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Characteristics of the norepinephrine-sensitive Ca2+ store in vascular smooth muscle.

A comparison was made between the properties of the norepinephrine- and caffeine-sensitive Ca2+ store in both intact and skinned smooth muscle of the rabbit mesenteric artery. After a first application of 10(-5) M norepinephrine, reapplication of norepinephrine did not induce a second contraction in Ca2+-free medium. However, following this sequence 25 mM caffeine still induced a large contraction. The rates of Ca2+ leakage and Ca2+ filling of the norepinephrine-sensitive store were much faster than those of the caffeine-sensitive one. The amplitude of the norepinephrine-induced contraction in Ca2+-free medium also depended on the amount of Ca2+ present in the caffeine-sensitive store. In the saponin-treated skinned muscle caffeine induced a Ca2+ release only after loading with Ca2+, whereas norepinephrine was unable to induce Ca2+ release in the skinned preparation even after loading with Ca2+. The release of Ca2+ from the caffeine-sensitive store could be activated by Ca2+ itself when the skinned muscle was loaded with Ca2+ above 10(-6) M. These results suggest that the norepinephrine-sensitive Ca2+ store is distinct from a large fraction of the caffeine-sensitive one, and that the norepinephrine-sensitive store is close to the cell membrane. In vascular smooth muscle, under physiological conditions, Ca2+ released from the norepinephrine-sensitive store by norepinephrine may induce Ca2+ release from the caffeine-sensitive Ca2+ store which may be comprised of the sarcoplasmic reticulum.

Animals↗

In vivo measurement of neuronal uptake of norepinephrine in the human heart.

Neuronal uptake (Uptake-1) of the sympathetic neurotransmitter norepinephrine from the circulation in the human heart was assessed in vivo with three techniques. 1) Cardiac removal of intravenously infused tracer-labeled norepinephrine was measured before and after Uptake-1 blockade with desipramine; 2) the difference between the fractional extraction of radioactive norepinephrine and of radioactive isoproterenol, which is not a substrate for neuronal uptake, was used to estimate the removal of norepinephrine by Uptake-1 in the heart compared with other vascular beds (arm, leg, brain, and lungs); and 3) regional arteriovenous differences in radioactive and endogenous dihydroxyphenylglycol (DHPG), an exclusively intraneuronal metabolite of norepinephrine, were compared in these beds. In untreated patients, cardiac removal of radioactive norepinephrine averaged 79%, whereas in desipramine-treated patients, cardiac removal of radioactive norepinephrine averaged 19%, a value similar to that of isoproterenol in untreated patients (14%), confirming that in the heart the non-neuronal removals of isoproterenol and norepinephrine were similar. In the heart, 69% of delivered norepinephrine was estimated to be removed by Uptake-1, a much higher percentage than that in the arm (14%), leg (7%), brain (10%), and lungs (4%). The cardiac arteriovenous increment in endogenous DHPG (137%) far exceeded that of the other beds (49%, 26%, 39%, and -19%, respectively), and radioactive DHPG in the great cardiac vein exceeded arterial levels by 113%, whereas in the other beds, arterial radioactive DHPG exceeded venous levels. The results indicate that the human heart is exceptionally dependent on neuronal uptake for in vivo removal of circulating norepinephrine.

Desipramine↗

Cardiac norepinephrine kinetics in hypertrophic cardiomyopathy.

We examined the uptake and release of norepinephrine in the cardiac circulation and other regional vascular beds in 11 patients with hypertrophic cardiomyopathy (HCM) and in 10 control subjects during simultaneous infusion of tracer-labeled norepinephrine and isoproterenol. Cardiac neuronal uptake of norepinephrine was assessed by comparing regional removal of tracer-labeled norepinephrine with that of tracer-labeled isoproterenol (which is not a substrate for neuronal uptake) and by the relation between production of dihydroxyphenylglycol (DHPG), an exclusively intraneuronal metabolite of norepinephrine, and regional spillover of norepinephrine. Cardiac extraction of norepinephrine averaged 59 +/- 17% in the patients with HCM, significantly less than in the control subjects (79 +/- 13%, p less than 0.05), whereas cardiac extraction of isoproterenol was similar in the two groups (13 +/- 23% versus 13 +/- 14%), indicating that neuronal uptake of norepinephrine was decreased in the patients with HCM. The cardiac arteriovenous difference in norepinephrine was significantly larger in the patients with HCM than in the control subjects (73 +/- 77 versus 13 +/- 50 pg/ml, p less than 0.05), as was the product of the arteriovenous difference in norepinephrine and coronary blood flow (7.3 +/- 7.3 versus 0.8 +/- 3.0 ng/min, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Transient ischemia reduces norepinephrine release during sustained ischemia. Neural preconditioning in isolated rat heart.

Endogenous catecholamine release may play a role in ischemic preconditioning either as a trigger or as a target within the process of myocardial preconditioning. Therefore, we investigated the effect of transient ischemia (TI) on norepinephrine release during sustained ischemia in isolated rat hearts. TI was induced by multiple cycles of global ischemia followed by reperfusion with a duration of 5 minutes each, comparable to ischemic preconditioning protocols. After TI, norepinephrine release was evoked by either sustained global ischemia, anoxia, cyanide intoxication, tyramine, or electrical stimulation. During TI, no washout of norepinephrine was observed, and tissue concentrations of norepinephrine were not changed. TI, however, reduced norepinephrine overflow after 20 minutes of sustained ischemia from 239 +/- 26 pmol/g (control) to 79+/-8 pmol/g (67% reduction, P <.01 ). A similar reduction of ischemia-induced norepinephrine release from 192 +/- 22 pmol/g (control) to 90 +/- 15 pmol/g was observed when hearts underwent transient anoxia without glucose (P < .05). When reperfusion between TI and sustained ischemia was prolonged from 5 to 90 minutes, the inhibitory effect of TI on norepinephrine release was gradually lost. Susceptibility to TI was a unique feature of norepinephrine release induced by sustained ischemia, since release of norepinephrine evoked by anoxia, cyanide intoxication, tyramine, or electrical stimulation remained unaffected by TI. We propose a protective effect of TI on neural tissue, which may reduce norepinephrine-induced damage during prolonged myocardial ischemia.

Animals↗

Mechanism of suppression of vasopressin during alpha-adrenergic stimulation with norepinephrine.

Recent studies have demonstrated that the water diuresis associated with intravenous infusion of norepinephrine is mediated primarly by suppression of antidiuretic hormone (ADH) release. To investigate whether the increase in cerebral perfusion pressure with intravenous norepinephrine (0.5 mug/kg/min) is directly responsible for suppression of ADH release, the carotid circulation of dogs was pump-perfused bilaterally to selectively increase cerebral perfusion pressure. In six experiments cerebral perfusion pressure was increased from a mean of 125 to 151 mm Hg and then returned to 120 mm Hg. This maneuver was not associated with a reversible increase in renal water excretion. The possibility was also examined that norepinephrine exerts a direct central effect to suppress ADH release. In 12 experiments norepinephrine was infused into the carotid artery in a subpressor dose (0.12 mug/kg/min) estimated to equal the amount of the catecholamine reaching the cerebral circulation with intravenous norepinephrine. The urinary osmolality (Uosm) was not significantly altered with intracarotid norepinephrine (932 to 959 mosmol/kg H(2)O. The possibility was also examined that changes in autonomic neural tone from arterial baroreceptors is responsible for suppression of ADH release with intravenous norepinephrine. In sham-operated animals intravenous norepinephrine diminished Uosm from 1,034 to 205 mosmol/kg H(2)O (P<0.001) whereas in animals with denervated arterial baroreceptors intravenous norepinephrine was not associated with a significant alteration in Uosm (1,233 to 1,232 mosmol/kg) H(2)O. These different effects on urinary osmolality occurred in the absence of differences in plasma osmolality and volume status. The results therefore indicate that norepinephrine primarily suppresses ADH release by altering autonomic baroreceptor tone rather than by a direct central or pressor effect of the catecholamine. This same mechanism may be the primary pathway for other nonosmotic influences on ADH release.

Animals↗

The role of membrane depolarization in norepinephrine-induced contractions of the rabbit mesenteric resistance artery.

Changes in membrane potential during norepinephrine-induced contractions in the rabbit mesenteric resistance artery (3rd or 4th branch) were investigated using microelectrodes. Norepinephrine at concentrations greater than 10(-6) M depolarized the membrane and induced contractions dose-dependently. Maximum effects were produced by 10(-4) M norepinephrine. Depolarization was maintained at almost steady level during 15 min application of norepinephrine. During the same period, contractions continued with slight decay. Oscillatory contractions were observed at more than 3 X 10(-6) M norepinephrine, and occasionally persisted throughout the application of norepinephrine. Treatments with Ca2+-rich 1 mM EGTA solution, 10(-5) M diltiazem, 3 X 10(-6) M D600 and 1 mM La3+ did not significantly affect the amount of depolarization induced by 10(-4) M norepinephrine; however, contractions were greatly inhibited by these treatments. Replacement of Na+ by choline markedly reduced depolarization while contractions were not affected. In Ca2+ -free Na+-free solution, no depolarization was induced, while contractions were still produced by norepinephrine, indicating that Cl- was not essential for membrane depolarization. These results suggest that contractions of the rabbit mesenteric resistance artery to norepinephrine are mainly due to the enhanced influx of extracellular Ca2+ which is not dependent on potential-sensitive mechanisms. Depolarization is thought to be due to the increase in the membrane permeability to Na+ and Cl- which is coincidentally produced by norepinephrine. The membrane potential oscillations were dependent on Ca entry but could not be shown to be the result of fluctuations in Ca current.

Animals↗

Norepinephrine, epinephrine, and dopamine contents of the cardiovascular system in long-term diabetics.

Norepinephrine, epinephrine, and dopamine concentrations were studied in the cardiovscular system of postmortem material obtained from six long-term diabetics and six control subjects. Norepinephrine concentration was considerably reduced in the cardiovascular system of the diabetic patients. The mean norepinephrine concentration in the apex of the heart, the radial artery, the posterior tibial artery, and the femoral artery in the diabetics averaged 6, 9, 12, and 20 per cent, respectively, of the corresponding mean values in the controls. Epinephrine was present in the cardiovascular system in the controls but in small amounts in comparision with norepinephrine. There was no correlation between the epinephrine and the norepinephrine concentrations in the tissue. In the diabetics the epinephrine concentration in the heart and in the arteries did not differ from the values obtained in the controls. The dopamine concentration averaged 11 per cent of the norepinephrine concentration in the cardiovascular system in the controls. There was a strong correlation between tissue concentrations of dopamine and of norepinephrine. In the diabetics the dopamine concentration was reduced, but relatively less than that of norepinephrine, and constituted 53 per cent of the norepinephrine concentration. It is suggested that the depletion of the norepinephrine stores in the heart in diabetic patients may in part be responsible for their reduced survival rate in acute myocardial infarction.

Adult↗

Effect of methamphetamine on norepinephrine metabolism in various regions of brain.

The effects of methamphetamine on tritiated and endogenous norepinephrine metabolism was examined in various regions of brain. In acute experiments, 30 minutes or 5 hours after methamphetamine i.p., 3H-norepinephrine was injected into the cisterna magna. In chronic experiments, rats were administered increasing doses of methamphetamine twice a day for 17 days, then 18 hours after the last dose of methamphetamine, 3H-norepinephrine was injected intracisternally. All rats were killed 5 minutes after the intracisternal injection and their brains removed, dissected into five parts and assayed for endogenous norepinephrine, 3H-norepinephrine and its metabolites. In rats treated acutely, methamphetamine caused a significant block in uptake of 3H-norepinephrine and a marked increase in the content of 3H-normetanephrine in all regions except the cortex. Five hours after methamphetamine administration, increased levels of 3H-norepinephrine occurred in the pons-medulla, whereas endogenous norepinephrine content tended to decrease in most regions. In rats treated chronically, enhanced accumulation of 3H-norepinephrine was also confined to the pons-medulla region, whereas endogenous levels of norepinephrine were high in the pons-medulla and low in the hypothalamus and cortex. These data suggest that chronic administration of methamphetamine affects either catecholaminergic nerve cell bodies or nerve terminals in the pons-medulla differentially, as compared to other regions studied.

Animals↗

Effects of moderate hypothermia on norepinephrine release evoked by ouabain, tyramine and cyanide.

Using the dialysis technique, we examined the effect of moderate hypothermia on the norepinephrine efflux evoked by ouabain, tyramine and cyanide in anesthetized cats. Dialysis probes were implanted in the left ventricular myocardium, and we measured the dialysate norepinephrine levels as an indicator of norepinephrine output at the cardiac sympathetic nerve endings. Through the dialysis probe, locally applied ouabain, tyramine and cyanide induced the norepinephrine efflux. The addition of desipramine (neuronal norepinephrine transport blocker, 100 microM) suppressed the norepinephrine efflux evoked by ouabain, tyramine and cyanide. This finding suggests that pharmacological agent-induced norepinephrine efflux was due to carrier-mediated outward norepinephrine transport. Moderate hypothermia (27.4 +/- 0.2 degrees C) caused suppression of the norepinephrine efflux evoked by ouabain, tyramine and cyanide. We conclude that moderate hypothermia suppresses the non-exocytotic norepinephrine release evoked by ouabain, tyramine and cyanide.

Animals↗

Norepinephrine-induced plasma dopamine decrease in man: pharmacological evidence of the involvement of alpha 2-adrenoceptors.

OBJECTIVE: The purposes of this study were: (1) to test whether intravenous infusion of norepinephrine can affect plasma dopamine levels; and (2) to explore to what extent dopamine-2 or alpha 2-receptors play a role in this response. DESIGN: Norepinephrine infusion in man was performed to test whether the increase in norepinephrine during sympathetic stimulation can affect dopamine release. Specific antagonists of presynaptic dopamine-2 and alpha 2-receptors were administered to test the receptor(s) involved in this possible regulatory phenomenon. METHODS: Plasma catecholamine levels were investigated in seven normal subjects before and after administration of domperidone (dopamine-2 antagonist), yohimbine (alpha 2-antagonist) and norepinephrine. RESULTS: Both oral domperidone and yohimbine induced a significant increase in both plasma norepinephrine and plasma dopamine. Norepinephrine infusion induced a significant decrease in plasma dopamine. Pretreatment with domperidone only partially counteracted this inhibitory effect of norepinephrine infusion, whereas yohimbine fully counteracted it. CONCLUSIONS: Our data show that norepinephrine may act as a hormone at plasma concentrations as low as 450 pg/ml. The norepinephrine-induced plasma dopamine decrease seems to be alpha 2-adrenoceptor-mediated. This norepinephrine effect may be involved in the physiologic decrease in plasma dopamine that we demonstrated in the upright position in normal subjects.

Administration, Oral↗

Effects of 6-hydroxydopamine and reserpine on amphetamine-induced release of norepinephrine in rat cerebral cortex.

Amphetamine released 3-H-norepinephrine from rat cerebral cortex tissue which had previously accumulated the 3-H-amine. Destruction of noradrenergic nerve endings by pretreatment of the rats with 6-hydroxydopamine inhibited the accumulation of 3-H-norepinephrine by the tissue and reduced the proportion of the 3-H-amine which was released by amphetamine. Inhibition of storage of 3-H-norepinephrine within nerve endings by pretreatment of the animals with reserpine also reduced accumulation of 3-H-norepinephrine but did not reduce the proportion of the accumulated 3-H-amine which was released by amphetamine. The addition of desipramine (an inhibitor of neuronal uptake) further reduced the accumulation of 3-H-norepinephrine in animals pretreated with reserpine but had no further effect in animals pretreated with 6-hydroxydopamine. A greater proportion of the 3-H-norepinephrine was converted to 3-H-deaminated metabolites in tissues of reserpine-treated animals than in the tissues of control or 6-hydroxydopamine-treated rats. Amphetamine-induced release of 3-H-norepinephrine was partially calcium dependent in tissues from control animals. After reserpine treatment, amphetamine-induced release of norepinephrine was independent of calcium, whereas potassium-mediated release was still markedly calcium dependent. These experiments indicate that amphetamine releases 3-H-norepinephrine primarily from storage sites within central adrenergic nerve endings. An analysis of the time course of release from tissues of rats treated with reserpine suggests that amphetamine is equally capable of releasing 3-H-norepinephrine from granular sites which are susceptible to reserpine and from reserpine-insensitive sites.

Amphetamine↗

Prevalence and determinants of elevated plasma norepinephrine concentration in compensated cirrhosis.

OBJECTIVES: Elevation of plasma norepinephrine concentration in patients with cirrhosis and ascites is attributed to sympathetic activation due to arterial underfilling. Plasma norepinephrine should thus be normal in patients without sodium retention. We examined the prevalence and determinants of elevated plasma norepinephrine concentration in compensated cirrhosis. METHODS: Forty-six studies were performed on 37 patients; nine were studied twice. Between studies, elevated plasma norepinephrine concentration fell to normal in eight patients. Standard clinical and laboratory methods were used for all measurements. RESULTS: Plasma norepinephrine was elevated (> 1.89 nmol/L) in 31 studies. Patients with normal and elevated values were similar with respect to arterial pressure, cardiac output, systemic resistance, heart rate, plasma renin activity, and plasma atrial natriuretic factor concentration. Liver function, as indicated by plasma clearance of cholic acid, antipyrine, and caffeine, was similar in the two groups, but patients with elevated norepinephrine concentration had significantly increased plasma caffeine concentrations. Plasma norepinephrine concentration significantly correlated with plasma caffeine concentration but not with any hemodynamic or neurohormonal variables. Arterial pressure fell in repeatedly studied patients in whom plasma norepinephrine concentration declined. Moreover, the changes in arterial pressure and plasma norepinephrine concentration were significantly, directly correlated. CONCLUSIONS: Sympathetic activation is common in "compensated" cirrhosis. This is not because of arterial underfilling. Indeed, blood pressure and norepinephrine concentration maintained a normal physiological relationship in repeatedly studied patients. Elevated plasma caffeine concentration as a consequence of impaired hepatic metabolic function may contribute to sympathetic activation in some patients.

Caffeine↗

Norepinephrine-evoked pain in fibromyalgia. A randomized pilot study [ISRCTN70707830].

BACKGROUND: Fibromyalgia syndrome displays sympathetically maintained pain features such as frequent post-traumatic onset and stimuli-independent pain accompanied by allodynia and paresthesias. Heart rate variability studies showed that fibromyalgia patients have changes consistent with ongoing sympathetic hyperactivity. Norepinephrine-evoked pain test is used to assess sympathetically maintained pain syndromes. Our objective was to define if fibromyalgia patients have norepinephrine-evoked pain. METHODS: Prospective double blind controlled study. PARTICIPANTS: Twenty FM patients, and two age/sex matched control groups; 20 rheumatoid arthritis patients and 20 healthy controls. Ten micrograms of norepinephrine diluted in 0.1 ml of saline solution were injected in a forearm. The contrasting substance, 0.1 ml of saline solution alone, was injected in the opposite forearm. Maximum local pain elicited during the 5 minutes post-injection was graded on a visual analog scale (VAS). Norepinephrine-evoked pain was diagnosed when norepinephrine injection induced greater pain than placebo injection. Intensity of norepinephrine-evoked pain was calculated as the difference between norepinephrine minus placebo-induced VAS scores. RESULTS: Norepinephrine-evoked pain was seen in 80 % of FM patients (95% confidence intervals 56.3 - 94.3%), in 30 % of rheumatoid arthritis patients and in 30 % of healthy controls (95% confidence intervals 11.9 - 54.3) (p < 0.05). Intensity of norepinephrine-evoked pain was greater in FM patients (mean +/- SD 2.5 +/- 2.5) when compared to rheumatoid arthritis patients (0.3 +/- 0.7), and healthy controls (0.3 +/- 0.8) p < 0.0001. CONCLUSIONS: Fibromyalgia patients have norepinephrine-evoked pain. This finding supports the hypothesis that fibromyalgia may be a sympathetically maintained pain syndrome.

Journal Article↗

Affinities of venlafaxine and various reuptake inhibitors for the serotonin and norepinephrine transporters.

In vitro radioligand binding studies were carried out in rat brain membranes to assess the affinity of various reuptake inhibitors for the serotonin (5-hydroxytryptamine, 5-HT) and the norepinephrine transporters using the selective ligands [3H]cyanoimipramine and [3H]nisoxetine, respectively. The selective 5-HT reuptake inhibitors paroxetine, indalpine and fluvoxamine displayed a high affinity for the 5-HT transporter, whereas the norepinephrine reuptake inhibitor desipramine had a high affinity for the norepinephrine transporter. Duloxetine, a dual 5-HT and norepinephrine reuptake inhibitor, displayed a high affinity for both the 5-HT and the norepinephrine transporters. Interestingly, venlafaxine, a dual 5-HT and norepinephrine reuptake inhibitor, displayed only a moderate affinity for the 5-HT transporter (Ki = 74 nM) and a very low affinity for the norepinephrine transporter (Ki = 1.26 microM). The relatively low affinities of venlafaxine contrast with its potent in vivo 5-HT and norepinephrine reuptake blocking properties. These results raise the possibility that the in vivo effects on the 5-HT and norepinephrine reuptake observed with venlafaxine may not be mediated solely by its binding to the [3H]cyanoimipramine and [3H]nisoxetine binding sites.

Animals↗

Dual effects of intravenous anesthetics on the function of norepinephrine transporters.

BACKGROUND: Norepinephrine transporters (NETs) terminate the neuronal transmission of norepinephrine, which is released from noradrenergic neurons. To investigate the interaction with NET, the authors examined the effects of short- and long-term treatment with anesthetics on the activity and mRNA level of NET. METHODS: To assay [3H]norepinephrine uptake, bovine adrenal medullary cells in culture were incubated with [3H]norepinephrine in the presence of intravenous anesthetics, including propofol, thiamylal, and diazepam. To study the direct interaction between the anesthetics and NET, the effect of propofol on the binding of [3H]desipramine to the plasma membrane was examined. To study the long-term effect of anesthetics, [3H]norepinephrine uptake by cells pretreated with propofol for 6-24 h and [3H]desipramine binding after pretreatment for 12 h were measured. Simultaneously, we examined the effect of anesthetics on the expression of NET mRNA using the reverse transcriptase-polymerase chain reaction. RESULTS: All of the intravenous anesthetics inhibited [3H]norepinephrine uptake in a concentration-dependent manner. The active concentrations of propofol (1-3 microm) and thiamylal (< or = 30 microm) were similar to those encountered clinically. The kinetic analysis revealed that all the anesthetics noncompetitively inhibited [3H]norepinephrine uptake. Propofol inhibited [3H]desipramine binding with a potency similar to that observed in [3H]norepinephrine uptake. Scatchard analysis showed that propofol competitively inhibited [3H]desipramine binding. On the other hand, long-term treatment of cells with propofol (10 microm) enhanced the NET functional activity and [3H]desipramine binding, and also increased the level of NET mRNA. CONCLUSIONS: These results suggest that intravenous anesthetics have a dual effect on NET; short-term treatment causes inhibition, whereas long-term treatment leads to up-regulation. The interaction of intravenous anesthetics with NET may modulate the neuronal transmission of norepinephrine during anesthesia.

Adrenal Medulla↗

Pharmacological properties of naturally occurring variants of the human norepinephrine transporter.

The human norepinephrine transporter (hNET) gene has five sequence polymorphisms that predict amino acid substitutions in the transporter protein: Val69Ile, Thr99Ile, Val245Ile, Val449Ile, and Gly478Ser. In order to functionally characterize the naturally occurring transporter variants, we used site-directed mutagenesis to establish the hNET variants and compared some basic pharmacological properties (uptake of norepinephrine and its inhibition by the tricyclic antidepressant desipramine) in COS-7 cells transiently expressing variant hNETs and wild-type hNET. None of the hNET variants displayed changes in the potency (Ki) of desipramine for inhibition of norepinephrine uptake. Furthermore, variants Val69Ile, Thr99Ile, ValZ45Ile, and Val449Ile did not affect kinetic constants (Km, Vmax) of norepinephrine uptake. However, COS-7 cells expressing the hNET variant Gly478Ser displayed an approximately four-fold increase in the Km for norepinephrine, while the Vmax was unaffected. The increase in the Km, which is equivalent to a four-fold reduction in the affinity of the variant hNET for its natural substrate norepinephrine, indicates that the glycine in position 478 is part of a substrate recognition domain. The reduced clearance of released norepinephrine by reuptake through the Gly478Ser variant might cause an increase in the synaptic and the circulating concentration of norepinephrine. Elevated norepinephrine concentrations have been associated with human diseases and it will be interesting to explore a possible contribution by the Gly478Ser variant to certain disease states.

Amino Acid Substitution↗

Inhibition of nonexocytotic norepinephrine release by desipramine reduces myocardial infarction size.

During myocardial ischemia, a substantial accumulation of norepinephrine occurs in the ischemic zone due to a local nonexocytotic release of norepinephrine. Norepinephrine release is driven by the neuronal monoamine transporter (NET), which reverses its usual transmembrane transport direction. We investigated whether this local accumulation of norepinephrine contributes to irreversible myocardial injury in an in vivo model of myocardial infarction. Male, anaesthetized Wistar rats were subjected to 30 min coronary occlusion and subsequent 120 min reperfusion. Five minutes prior to coronary occlusion, the NET inhibitor desipramine was administered intravenously. Infarct size (IS) was determined by TTC-staining and was related to the area at risk (AAR). The influence of desipramine on cardiac norepinephrine release was investigated in isolated perfused hearts with 30 min of regional ischemia. Norepinephrine was measured in the effluent from the hearts by HPLC and electrochemical detection. Desipramine (0.1-0.8 mg/kg) dose-dependently reduced infarct size (IS/AAR) from 0.54 to 0.21 and suppressed postischemic norepinephrine release from 245 to 108 pg/mL. In summary, the data indicate that nonexocytotic release of norepinephrine in myocardial ischemia exaggerates acute ischemic damage, because suppression of ischemia-induced release of norepinephrine by the tricyclic antidepressant desipramine effectively reduces infarct size in an in vivo model of myocardial ischemia.

Adrenergic Uptake Inhibitors↗

The peripheral kinetics of norepinephrine in depressive illness.

Sympathetic nervous system function was studied in patients with primary depressive illness. Tritiated norepinephrine was used to measure the rate of entry to plasma of norepinephrine released from sympathetic nerves ("norepinephrine spillover rate"), and to assess the neuronal uptake of norepinephrine by studying the removal of norepinephrine from plasma. Norepinephrine spillover was elevated in five of 11 patients. This abnormality, which was unrelated to the presence of individual vegetative symptoms, occurred exclusively in patients with endogenous depression. The rapid-removal phase of the disappearance of tritiated norepinephrine from plasma, which seemed to correspond with neuronal uptake of norepinephrine, was accelerated in patients with depressive illness, providing presumptive evidence of increased neuronal uptake. If norepinephrine uptake is also accentuated within the brain, a functional deficiency of the transmitter at adrenergic receptor sites might result.

Adult↗