Frequency‐Dependence of3H‐Noradrenaline Release from Rabbit Pulmonary Artery: Effect of α‐Adrenoceptor Antagonists and Inhibitors of Transmitter Inactivation

Abstract:The aim of this study was to examine the modulating role of presynaptic α2‐adrenoceptors on transmitter release from vascular sympathetic neurones. This was done by examining the influence of removal of inactivation pathways on the effect of α‐adrenoceptor antagonists on the release of transmitter from noradrenergic neurones. The rabbit main pulmonary artery preloaded with3H‐noradrenaline (3H‐NA) was used. The artery was stimulated with 300 pulses at various frequencies (1, 3, 10 and 30 Hz). Pargyline (3 × 10−4M) increased the stimulation‐evoked3H‐overflow at 1 and 3 Hz and decreased it at 30 Hz. U‐0521 (3′,4′‐dihydroxy‐2‐methylpropiophenone; 3 × 10−6M) enhanced the overflow at 1 Hz and had no effect at 3–30 Hz. Corticosterone (4 × 10−5M) did not alter the stimulation‐evoked3H‐overflow at 1–30 Hz. Cocaine (3 × 10−6M) enhanced the3H‐overflow slightly at 1–30 Hz. At 3 × 10−5M, cocaine enhanced3H‐overflow at 1 Hz and reduced it at 30 Hz. Neither corticosterone (4 × 10−5M) nor propranolol (10−7M) modified this effect of cocaine. Propranolol (10−7M) alone decreased the3H‐overflow at 30 Hz and had no effect at 1–10 Hz. Phenoxybenzamine (10−6M) and chlorpromazine (3 × 10−6M) potentiated the stimulation‐evoked3H‐overflow at 1–30 Hz. Phentolamine (10−6M) decreased the3H‐overflow at 1 Hz and enhanced it at 3–30 Hz. Rauwolscine (10−6M) enhanced the stimulation‐evoked3H‐overflow maximally at 10 Hz and had no effect at 1 and 30 Hz. Cocaine (3 × 10−5M), cocaine (3 × 10−5M) + corticosterone (4 × 10−5M), pargyline (3 × 10−4M) and U‐0521 (3 × 10−6M), but not corticosterone (4 × 10−5M), increased the rauwolscine‐induced enhancement at 1 and 3 Hz, but had no influence at 10 and 30 Hz. It is concluded that at a low frequency (1 Hz) of nerve stimulation, inhibition of either neuronal uptake, extraneuronal uptake, monoamine oxidase (MAO) or catechol‐O‐methyltransferase (COMT) causes an enhancement in transmitter overflow that is due to removal of inactivation pathways. The enhancement is not mediated via facilitatory β‐adrenoceptors. At higher frequencies (3–30 Hz) inhibition of either neuronal uptake or MAO causes a sufficient amount of transmitter in the neuromuscular gap to activate the presynaptic α‐adrenoceptor mediated negative feed‐back system causing a decrease in transmitter release. α‐ Adrenoceptor antagonists enhance the stimulation‐evoked release of3H‐NA only when the junctional gap concentration of transmitter is sufficient to trigger the presynaptic α‐adrenoceptor auto‐inhibitory system.