vascular resistance (FVR, mean arterial pressure/FBF) was calculated. The effects of vasodilation induced by sodium nitroprusside (SNP, nitric oxide donor) or diazoxide (activator of the ATP-dependent potassium channel) on norepinephrine-mediated vasoconstriction were examined. Also, the effects of potassium channel blockers on vasodilation associated with potassium channel activation were determined. Intraarterial SNP infusion (2 microg/min/dL) increased forearm blood flow by 235%, from (mean +/- SEM) 2.8 +/- 0.7 to 9.4 +/- 1.5 mL/min/dL (P < 0.0001). Subsequent norepinephrine infusion (10, 30, 100, 300, 1000 ng/min/dL) increased FVR dose-dependently from 13 +/- 4 AU to 249 +/- 45 AU at the highest norepinephrine infusion. Intraarterial diazoxide infusion (1 mg/min/dL) increased FBF by 209% from 2.2 +/- 0.3 to 6.8 +/- 1.0 mL/min/dL (P < 0.001). Subsequent norepinephrine infusion increased FVR from 18 +/- 5 to 51 +/- 6 AU at the highest norepinephrine infusion rate (n = 10), significantly different from the norepinephrine-induced effects during SNP coinfusion (P < 0.001). Diazoxide-induced fall in FVR in the infused forearm was inhibited by potassium channel blockers tetraethyl ammonium (1 mg/min/dL, n = 10, P = 0.004) and quinine (50 microg/min/dL, n = 10, P = 0.016). Vasodilation induced by vascular potassium channel activation is associated with an impressive reduction in the vasoconstrictor response to norepinephrine in humans. In accordance with animal experiments, this indicates that potassium channel activation could account for the diminished norepinephrine sensitivity in septic patients. Vasodilation associated with potassium channel activation can be inhibited by pharmacological potassium channel blockade. The possible role of potassium channel blockers during sepsis-induced potassium channel activation and vasodilation in humans needs further elucidation.

Adult↗

PubMed1978

Norepinephrine: hormone and neurotransmitter in man.

To determine whether norepinephrine could subserve a hormonal as well as a neurotransmitter function, norepinephrine was infused for 60 min into each of five normal young men in doses of 0.1, 0.5, 1.0, 2.5, and 5.0 microgram/min. After infusion, the plasma norepinephrine concentration fell with a mean (+/-SD) half-time of 2.4 +/- 0.7 min. The mean (+/-SD) norepinephrine metabolic clearance rate was 3,070 +/- 200 ml/min. The calculated basal plasma norepinephrine production rate was 0.7 microgram/min. The blood pressure and circulating glycerol, acetoacetate, beta-hydroxybutyrate, and glucose (increased) and the heart rate and circulating insulin, lactate, pyruvate, and alanine (decreased) exhibited highly significant parabolic relationships with the steady-state plasma norepinephrine concentrations. However, norepinephrine levels in excess of 1,800 pg/ml were required to produce hemodynamic and/or metabolic effects. Thus, under usual conditions, the biologic actions of norepinephrine can be attributed only to its sympathetic neurotransmitter function. Plasma norepinephrine concentrations do at times exceed 1,800 pg/ml during exercise and during major acute illness. Thus, under conditions of stress, norepinephrine may subserve a hormonal, as well as a neurotransmitter, function.

Adult↗

PubMed1994

Constitutive nonexocytotic norepinephrine release in sympathetic curves of in situ canine heart.

Nonexocytotic norepinephrine bulk overflow from sympathetic nerves has been previously demonstrated in the perfused isolated heart only after inhibition of sympathetic nerve metabolism by hypoxia, ischemia, or metabolic inhibitors. The measurement, however, ignores simultaneous uptake of norepinephrine by sympathetic nerves. We quantitated simultaneous norepinephrine uptake and release in pentobarbital-anesthetized dogs by the use of a transient tracer approach, the multiple indicator dilution technique, combined with measurement of endogenous arterial and venous plasma norepinephrine levels. Sympathetic vesicles were previously depleted by reserpine, and desipramine was used to inhibit the neuronal membrane pump. Labeled albumin, sucrose, and norepinephrine were injected into the coronary artery, and sequential samples were collected from the coronary sinus. Reserpine pretreatment significantly depleted tissue and decreased plasma norepinephrine levels; tracer norepinephrine uptake increased slightly, and there was a substantial decrease in the rate of release of unlabeled norepinephrine. Desipramine then decreased tracer uptake and virtually eliminated norepinephrine release. We conclude that desipramine-suppressible, constitutive nonexocytotic norepinephrine release is present in cardiac sympathetic nerves.

Animals↗

PubMed2004

Effect of age on cutaneous vasoconstrictor responses to norepinephrine in humans.

To test the hypothesis that cutaneous vasoconstrictor responsiveness to exogenous norepinephrine is reduced in older compared with young subjects, dose-response relations between norepinephrine and skin blood flow were established. Seven doses of norepinephrine (1.10(-8) to 10(-2) log M) were perfused (2 microl/min) intradermally (4 min/dose) using cutaneous microdialysis (2 probes/subject). To account for possible differences in endogenous norepinephrine between groups, one microdialysis probe was perfused with bretylium tosylate to locally block noradrenergic vesicle release before establishing the norepinephrine dose-response relations. Skin blood flow was indexed via laser-Doppler flowmetry directly over both microdialysis probe sites and is expressed as cutaneous vascular conductance (laser-Doppler flux/mean arterial blood pressure). Local skin temperature was maintained at 34 degrees C at both sites throughout the protocol. Dose-response relation between norepinephrine and cutaneous vascular conductance was similar between control and bretylium-pretreated sites in young subjects (EC50 = -5.18 +/- 0.27 and -5.03 +/- 0.27 log M, respectively). In contrast, the dose-response relation was significantly shifted to the right (i.e., a higher dose of norepinephrine was needed to produce the same vasoconstrictor response) in the bretylium-pretreated site in older subjects (EC50 = -5.46 +/- 0.23 and -4.53 +/- 0.23 log M, respectively). Significant increases in EC50 were observed in older compared with young subjects at the bretylium-pretreated but not the control sites. These data indicate that cutaneous vasoconstrictor responsiveness is decreased in older subjects when endogenous release of norepinephrine is antagonized. Furthermore, these findings suggest that differences in presynaptic norepinephrine release between older and younger subjects are profound enough to affect dose-response relations between norepinephrine and cutaneous vascular conductance.

Adolescent↗

PubMed1985

Blood pressure and norepinephrine spillover during propranolol infusion in humans.

To determine whether a reflex increase of sympathetic nervous system activity contributes to maintenance of blood pressure during acute beta-adrenergic blockade, we measured plasma norepinephrine levels and norepinephrine kinetics during propranolol administration. During a 90-min infusion of propranolol (10 mg iv + 80 micrograms/min) in 12 normal subjects, heart rate fell from 56 +/- 2 to 49 +/- 2 (SE) beats/min (P less than 0.001), but there was no fall in mean arterial blood pressure (84 +/- 3 mmHg before and 86 +/- 3 mmHg after propranolol). Arterial plasma norepinephrine levels rose from 183 +/- 20 to 250 +/- 29 pg/ml during propranolol (P less than 0.001), suggesting increased sympathetic vasoconstrictor tone. However, isotope dilution studies using tritiated norepinephrine infusion showed that arterial plasma levels of tritiated norepinephrine rose from 743 +/- 78 to 1,002 +/- 101 dpm/ml during propranolol (P less than 0.001), indicating a reduction in the rate of norepinephrine clearance from plasma. The calculated fall in clearance from 1.90 +/- 0.13 to 1.42 +/- 0.11 1/min (P less than 0.001) entirely accounted for the rise in plasma norepinephrine, since the calculated rate of norepinephrine spillover into plasma remained at the base-line level of 340 +/- 40 ng/min during propranolol. In control studies on four subjects, arterial plasma norepinephrine levels and norepinephrine kinetics did not change from base line during the control period. We conclude that maintenance of blood pressure during propranolol infusion is not due to a reflex generalized increase of sympathetic vasoconstrictor tone.

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