SUBTYPE CLASSIFICATION OF THE PRESYNAPTIC ALPHA-ADRENOCEPTORS WHICH REGULATE [H-3] NORADRENALINE SECRETION IN GUINEA-PIG ISOLATED URETHRA

1 The following experiments were carried out to investigate the presence and type of functional presynaptic receptors in adrenergic nerves of the guinea-pig urethra. 2 The urethra from male guinea-pigs was incubated with [H-3]-noradrenaline and superfused with Tyrode solution in vitro. The fractional secretion of [H-3]-noradrenaline evoked by 300 electrical pulses was measured. 3 The [H-3]-noradrenaline secretion was positively frequency-dependent, yielding a half-maximal secretion at 8 +/- 5 Hz. Stimulation was usually applied at 5 Hz. 4 The [H-3]-noradrenaline secretion was not altered by noradrenaline (1 or 100-mu-M), norephedrine (1-mu-M), isoprenaline (0.1-mu-M), 5-hydroxytryptamine (10-mu-M), oxotremorine (10-mu-M), adenosine (0.2 mM), propranolol (1-mu-M), atropine (1-mu-M) or 8-phenyltheophylline (10-mu-M). 5 The [H-3]-noradrenaline secretion was enhanced by clonidine (3-mu-M), chlorpromazine (10-mu-M), metitepine (1-mu-M), 4-aminopyridine (0.5 mM), tetraethylammonium (2 mM), 3-isobutyl-1-methylxanthine (4 mM), 8-bromo cyclic AMP (1 mM) and forskolin (25-mu-M). 6 The alpha-adrenoceptor antagonists rauwolscine, yohimbine, phentolamine, prazosin and AR-C 239 maximally enhanced the [H-3]-noradrenaline secretion to about 300% of control. The partial alpha-adrenoceptor agonist oxymetazoline maximally enhanced the secretion to about 200% of control. The order of apparent EC50 values was rauwolscine < yohimine < phentolamine < oxymetazoline < prazosin < AR-C 239. 7 The enhancing effects of yohimbine (1-mu-M) with tetraethylammonium (2 mM), 8-bromo cyclic AMP (1 mM), or forskolin (25-mu-M) were additive, but not those of yohimbine (1-mu-M) with prazosin (10-mu-M), 4-aminopyridine (0.5 mM), or 3-isobutyl-1-methylxanthine (4 mM). 8 These results suggest that the [H-3]-noradrenaline secretion in the guinea-pig urethra is regulated by presynaptic alpha(2A)-adrenoceptors which may, in a cyclic AMP-independent manner, be coupled to a 4-aminopyridine-sensitive potassium channel. The secretion is not influenced by compounds acting at beta-adrenoceptors, muscarinic cholinoceptors or adenosine receptors.