Noradrenaline concentration

Figure 4.8 Noradrenaline concentration in dialysis samples from probes implanted in the rat frontal cortex. Spontaneous efflux of noradrenaline is stable throughout a 4h sampling period ( extended basals ) but is increased markedly when either the noradrenaline reuptake inhibitor, desipramine (5 pM), or the a2-adrenoceptor antagonist, atipamezole (0.5 pM), is infused into the extracellular fluid via the microdialysis probe ( retrodialysis )...

Fig. 4. Inhibition of noradrenaline release by and a2c-receptors. In atria from wild-type mice, exogenous noradrenaline completely inhibited release of H-noradrenaline from sympathetic nerves. After deletion of the a2A-receptor gene, the maximal inhibitory effect of noradrenaline was decreased, and knockout of the tt2c-receptor gene led to a rightward shift of the noradrenaline concentration response curve. Only in atria from mice lacking Uja- and a2c-receptors (a2Ac-KO) was the inhibitory effect of noradrenaline completely abolished, indicating that tt2A- and a2c-adrenergic receptors are both required for presynaptic feedback inhibition of transmitter release (adapted from Hein et al. 1999)...

The hydroxyl groups of the phenyl ring are a prerequisite for the activation of all adrenoceptors, if both are absent the molecule has only an indirect sympathomimetic effect (see Fig. 5). Indirect sympathomimetics only have a -, a2 and -adrenoceptor activity since they act via an increase of the noradrenaline concentration in the synaptic cleft. If the methyl-group at the N-position of adrenaline is substituted by a longer or more bulky moiety the molecule gains affinity for the and loses affinity for O -adrenoceptors. An isopropyl moiety is already the optimum for the affinity towards 0-adrenoceptors (isoprenaline), larger substituents enhance only the binding to the 2-subtype (for example fenoterol). 

The indirect sympathomimetic drugs can be used clinically for systemic or local vasoconstriction. Since the mechanism is an increase in the noradrenaline concentration there are always jSi-adrenoceptor-mediated effects like tachycardia and extrasystoles. Since the re-uptake of noradrenaline is necessary to sufficiently refill the axonal vesicles, a frequent use of indirect sympathetic drugs results in a loss of efficacy by transmitter exhaustion. This phenomenon of use-dependent loss of effect is called tachyphylaxis. 

Figure 5.3. Noradrenaline cumulative concentration-effect curves from guinea-pig hypoxic portal vein [21 Ij. All tissues were maintained in glucose-free physiological salt solution in hypoxic conditions. The vertical axis shows the mean force of contraction in response to each noradrenaline concentration on the horizontal axis. The statistical significance of differences between control (n = 20) and vitamin-E-treated (n = 25) muscle responses is shown by, P < 0.001. Vertical lines indicate the standard errors...

Several cases of hypertension have been associated with clozapine (SEDA-22, 57), and alpha2-adrenoceptor blockade has been proposed as a possible mechanism (28). Four patients developed pseudopheochromocytoma syndrome associated with clozapine (33) all had hypertension, profuse sweating, and obesity. The authors suggested that clozapine could increase plasma noradrenaline concentrations by inhibiting prcsynaptic reuptake mediated by alpha2-adrenoceptors. 

In 12 patients clonidine 50-100 micrograms/day relieved clozapine-induced sialorrhea, with good results in three and partial results in eight (178). Theoretically, the reduction in sialorrhea with clonidine could have been due to reduced plasma noradrenaline concentrations, resulting in less stimulation of unopposed p-adrenoceptors in the salivary glands. 

Mental stress is a risk factor for cardiovascular disease. In 24 patients with mild to moderate hypertension, amlodipine reduced the blood pressure rise during mental stress compared with placebo, but increased plasma noradrenaline concentrations (6). 

Maling TJ, Dollery CT. Changes in blood pressure, heart rate, and plasma noradrenaline concentration after sudden withdrawal of propranolol. BMJ 1979 2(6186) 366-7. 

In a dose-finding study with bosentan (100,500,1000, and 2000 mg/day) in 293 hjrpertensive patients (5) there were statistically significant falls in diastolic blood pressure with the 500 and 2000 mg/day doses. The effects were similar to that of enalapril 20 mg/day. The lowering of blood pressure was not associated with any changes in heart rate, plasma noradrenaline concentrations, plasma renin activity, or angiotensin II concentrations. 

Disulfiram in a dose of 250-300 mg/day does not affect pulse rate, blood pressure, or plasma noradrenaline concentrations, but 500 mg/day causes an increase in plasma noradrenaline, increased systolic blood pressure both recumbent and erect, and an increased erect pulse rate. The raised blood pressure does not reach hypertensive values, but the results suggest increased sympathetic nervous system activity in patients who take disulfiram. Caution should therefore be exercised in using disulfiram in hypertensive patients. Close monitoring of blood pressure is advised, and the dose of disulfiram should preferably be reduced to 250 mg/day (5). 

In 25 unmedicated subjects with hypertension yohimbine 22 mg increased mean blood pressure by an average of 5 mm Hg, plasma noradrenaline by 66%, and plasma dihydroxyphenylglycol by 25% at 1 hour after administration (3). The magnitude of the pressor response was unrelated to baseline pressure but correlated positively with baseline noradrenaline concentration and with the yohimbine-induced increment in plasma noradrenaline. 

A 16-year-old girl who took yohimbine in the form of an alleged aphrodisiac known as yo-yo had an acute dissociative reaction accompanied by weakness, paresthesia, and incoordination, followed by anxiety, headache, nausea, palpitation, and chest pain she also had hypertension, tachycardia, tachypnea, sweating, pallor, tremor, and an erythematous rash (17). Serum adrenaline and noradrenaline concentrations were raised. Her symptoms lasted about 36 hours and resolved spontaneously. 

Brown MJ. Simultaneous assay of noradrenaline and its deaminated metabohte, dihydroxyphenylglycol, in plasma a simplified approach to the exclusion of phaeochromocytoma in patients with borderline elevation of plasma noradrenaline concentration. Eur J Clin Invest 1984 14 67-72. 

Fig. 2. Variation with time in the noradrenaline concentration (ng/g) of rat brain. Each point...

Small shifts in the time scale between experiments mean that the summed effect is less impressive. We have no information as to why brain noradrenaline concentration varies with clock-hour. Since the form of the rhythm is different from that of locomotor activity, it presumably cannot be simply related to the sleep-wakefulness cycle. This problem is at present under investigation in our laboratory. 

An inca uscd production of cutcchuluinincs from a benign or malignuni tumour causes vasoconstriction. The increased catecholamine production may not be easy to confirm, as phaet)chromocytomas frequently secrete catecholamines episixlically. Urinary catecholamine metabolites (Fig.. 1) may not be elevated unless the patient has been symptomatic during the peritxl of urine collection. Plasma adrenaline and noradrenaline concentrations are usually increased but these measurements arc only available in a small number of centres. 

Responses, in terms of the increases in systolic (SBP) and diastolic (DBP) blood pressures, to test peptide and bradykinin are determined. After ganglion blockade with pentolinium (group GB) without or with added captopril (group GB+Cap), heart rate and plasma adrenaline and noradrenaline concentrations are determined. In some cases, the rats are not subjected to ganglion blockade and served as controls for animals in the GB group (control group). 

B5. Bhagavan, H. M., and Coursin, D. B., Effects of pyridoxin deficiency and DL-p-cjhlorophenylalanine administration to rats on 5-hydroxytryptamine and noradrenaline concentrations in brain and 5-hydroxytryptamine concentration in blood. Biochetn. J. 134, 763-767 (1973). 

A precise control of the noradrenaline concentration in the synaptic cleft is crucial for an efficient signal transduction. For deactivation, there are several mechanisms available. Prior to reaching the post-synaptic receptors, aroimd 90 % of the noradrenaline is reabsorbed into the pre-synaptic axoplasm. A certain amount is bound by extraneuronal cells, while another portion is deactivated by methylation and oxidative deamination. The oxidative deamination occurs via an imine in the mitochondria of nerve endings, in cells of the target organ, and in the liver. After oxidation or reduction of the aldehyde function. 

Indirecdy acting sympathomimetics release noradrenaline from the nerve endings and/or inhibit its re-uptake. Thereby, the noradrenaline concentration in the synaptic cleft is raised, and the sympathetic tone therefore increased. After repeated administration of higher doses, this effect is however restricted by the limited supply of newly synthesised noradrenaline. Typical representatives are ephedrine and the amphetamines (Fig. 6.39). The high polarity of catecholamines, associated with the two aromatic hydroxyl-groups, necessitates intravenous administration, and confines their activity to the periphery. Ephedrine, amphetamine, and as well methamphetamine exhibit in addition to their peripheral sympathomimetic effect also a central stimulating activity. 

In eight women with raised plasma adrenaline and noradrenaline concentrations secondary to various types of stress, takotsubo cardiomyopathy was associated with endothelial cell apoptosis [5 ]. 

Cocaine As weU as inhibiting acetaldehyde dehydrogenase, disulfiram inhibits dopamine beta-hydroxylase, increasing dopamine and reducing noradrenaline concentrations. 

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