Pronounced facilitation of endogenous noradrenaline release by presynaptic ?2-adrenoceptors in the vasculature of freely moving rats (original) (raw)

1988, Naunyn-Schmiedeberg's Archives of Pharmacology

The facilitation of the noradrenaline (NA) overflow by stimulation of the presynaptic ¢/-adrenoceptor of the rat portal vein was investigated, using the freely moving unanesthetized permanently cannulated rat as a model. The /~2-selective agonist fenoterol caused a maximal enhancement of about 300% of the basal NA level at a dose of 0.5 mg/kg: Following administration of cocaine (2.5 mg/kg plus 0.05 mg/kg/min) basal NA levels increased to •50% whereas combination of cocaine and fenoterol results in a dose dependant rise up to over 560% of the basal level (at a fenoterol dosage of 0.5 mg/kg). Blockade of the c~2adrenoceptors with yohimbine (0.5 mg/kg) which enhances the NA level to 486%, followed by 0.125 mg/kg fenoterol results in a further 2.53-fold rise to more than 1,200% of the basal level, indicating the pronounced counterregulatory role of the presynaptic c~2-adrenoceptor. After ganglionic blockade with hexamethonium (3 mg/kg plus 6 mg/kg/h) the effect of yohimbine (0.5 mg/kg) alone was diminished to 162%, but the additional facilitatory effect of 0.125 mg/kg fenoterol still was 1.82-fold, to 294% of the basal level, Combination of cocaine (2.5 mg/kg plus 0.05 mg/kg/min), yohimbine (0.5 mg/kg) and fenoterol (0.125 mg/kg) induced a rise to over 9,000 pg/ml NA (about 40-fold of the basal NA level). During electrical stimulation (2 Hz, 3 ms, 5 mA) of the local portal vein nervous plexus, the role of the inhibitory c~2-adrenoceptor becomes even more pronounced. Both in absence and in presence of cocaine, at the highest dose of fenoterol (0.5 mg/kg), the levels of electrically evoked release reverted to control values. However, after yohimbine (0.5 mg/kg) the evoked release was further enhanced by a much lower dosage of 0.125 mg/kg fenoterol to 450% of the control evoked release. This value was not changed significantly after ganglionic transmission blockade (hexamethonium 3 mg/kg plus 6 mg/kg/h). The results demonstrate that presynaptic/%adrenoceptors in the vasculature of the unanesthetized freely moving rat actually possess a pronounced capacity to facilitate NA release from sympathetic varicosities. Key words: Presynaptic //-adrenoceptors -Rat portal vein -Presynaptic c~2-adrenoceptors -Endogenous plasma catecholamines -Freely moving rat Recently, we introduced a new technique which allows the study of presynaptic modulation of the endogenous NA release from the portal vein nervous plexus of the unanesthetized, freely moving rat (Remie and Zaagsma 1986). Using this method we find in the present study, that vascular presynaptic/~-adrenoceptors actually possess a pronounced capacity to facilitate noradrenergic neurotransmission.