Acute tolerance to noradrenaline ("noradrenaline escape")]

The decline in arterial systemic blood pressure which follows the initial rise during i.v. perfusion of L-noradrenaline in normal rats has been compared with the same type of decline induced by metaraminol or phenylephrine, both alpha-sympathomimetic drugs (acute tolerance or escape). Vasoconstrictor activity of noradrenaline in shot i.v. injection is regularly decreased when acute tolerance develops. This hyposensitivity to NA indicates that a change in alpha-receptor affinity for circulating NA may explain the acute tolerance as well as the noradrenaline escape.     

Enhanced sensitivity to noradrenaline of the Ainu

A small dose of noradrenaline, which was ineffective in non-Ainu Japanese subjects, caused marked elevations in energy metabolism and plasma levels of FFA and total ketone bodies in the Ainu. The striking sensitivity to noradrenaline of the Ainu is assumed to indicate a characteristic feature of cold adaptability of this ethnic group.

---

Zusammenfassung Eine geringe Dosis Noradrenalin, die bei nicht-Ainu Japanern unwirksam war, bewirkte bei Ainus eine ausgeprägte Erhöhung des Stoffwechsels, des Plasmaspiegels, der freien Fettsäuren und der Gesamt-Ketonkörper. Die Noradrenalin-Empfindlichkeit der Ainus wird als Kennzeichen besonderer Kälteanpassungsfähigkeit erklärt, das für diesen Volksstamm kennzeichend ist.

---

Resume Une faible dose de noradrénaline, dose qui reste sans effet sur les Japonais n'appartenant pas à la race des Ainous, provoque au contraire une nette élévation du métabolisme énergétique chez les natifs de cette race. Cette élévation se signale notamment par le relèvement du taux des acides gras libres et des masses de kétone dans le sérum sanguin. L'extrême sensibilité des Ainous à la noradrénaline explique la facilité avec laquelle les gens de cette race s'adaptent au froid. Cette facilité d'adaptation est d'ailleurs une des caractéristiques de cette race.

---

---

This study was made as a part of J-IBP/HA.     

Urinary clearance of noradrenaline in the dog]

Glomerular filtration rate (GFR) and noradrenaline clearance are highly correlated in anesthetized dogs (ratio CNA-3H/GFR approximately 1).     

Differential alpha-mediated inhibition of dopamine and noradrenaline release in the parietal and occipital cortex following noradrenaline transporter blockade

Parietal and occipital cortices, while densely innervated by noradrenalin 2 (NA) projections, possess a comparatively sparse dopamine 2 (DA) innervation, even sparser than the prefrontal cortex. We previously reported that reboxetine and desipramine, two selective norepinephrine transporter (NET) blockers, at doses that maximally increase DA in the prefrontal cortex, do not increase DA in the parietal and occipital cortices. In the present study, we performed a full dose-response study of the effect of systemic reboxetine and desipramine on DA and NA in dialysates from the parietal and occipital cortices. Seven doses of reboxetine (0.1, 0.25, 0.5, 1.0, 2.5, 5.0 and 10 mg/kg) and four doses of desipramine (0.25, 1.0, 2.5 and 5.0 mg/kg) were tested. Reboxetine and desipramine differentially affected dialysate DA as compared with NA. Reboxetine increased DA maximally by about 100% after doses of 0.25-0.5 mg/kg and showed a bell-shaped dose-response function in both areas; desipramine did not affect DA in the parietal cortex and increased it in the occipital cortex only at 2.5 mg/kg. NA was maximally increased by 275% by 0.5-2.5 mg/kg reboxetine and by about 300% by 5.0 mg/kg desipramine with a more linear dose-response curve. The mechanism of peculiar dose-response function of dialysate DA after reboxetine and desipramine was further investigated by testing the effect of drugs on dialysate DA and NA under alpha(2) receptor blockade. Under local perfusion of the occipital cortex with idazoxan, an otherwise ineffective dose of reboxetine and desipramine (5 mg/kg) became effective in raising extracellular DA. In contrast, the effect of reboxetine on NA was potentiated, while that of desipramine was not affected. These results suggest that, in the parietal and occipital cortices, extracellular NA, raised by NET blockade, exerts a preferential inhibitory influence on DA release by acting on local alpha(2) receptors, thus accounting for the bell-shaped feature of the dose-response function of drugs on dialysate DA in these areas.     

Involvement of D1 dopamine receptors in the nicotine-induced noradrenaline release from hypothalamic and preoptic noradrenaline nerve terminal systems

Nicotine (4 × 2 mg/kg, i.p.) was given every 30 min for 2 h to male rats. Some rats were pretreated with the D1 dopamine (DA) receptor antagonist SCH 23390 (1 mg/kg, i.p.) or with the D2 DA receptor antagonist raclopride (1 mg/kg, i.p.), 5 min before nicotine treatment. Hypothalamic and preoptic catecholamine levels were measured by quantitative histofluorimetry in discrete DA and noradrenaline nerve terminal systems.Nicotine treatment produced a depletion of catecholamine stores in noradrenaline and DA nerve terminals of the hypothalamus, the preoptic area and the median eminence, an action which was counteracted by SCH 23390 but not by raclopride.The results indicate that hypothalamic D1 DA receptors may regulate the sensitivity of the nicotinic cholinoceptors and increase their ability to release hypothalamic noradrenaline. A possible role of D1 DA receptor antagonists to reduce the ability of nicotine treatment to produce rapid increases in LH, prolactin and corticosterone secretion and tonic arousal is implicated.     

The potentiation of cortical neuron responses to noradrenaline by 2-phenylethylamine is independent of endogenous noradrenaline

2-Phenylethylamine (PE) is an endogenous brain amine which produces sympathomimetic responses and potentiates cortical neuron responses to noradrenaline (NA). In order to examine further the mechanism of action of PE, extracellular recordings were made of the activity of single neurones in the cerebral cortex in urethane-anesthetized rats. Sympathomimetic responses to PE were blocked by pretreatment with reserpine, reserpine plus -methyl-p-tyrosine and desipramine. It is concluded that the sympathomimetic responses to PE are indirect. 2-Phenylethylamine potentiated cortical neuron responses to electrical stimulation of the locus coeruleus in a dose-dependent manner. This was seen when PE was given systemically (with as little as 1 g/kg) and iontophoretically. The effects of PE were not reproduced by its metabolite phenylacetic acid or its putative metabolite phenylethanolamine. Iontophoretic applications of PE (0–6 nA, 2–5 minutes) potentiated cortical neuron responses to iontophoretically applied NA, without affecting the spontaneous firing rate, or the responses to iontophoretically applied GABA or acetylcholine. This effect of PE was not blocked by pretreatment with -methyl-p-tyrosine or desipramine, and was potentiated by pretreatment with reserpine and reserpine plus -methyl-p-tyrosine. It is probable that the ability of PE to modulate neuronal responses to NA does not involve the presynaptic NA terminal or endogenous NA and it is likely that PE acts directly to increase the efficacy of NA. These findings are consistent with the hypothesis that the physiological role of PE is to modulate catecholaminergic transmission within the central nervous system.