The Contribution of cocoa additive to cigarette smoking addiction

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Page 162 of 207 RIVM report 650270002 Octopamine TWANL = MAC: No data available. TWAD =MAK: No data available. TWAUSA: No data available. STELNL: No data available. STELUSA: No data available. LTEL: No data available. TLV-C: No data available. TLV-CARCINOGENICITY: No data available. MAK-REPRODUCTION: No data available. Others: Reference value: The plasma octopamine levels were measured in a population of 33 normal individuals ranging in age from 19 to 94 years. Significantly higher plasma octopamine levels were found in the age group 70-94 years. Excluding those individuals over the age of 70 years, the range of values was 0 to 0.68 ng per ml, with a mean value of 0.23 ng per ml (n = 25) (7). Serum octopamine levels in health control subjects were 1.75 ± 0.19 ng/ml (8). CLASS EG Carc. Cat.: No data available. IARC-category: No data available. CEC: No data available. Critical assessment The octopamine level in cocoa or in cigarette smoke is unknown. Also the environmental level and data on human exposure are not available. Furthermore, data on combustion products of octopamine are not available. Octopamine is a natural compound in the human body with a mean plasma value of 0.23 ng/ml. Conclusion No data are available to evaluate the octopamine exposure through cigarette smoking. PHARMACODYNAMICS Mechanism of action Octopamine receptors in vertebrates are not found, although specific octopamine receptors have been cloned in invertebrates. Octopamine is known to exert adrenergic effects in mammals. It has been shown that octopamine can stimulate α2 - adrenoceptors (ARs) in Chinese hamster ovary cells transfected with human α2-ARs (9). Octopamine has about 1/100 th the α-adrenergic activity of noradrenaline in rats (10). Octopamine stimulates lipolysis through ß3 -rather than ß1 -or ß2-AR activation in white adipocytes from different mammalian species. Octopamine is fully lipolytic in garden dormouse and Siberian hamster while tyramine was ineffective. Although being around one hundred-fold less potent than noradrenaline, octopamine was slightly more potent in these hibernators known for their high sensitivity to ß3-AR agonists than in rat and markedly more active than in human adipocytes known for their limited responses to ß3-AR agonists. Octopamine reduced insulin-dependent glucose transport in rat fat cells, a response also observed with noradrenaline and
RIVM report 650270002 Page 163 of 207 Octopamine selective ß3-AR agonists but not with ß1-or ß2-agonists. Human adipocytes, which endogenously express a high level of α2-ARs, exhibited a clear α2 -adrenergic antilipolytic response to adrenaline but not to octopamine. In Syrian hamster adipocytes, which also possess α2-ARs, octopamine induced only a weak antilipolysis. Octopamine is a substrate of fat cell amine oxidases, with an apparent affinity similar to that of noradrenaline. Thus, octopamine could be considered as an endogenous selective ß3-AR agonist (11). Octopamine stimulates adenylate cyclase. Via experimentation it was suggested that octopamine acts on intestinal dopamine D1-receptor sites to produce relaxation of rabbit jejunum through an increase of cAMP (cyclic adenosine monophosphate) (12). Recently, a family of related mammalian 15 G protein-coupled receptors was identified of which two members (TA1- and TA2-receptors) have been shown to specifically bind and/or be activated by trace amines, such as phenylethylamine and tryptamine. However, these receptors display low affinity for octopamine (13). Pulmonary system breathing frequency: no data available. tidal volume: no data available. lung compliance: no data available. airway resistance: Noradrenaline is 6000 fold more potent than octopamine to activate ß1-adrenergic receptors in guinea-pig atria and trachea. Octopamine had no detectable activity in concentrations as high as 10 -4 M on the ß2-adrenoreceptor of the isolated trachea. If octopamine is co-released with noradrenaline in amounts proportional to their concentration, their activities at these structures are too low to be physiologically significant (14). Cardiovascular system blood pressure: Effects of octopamine on sinus rate and atrial contractility were investigated using the isolated atrium preparation of dog. When octopamine, dopamine or noradrenaline was administered into the cannulated sinus node artery, positive chronotropic and inotropic responses were dose-related. The DR50 values (dose ratio at 50% maximum response) of octopamine, dopamine and noradrenaline were roughly 30-100: 30:1, respectively. The duration of action of octopamine was longest. The positive chronotropic and inotropic responses to octopamine are mainly due to tyramine-like action (15). The perfusion of octopamine in pig produces an increase of cardiac output and decreases the pulmonary vascular resistances. The changes in the lung circulation are exerted by the direct action of this drug on nervous control of vascular walls (octopamine dose is not mentioned in the abstract) (16). Octopamine injected in lateral ventricle of conscious spontaneously hypertensive rats decreased systolic blood pressure (SBP). The administration of pargyline, a MAO inhibitor, which increased brain octopamine, resulted in a reduction of systolic blood pressure. Octopamine hypotension was not antagonized by selective antagonists of post-synaptic α-adrenoceptors, indicating that octopamine may be involved in central blood pressure regulation (octopamine dose was not mentioned in the abstract) (17). Experiments on rat mesenteric arterioles, metarterioles and aortae demonstrate that octopamine is between 60 and 15,000 times less potent than noradrenaline on rat arterioles and metarterioles and is incapable of eliciting more than 40% occlusion of these terminal vessels. It is suggested that such data support the concept that octopamine, could serve as a
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The Contribution of cocoa additive to cigarette smoking addiction

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