NERVE ACTIVITY-DEPENDENT VARIATIONS IN CLEARANCE OF RELEASED NORADRENALINE - REGULATORY ROLES FOR SYMPATHETIC NEUROMUSCULAR-TRANSMISSION INRAT TAIL ARTERY

The aim of this study was to find out if clearance of noradrenaline re leased from sympathetic nerve terminals in rat isolated tail artery is a physiological variable and if so, to determine its role for the nor adrenaline-mediated neurogenic contraction. The per pulse release of n oradrenaline induced by electrical nerve stimulation and the fluctuati ons of the level of noradrenaline at the receptors driving the contrac tions were assessed from the electrochemically determined noradrenalin e oxidation current at a carbon fibre electrode at the surface of the artery. Both were compared with the noradrenaline-mediated neurogenic contraction. The effects on these parameters of cocaine or desipramine , or of corticosterone, were used to assess the relative roles of neur onal and extraneuronal uptake, respectively. The effects of cocaine or desipramine, which enhance the noradrenaline level at the receptors b y blocking neuronal reuptake, were compared with those of yohimbine, p resumed to act exclusively by enhancing the per pulse release of norad renaline. The results seem to support the following tentative conclusi ons. Clearance of released noradrenaline occurs by neuronal uptake and diffusion, while extraneuronal uptake is negligible. The noradrenalin e-induced neurogenic contraction is mediated via adrenoceptors on cell s near the plane of the nerve plexus; the excitation spreads from thes e cells throughout the syncytium. The contractile response to exogenou s noradrenaline may also be mediated via receptors on the innervated k ey cells. Reuptake of noradrenaline into the releasing varicosities, i .e. in ''active junctions'', is highly efficient for single quanta but rapidly saturated by repeated release, while reuptake of noradrenalin e in the ''surround'' of active junctions is probably rarely saturated and more independent of nerve activity. Saturation of the transporter by repeated release of quanta from the same varicosity and the conseq uent accumulation of ''residual'' noradrenaline and increased diffusio n out of the junction and recruitment of noradrenaline receptors in th e surround may be the cause of the rapid growth of the contraction dur ing a high frequency train. Diffusion of released noradrenaline away f rom the postjunctional receptors is restricted by a local nerve activi ty-dependent buffering mechanism which, in spite of fading of the per pulse release, helps maintain the noradrenaline concentration at the r eceptors and the contraction during long high-frequency trains. Reacti vation of the clearance mechanisms upon cessation of nerve activity ac celerates the relaxation. This ''plasticity'' of noradrenaline clearan ce enables the vessel to virtually ignore nerve impulses at low freque ncy, contract briskly in response to high-frequency bursts, maintain t ension during long trains at high frequency in spite of a declining pe r pulse release of noradrenaline, and relax rapidly upon cessation of nerve activity.