Cyclosporin effect on noradrenaline release from the sympathetic nervous endings of rat aorta.
Arterial hypertension is one of the main side effects of cyclosporin treatment and seems to be due to activation of the sympathetic nervous system. Some authors hypothesized that cyclosporin may act on the sympathetic nervous endings increasing catecholamine release, in agreement with our previous works which demonstrated an increase in rat plasma catecholamine levels after 30 mg/kg per day cyclosporin treatment for 7 weeks. Therefore, the aim of this work was to study the cyclosporin mechanism responsible for that increase in plasma catecholamines. Male Wistar rats were used. Noradrenaline release was performed in vitro experiments after loading rat aorta abdominal segments with 3H-noradrenaline (3H-NA). The release of 3H-NA was measured after electrical stimulation in the presence of 10(-6)M cyclosporin. In another set of experiments electrical stimulation was replaced by a pulse addition of cyclosporin (10(-6)M). Another group of rats was treated with 30 mg/kg per day cyclosporin for 7 weeks and catecholamine contents in aorta abdominal segments and adrenals were measured by high performance liquid chromatography system with electrochemical detection (HPLC-ECD). An increase in the 3H-NA release was observed in both types of in vitro experiments. Since cocaine abolished these cyclosporin effects, the obtained results suggest that cyclosporin may act on the catecholamine transporter across the membrane. In addition, after the 7 weeks of cyclosporin treatment, a significant decrease in catecholamine aorta contents was verified but in adrenals there was no difference regarding to controls. However, the dopamine synthesis/degradation ratio measured by the DA/DOPAC ratio suggests an increase in dopamine synthesis. These facts are in agreement with the enhanced plasma catecholamine levels and with the hypothesis of tissue catecholamine depletion. However, they do not explain the increase in plasma adrenaline levels, since adrenaline is a reflex of adrenal activity. The synthesized dopamine in adrenals seems to be unable to reach vesicles and to be metabolized in adrenaline. The observed decrease in HVA adrenal levels may be a consequence of extraneuronal uptake inhibition or inhibition by cyclosporin of the direct o-methylation of DOPAC. In conclusion, our results suggest that cyclosporin increases catecholamine release from the sympathetic nervous endings by a tyramine-like effect, i.e. by acting directly on the catecholamine transporter of the membrane.
Tavares
Paula
P
Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, 3049 Coimbra codex, Portugal.
Fontes Ribeiro
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Teixeira
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D000320:Adrenergic Fibers / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D008297:Male; D009411:Nerve Endings / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D016572:Cyclosporine; D009638:Norepinephrine