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PubMed2004

Interaction between norepinephrine, oxytocin, and nitric oxide in the stimulation of gonadotropin-releasing hormone release from proestrous rat basal hypothalamus explants.

In the proestrous female rat, norepinephrine, oxytocin and nitric oxide (NO) all participate in the regulation of the preovulatory gonadotropin-releasing hormone (GnRH) surge. Recent studies from our laboratory have demonstrated that oxytocin induces dose-dependent release of GnRH from proestrous basal hypothalamus explants. The present studies were undertaken to determine whether norepinephrine could also stimulate GnRH release from similar explants, to identify the receptors responsible for this effect and to investigate interactions between norepinephrine, oxytocin and NO. Norepinephrine significantly stimulated GnRH release from proestrous basal hypothalamus explants, and coadministration of the alpha(1)-adrenergic antagonist prazosin blocked this effect. Combined administration of oxytocin and norepinephrine stimulated significantly more GnRH release than either drug alone, and this stimulation was blocked by inhibition of NO synthase, or by an oxytocin receptor antagonist. NO production was measured from the same samples using a modified Griess reaction. Oxytocin, but not norepinephrine, significantly increased NO production, as did norepinephrine and oxytocin in combination. Oxytocin receptor antagonist administration attenuated the stimulation of NO production by norepinephrine/oxytocin. These results demonstrate for the first time that oxytocin and norepinephrine dramatically stimulate GnRH release from basal hypothalamus explants harvested on the afternoon of proestrus, and indicate that this involves oxytocin receptor and NO-dependent mechanisms.

Adrenergic alpha-Agonists↗

PubMed1992

Phorbol esters cause preferential secretion of norepinephrine from bovine chromaffin cells.

Differential secretion of norepinephrine and epinephrine was studied in cultured bovine chromaffin cells. Nicotinic agonists and 55 mM K+ evoked a slightly greater release of norepinephrine than of epinephrine: The percentage of norepinephrine secreted was 1.5 to two times greater than the percentage of epinephrine secreted. In contrast, when the cells were treated with phorbol 12,13-dibutyrate, the percentage of norepinephrine released was six to eight times greater than that of epinephrine released. Similar results were obtained in experiments with cultures highly enriched in either norepinephrine-containing cells or epinephrine-containing cells. In response to 55 mM K+, catecholamine release from norepinephrine-containing cells was two times greater than that from epinephrine-containing cells. In response to phorbol 12,13-dibutyrate, secretion from norepinephrine-containing cells was 13 times greater than that from epinephrine-containing cells. These results suggest that protein kinase C plays a specific role in the regulation of catecholamine secretion from norepinephrine-containing cells.

Animals↗

PubMed1998

Effects of norepinephrine on NMDA-induced neurotoxicity in cerebellar granular cell culture of rat pups.

In this study, norepinephrine was tested in 0.1, 1, 10, 25 and 50 microM doses in 100 microM NMDA toxicity on cerebellar granular cell culture of rats. NMDA in 100 microM concentration induced cell death significantly with respect to controls. Death cell population was 1.08 +/- 0.44% in control and 22.15 +/- 2.46% in 100 microM NMDA (P < 0.0001). None of the norepinephrine concentrations administrated 15 min prior to NMDA was able to reduce death cell scores to control levels. Results were 8.75 +/- 0.83% in 0.1 microM, 7.0 +/- 1.01% in 1 microM, 17.25 +/- 1.31% in 10 microM, 35.5 +/- 1.38% in 25 microM and 17.9 +/- 1.72% in 50 microM norepinephrine plus 100 microM NMDA administrated groups (P < 0.0001 for all with respect to control). Labetalol, as an alpha and beta blocker in 0.5 microM concentration which was given 15 min prior to norepinephrine was able to block the effects of it. In comparison with 100 microM NMDA administered group, only low doses of norepinephrine reduced the death cell scores significantly (for 0.1 and 1 microM norepinephrine plus NMDA groups; P < 0.0001). For 10 and 50 microM norepinephrine plus NMDA groups, death cell scores were found statistically insignificant from the NMDA-administered group (P > 0.05 for both) while for the 25 microM norepinephrine plus NMDA group, the death cell score was found to be statistically increased (P < 0.0001).

Adrenergic alpha-Agonists↗

PubMed2005

Ectonucleoside triphosphate diphosphohydrolase 1/CD39, localized in neurons of human and porcine heart, modulates ATP-induced norepinephrine exocytosis.

Using a guinea pig heart synaptosomal preparation, we previously observed that norepinephrine (NE) exocytosis was attenuated by a blockade of P2X purinoceptors, potentiated by inhibition of ectonucleoside triphosphate diphosphohydrolase-1 (E-NTPDase1)/CD39, and reduced by soluble CD39, a recombinant form of human E-NTPDase1/CD39. This suggests that norepinephrine and ATP are coreleased upon depolarization of cardiac sympathetic nerve endings and that ATP enhances norepinephrine exocytosis by an action modulated by E-NTPDase1/CD39 activity. Whether E-NTPDase1/CD39 is localized to cardiac neurons and modulates norepinephrine exocytosis in intact heart tissue remained untested. We report that E-NTPDase1/CD39 is selectively localized in human and porcine cardiac neurons and that depolarization of porcine heart tissue elicits omega-conotoxin-inhibitable release of both norepinephrine and ATP. Inhibition of E-NTPDase1/CD39 with ARL67156 markedly potentiated ATP release, demonstrating that E-NTPDase1/CD39 is a major determinant of ATP availability at sympathetic nerve terminals. Notably, inhibition of E-NTPDase1/CD39 enhanced both ATP and NE exocytosis, whereas administration of soluble CD39 reduced both ATP and NE exocytosis. The strong correlation between ATP and norepinephrine release was abolished in the presence of the purinergic P2X receptor (P2XR) antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS). We conclude that released ATP governs norepinephrine exocytosis by activating presynaptic P2XR and that this action is controlled by neuronal E-NTPDase1/CD39. Clinically, excessive norepinephrine release is a major cause of arrhythmic and coronary vascular dysfunction during myocardial ischemia. By curtailing NE release, in addition to its effects as an antithrombotic agent, soluble CD39 may constitute a novel therapeutic approach to ischemic complications in the myocardium.

Adenosine Triphosphatases↗

PubMed2004

Epinephrine activates both Gs and Gi pathways, but norepinephrine activates only the Gs pathway through human beta2-adrenoceptors overexpressed in mouse heart.

Isoproterenol increases and decreases contractile force at low and high concentrations, respectively, through beta(2)-adrenoceptors overexpressed in transgenic mouse heart (TG4), consistent with activation of both G(s) and G(i) proteins. Using TG4 hearts, we demonstrated that epinephrine behaves like isoproterenol, but norepinephrine does not. Epinephrine both increased (-log EC(50)M = 9.4) and decreased (-log EC(50)M = 6.5) left atrial force. Pertussis toxin (PTX) abolished the negative inotropic effects of epinephrine, consistent with mediation through G(i) protein. Norepinephrine only increased contractile force (-log EC(50)M = 7.5). Norepinephrine (10-100 microM) prevented the positive inotropic effects but hardly affected the negative inotropic effects of epinephrine. Cardiodepressive epinephrine concentrations (1-10 microM) antagonized the positive inotropic effects of norepinephrine. In the free wall of TG4 right ventricle, norepinephrine and low epinephrine concentrations caused positive inotropic effects, and high epinephrine concentrations caused PTX-sensitive negative inotropic effects, as observed in the left atrium. Epinephrine (10 nM), a concentration causing maximum increase in contractile force, and norepinephrine (1 and 100 microM) increased cAMP-dependent protein kinase activity in TG4 left ventricle. Cardiodepressive concentrations of epinephrine (1 and 100 microM) did not increase cAMP-dependent protein kinase activity. The inotropic results were simulated with a model of two beta(2)-adrenoceptor sites. For one site involved in receptor coupling to G(s), both epinephrine and norepinephrine compete. The other site, recognized by epinephrine but not by norepinephrine, leads to receptor G(i) coupling.

Animals↗

PubMed1992

Effect of omega-3 fatty acids, docosahexaenoic and eicosapentaenoic, on norepinephrine-induced contractions.

The relaxant responses of the rat thoracic aorta to omega-3 fatty acids, docosahexaenoic and eicosapentaenoic, on norepinephrine- and potassium-induced contractions were investigated. Relaxation was enhanced in vessels contracted with norepinephrine. Docosahexaenoic acid at concentrations as low as 1, 3, and 10 microM evoked significant relaxant responses (15, 23, 30%) in norepinephrine-contracted vessels as compared with responses (5, 9, 12%) in potassium-contracted vessels. Results for eicosapentaenoic acid under similar conditions were 3, 8, and 19% in norepinephrine-contracted vessels and 3, 3, and 8% in potassium-contracted vessels. Pretreatment with eicosapentaenoic (10 microM) or docosahexaenoic acids (1-10 microM) decreased the contractile response to physiologic concentrations of norepinephrine. In the presence of calcium-free medium, the omega-3 fatty acids (1-30 microM) significantly abolished sustained norepinephrine contractions but did not reduce the phasic contractions when incubated prior to norepinephrine contraction. Comparatively, the effects of docosahexaenoic acid were greater than eicosapentaenoic acid. These findings suggest that the relaxant effects of the omega-3 fatty acids are specific to the mode of contraction, i.e., alpha-adrenoceptor stimuli. This effect may be related to intracellular calcium mechanisms, since both fatty acids reversed norepinephrine-induced sustained contractions in the absence of extracellular calcium.

Animals↗

PubMed1989

Stimulation of glucose transport by insulin and norepinephrine in isolated rat brown adipocytes.

The effects of insulin and norepinephrine on glucose transport, glucose uptake, and cell respiration were investigated in isolated rat brown adipocytes. Glucose transport and uptake were determined using [U-14C]-D-glucose and 2-deoxy-[1,2-3H]-D-glucose, respectively. Brown adipocyte respiration was measured polarographically. Dose-response experiments revealed that insulin stimulated D-glucose transport and 2-deoxyglucose uptake between 10(-11) and 10(-7) M with a maximal four- to sixfold stimulation. In the absence of insulin, norepinephrine concentrations ranging from 10(-7) to 10(-7) M also enhanced glucose transport and uptake with a maximal two- to fourfold stimulation. Experiments with alpha- and beta-adrenergic agonists and antagonists showed that the effect of norepinephrine was predominantly mediated via beta-adrenergic pathways. Dibutyryl cyclic AMP and 3-isobutyl-1-methylxanthine also increased glucose transport, suggesting that the effects of norepinephrine are cyclic AMP dependent. Moreover, norepinephrine (10(-8) M) enhanced insulin sensitivity for glucose transport [half-maximum velocity constant (1/2 V max)] but failed to potentiate insulin responsiveness (Vmax). On the other hand, insulin (10(-9) M) had no effect on basal respiration but rapidly inhibited the calorigenic effect of norepinephrine (10(-7) M) by greater than 50%. These results demonstrate that 1) in the absence of insulin, physiological concentrations of norepinephrine stimulate glucose transport via beta-adrenergic pathways, 2) the neurohormone synergistically potentiates brown adipocyte submaximal insulin responses for glucose transport, and 3) insulin counteracts the effects of norepinephrine on brown adipocyte thermogenesis despite the fact that both hormones enhance glucose uptake.

1-Methyl-3-isobutylxanthine↗

PubMed1984

Chronic norepinephrine infusion and insulin and glucagon secretion in the dog.

The effect of epinephrine on glucose homeostasis has been studied extensively in many species, but there is little data on the effects of another catecholamine, norepinephrine. This study was designed to examine the alterations that occur in insulin and glucagon secretion during a chronic low-dose infusion of norepinephrine in free-roaming dogs. A total of four intravenous glucose tolerance tests and insulin-induced hypoglycemia tests were performed on each of five dogs infused with norepinephrine (1.4 g/min) for 3 mo and on each of eight control dogs. The infusion resulted in a threefold increase in plasma norepinephrine without a significant effect on blood pressure. Fasting serum glucose was elevated significantly in the norepinephrine-infused dogs [102.4 +/- 2.1 vs. 92.8 +/- 1.7 (SE) mg/100 ml]. Fasting plasma glucagon was elevated by the norepinephrine infusion (58.4 +/- 7.6 vs. 31.3 +/- 3.1 pg/ml), whereas fasting serum insulin was inhibited (12.3 +/- 1.3 vs 16.8 +/- 1.7 U/ml). Glucagon secretion in response to hypoglycemia was markedly enhanced in the infused dogs compared with controls. It has been reported that the infusion of norepinephrine in humans will inhibit insulin secretion and increase serum glucose concentrations but have no effect on serum glucagon concentrations. The stimulation of glucagon by norepinephrine has been demonstrated in the isolated, perfused canine pancreas but has not been reported previously in the free-roaming dog.

Adrenal Glands↗

PubMed1984

In vivo stimulation of pancreatic hormone secretion by norepinephrine infusion in the dog.

Norepinephrine is generally regarded as an inhibitor of insulin release. It has been shown, however, that under hyperglycemic circumstances, norepinephrine infused at a high dose may also stimulate insulin secretion. The goals of this study were, under normoglycemic conditions, to confirm this stimulatory effect and to determine whether a beta-adrenergic mechanism or central neural pathways were involved. Secretion of pancreatic somatostatin and glucagon were also studied. Fasted, anesthetized dogs had norepinephrine (2 micrograms X kg-1 X min-1) infused into a peripheral vein for 60 min; blood was sampled from the pancreaticoduodenal vein. Norepinephrine stimulated insulin, somatostatin, and glucagon secretion without significant changes in either blood glucose concentration or pancreaticoduodenal venous blood flow. The stimulatory effect of norepinephrine on the three hormones was abolished by propranolol pretreatment, thus implicating a beta-adrenergic mechanism. Because bilateral cervical vagotomy prevented stimulation of insulin secretion by norepinephrine, central neural pathways must have been involved in the stimulatory process. However, norepinephrine-induced glucagon secretion was not decreased by vagotomy, showing that the stimulation was due to either a direct action on the pancreatic A cell or of a central pathway not mediated via the vagus nerve. Norepinephrine-induced somatostatin secretion was partly reduced by vagotomy, indicating that several mechanisms could be implicated.

Animals↗

PubMed1997

Altered vascular norepinephrine responses in portal hypertensive intestine: role of PKA and guanylate cyclase.

The purpose of the present study was to determine whether selective blockade of adenosine 3',5'-cyclic monophosphate (cAMP)- or guanosine 3',5'-cyclic monophosphate (cGMP)-mediated events modulated norepinephrine responses in intestinal microvessels of normal and portal hypertensive rats. Vascular norepinephrine responses were evaluated before and after inhibition of cAMP-dependent protein kinase [protein kinase A(PKA)] with Rp-adenosine 3',5'-cyclic monophosphothioate (Rp-cAMPS) or guanylate cyclase with LY-83583. Male Sprague-Dawley rats were divided into two groups: those with portal hypertension by portal vein stenosis and normal controls. The small intestine was prepared for microcirculatory studies. Arteriolar diameter and erythrocyte velocity were monitored, and microvascular flow was calculated from velocity and diameter data. The preparation was challenged with incremental concentrations of norepinephrine before and after addition of Rp-cAMPS (50 microM) or LY-83583 (30 microM). Arteriolar diameter and blood flow were significantly elevated in portal hypertensive rats; norepinephrine responses were significantly depressed. LY-83583 did not alter arteriolar diameter, blood flow, or norepinephrine responsiveness in normal or portal hypertensive rats. Rp-cAMPS did not affect arteriolar diameter, blood flow, or norepinephrine responsiveness in normal rats. However, in portal hypertensive rats, Rp-cAMPS reduced blood flow by approximately 20% (P < 0.05) and completely restored vascular norepinephrine responses to normal. The results indicate that cAMP- but not cGMP-dependent events are primarily responsible for the loss of microvascular norepinephrine responsiveness in portal hypertensive intestine.

Aminoquinolines↗

PubMed2004

Nitric oxide decreases the biological activity of norepinephrine resulting in altered vascular tone in the rat mesenteric arterial bed.

Nitric oxide (NO) reacts with catecholamines resulting in their deactivation. In this study, we demonstrated that coincubation of NO donors with sympathetic neurotransmitters decreased the amount of norepinephrine detected but not ATP or neuropeptide Y (NPY). Furthermore, we found that the ability of norepinephrine to increase perfusion pressure in the isolated perfused mesenteric arterial bed of the rat was attenuated by the incubation of norepinephrine with the NO donor diethylamine NONOate. Conversely, the vasoconstrictive ability of NPY and ATP was unaffected by incubation with NONOate. Periarterial nerve stimulation in the presence of the NO synthase (NOS) inhibitor Nomega-nitro-l-arginine methyl ester (l-NAME) resulted in an increase in both perfusion pressure response and norepinephrine levels. This was prevented by l-arginine, demonstrating that the effects of l-NAME were indeed specific to the inhibition of NOS. To confirm that NO was not altering the release of norepinephrine from the sympathetic nerve via presynaptic activation of guanylate cyclase, we repeated the experiments in the presence of the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]-quinoxaloine-one (ODQ). Unlike l-NAME, ODQ infusion did not increase norepinephrine overflow, demonstrating that modulation of norepinephrine by NO at the vascular neuroeffector junction of the rat mesenteric vascular bed is not the result of presynaptic guanylate cyclase activation. These results demonstrate that, in addition to being a direct vasodilatator, NO can also alter vascular reactivity at the sympathetic neuroeffector junction in the rat mesenteric bed by deactivating the vasoconstrictor norepinephrine.

Animals↗

PubMed1984

Effect of beta-adrenergic blockade on in vivo norepinephrine release in canine heart.

The beta-adrenergic blockade-induced reduction in myocardial norepinephrine overflow during sympathetic stimulation was examined by use of the multiple indicator-dilution technique. A kinetic model incorporating the effects of flow, capillary permeability surface product for norepinephrine, the interstitial uptake rate constant for neurotransmitter, and plasma norepinephrine input and output values was used to estimate the rate of local release of norepinephrine into the interstitial space. The model was tested by first examining the effects of two drugs that increase myocardial norepinephrine overflow during sympathetic stimulation by differing mechanisms: desmethylimipramine, a norepinephrine uptake inhibitor, and phentolamine, an alpha-adrenergic blocker. The uptake inhibitor was demonstrated to reduce interstitial uptake and the alpha-blocker to increase local neurotransmitter release, without change in blood flow. The beta-adrenergic blocker, in contrast, reduced coronary blood flow and decreased the capillary norepinephrine permeability surface product but did not change the rate of local release. The decreased norepinephrine overflow after beta-blockade was deduced to result from the decrease in transcapillary flux and secondary increase in interstitial uptake.

Adrenergic beta-Antagonists↗

PubMed1988

Endothelium inhibits norepinephrine release from adrenergic nerves of rabbit carotid artery.

The overflow of endogenous norepinephrine caused by transmural electrical stimulation or depolarization with potassium was smaller in superfused segments of the rabbit carotid artery with intact endothelium than in segments denuded of endothelium. In segments preincubated with [3H]norepinephrine, the lesser overflow was found to be partially due to metabolism by the endothelium of the neurotransmitter. Even after treatment to block the disposition of norepinephrine, the endothelium acted as a partial physical barrier to the overflow of norepinephrine into the lumen of arteries superfused and perfused selectively. However, a lesser overflow of norepinephrine to the adventitia of the artery accounted for the majority of the difference in overflow between segments with and without endothelium. The inhibition by the endothelium of the overflow of norepinephrine from adrenergic nerves was unaffected by blocking prejunctional alpha 2-adrenoceptors, prostaglandin synthesis, free radicals, or guanylate cyclase. Vasodilators released from the endothelium of a donor artery inhibited contractions caused by adrenergic nerve stimulation of a bioassay artery but failed to inhibit norepinephrine release. These observations indicate that the endothelium 1) metabolizes norepinephrine, 2) acts as a physical barrier to its overflow into the blood vessel lumen, and 3) inhibits the release of the adrenergic transmitter from adrenergic nerves.

Adrenergic Fibers↗

PubMed1993

Effect of norepinephrine on rat basilar artery in vivo.

In anesthetized rats, we used a cranial window to examine effects of topical norepinephrine on diameter of the basilar artery in vivo. Topical application of norepinephrine increased the diameter of the basilar artery. NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, inhibited vasodilatation to acetylcholine but did not attenuate dilator responses to norepinephrine. Indomethacin also did not attenuate vasodilatation in response to norepinephrine. Dilatation of the basilar artery to norepinephrine was inhibited by propranolol and the beta 1-antagonist atenolol but not by the beta 2-antagonist butoxamine. Thus dilatation of the basilar artery in response to norepinephrine is produced by activation of beta 1-receptors and is not mediated by endothelium-derived relaxing factor or prostanoids. Glibenclamide, a selective inhibitor of ATP-sensitive K+ channels, partially inhibited vasodilatation in response to norepinephrine. Forskolin, a direct activator of adenylate cyclase, also increased the diameter of the basilar artery, and glibenclamide attenuated the dilatation. Thus dilatation of rat basilar artery in response to norepinephrine is mediated, in part, by activation of ATP-sensitive K+ channels, and activation of these K+ channels may be achieved by an adenosine 3',5'-cyclic monophosphate-dependent mechanism.

Animals↗

PubMed1997

Pulmonary clearance and release of norepinephrine and epinephrine in newborn lambs.

To examine the pulmonary kinetics of the catecholamines norepinephrine and epinephrine immediately after birth, eight fetal lambs were instrumented with vascular catheters under general anesthesia at 133-134 days gestation (term = 147 days) and were delivered by cesarean section 1 wk later. Pulmonary norepinephrine and epinephrine kinetics were then studied 1 and 4 h after birth using radiotracer dilution methodology. The pulmonary fractional extraction of norepinephrine was similar in 1-h (0.111 +/- 0.021) and 4-h (0.117 +/- 0.023) lambs and constituted 24 +/- 5 and 32 +/- 9% of total body norepinephrine clearance, respectively. Pulmonary removal of epinephrine was less pronounced with a fractional extraction of 0.035 +/- 0.017 in 1-h and 0.036 +/- 0.013 in 4-h lambs, which corresponded to 8 +/- 4 and 9 +/- 3% of total body epinephrine clearance, respectively. Pulmonary spillover of norepinephrine into the circulation was similar in 1-h (79 +/- 26 ng.min-1.kg-1) and 4-h (82 +/- 18 ng.min-1.kg-1) lambs, and this comprised 27 +/- 8 and 42 +/- 8% of total body norepinephrine spillover, respectively. Pulmonary epinephrine spillover was not detectable at 1 h, but it occurred in all 4-h lambs, averaging 4.7 +/- 0.8 ng.min-1.kg-1 or 20 +/- 6% of epinephrine total body spillover. These findings indicate that the lungs of newborn lambs 1) are a major site for removal of norepinephrine and epinephrine from the circulation; 2) release a substantial quantity of norepinephrine into the circulation, consistent with the presence of tonic pulmonary sympathetic nerve activity; and 3) constitute a significant extra-adrenal source of plasma epinephrine.

Animals↗

PubMed1991

Effects of desipramine on sympathetic nerve firing and norepinephrine spillover to plasma in humans.

In isolated organs, or when given in low dose intra-arterially, tricyclic antidepressant drugs are known to block reuptake of norepinephrine into sympathetic nerve varicosities, with a resultant increased norepinephrine washout. On the other hand, systemic administration of such drugs in humans reduces norepinephrine spillover to plasma. To clarify these seemingly contradictory findings, we have measured concurrently muscle sympathetic activity in the peroneal nerve (microneurography) and rates of norepinephrine spillover to plasma for the body as a whole and for the heart, the kidneys, and the forearm (radiotracer technique), both before and after intravenous infusion of desipramine, 0.5 mg/kg. Desipramine lowered the overflow of norepinephrine to plasma for the body as a whole and from the forearm and the kidneys (by 30-50%) but increased cardiac norepinephrine spillover by 25%. Both the number of sympathetic bursts per min in the peroneal nerve and their mean voltage amplitudes were markedly reduced after desipramine; total activity (bursts/min x mean burst amplitude) fell by approximately 90%. The effects of desipramine on norepinephrine spillover are explicable in terms of inhibition of central sympathetic outflow, balanced against the local blockade of transmitter reuptake. In most sites, the predominant effect is a reduction of norepinephrine overflow. For the heart, where reuptake is so important in transmitter disposition, the net effect is increased overflow.

Adult↗

PubMed1992

Central nervous system catecholamine content and norepinephrine release after AV3V ablation.

Electrolytic ablation of the periventricular tissue surrounding the anteroventral third cerebral ventricle (AV3V-X) results in immediate increases in norepinephrine release in the paraventricular hypothalamic nucleus/anterior hypothalamus (P/A) and in the dorsomedial medulla (DM) and depletion of norepinephrine and epinephrine throughout the brain. The present study determined whether catecholamine depletion and/or altered norepinephrine release persisted after recovery from the acute effects of AV3V-X. Fourteen to eighteen days after surgery, catecholamine concentrations throughout the brain and norepinephrine release in the P/A and DM during hemorrhage were measured in control-operated and AV3V-X rats. AV3V-X decreased epinephrine content only in the midbrain, increased norepinephrine only in the cortex, and produced no differences in central nervous system dopamine. Hemorrhage-induced norepinephrine release was significantly greater in the P/A of AV3V-X rats than in control animals, whereas norepinephrine release in the DM increased equally in both groups. Thus AV3V-X does not result in chronic global central nervous system catecholamine depletion and enhances norepinephrine release in the P/A during hemorrhage.

Animals↗

PubMed1990

Effect of norepinephrine on diaphragm contractility and blood flow.

Recent studies have shown that diaphragm fatigue can be reversed by mechanical augmentation of phrenic arterial flow. The purpose of the present experiment was to determine whether it was possible to pharmacologically augment diaphragm blood flow and reverse fatigue by the administration of norepinephrine. Four groups of studies were performed, all employing our previously described in situ isometric canine diaphragm strip preparation (Supinski et al., J. Appl. Physiol. 60: 1789-1796, 1986). Group I studies examined the effects of norepinephrine on the contractility of the nonfatigued diaphragm in normotensive dogs, group II studies examined the effects of this drug on the contractility of the fatigued diaphragm in normotensive animals, and group III studies examined the effect of this drug on the contractility of the fatigued diaphragm in hypotensive animals. Group IV studies examined the effect of norepinephrine in normotensive animals in which the phrenic artery was cannulated and pump perfused at constant flow. Fatigue was induced in group II, III, and IV studies by rhythmically stimulating the diaphragm via intramuscular electrodes. Norepinephrine had no effect on the contractility of the nonfatigued diaphragm (group I). In normotensive (group II) and hypotensive animals (group III), norepinephrine elicited dramatic increases in arterial blood pressure and phrenic arterial flow and produced a significant upshift in the force-frequency curve of the fatigued diaphragm. However, when phrenic flow was held constant (group IV experiments), norepinephrine failed to augment the contractility of the fatigued diaphragm. These results indicate that 1) norepinephrine can increase phrenic blood flow and augment the contractility of the fatigued diaphragm in both normotensive and hypotensive conditions and 2) this effect of norepinephrine to partially reverse fatigue is secondary to its action to augment diaphragmatic blood flow.

Animals↗