The mechanism of action of AMP-induced inhibition of sympathetic neurotransmission in the isolated vas deferens of the rat and guinea-pig.
1. The proposal that adenosine 5'-monophosphate (AMP) can be used as a selective antagonist of ATP at P2-purinoceptors on smooth muscle was investigated by examining the electrical and mechanical responses of guinea-pig and rat vasa deferentia to stimulation of sympathetic nerves and to exposure to exogenous agonists. 2. The magnitude of the contractile response of the rat vas deferens to field stimulation of the sympathetic nerves was reduced by addition of AMP. This effect was rapid in onset and readily reversed by washout. 3. The action of AMP on these contractile responses was reversed by the subsequent addition of the specific P1-purinoceptor antagonist 8-phenyltheophylline (8-PT). 8-PT on its own had no significant effect on contractile responses to nerve stimulation. 4. The magnitude of excitatory junction potentials (e.j.ps) in the guinea-pig vas deferens evoked by a train of stimuli at 0.5 Hz was reduced in a dose-dependent manner by introduction of AMP (10(-6)-10(-3)M). The inhibitory effect of 10(-5) M AMP on e.j.p. magnitude was completely and rapidly reversed by introduction of 10(-5)M 8-PT. The effect of 10(-4)M AMP was partially reversed by 10(-5) 8-PT. 5. The contractile responses of the guinea-pig vas deferens to exogenously applied adenosine 5'-triphosphate (ATP) were not reduced by AMP, even at a concentration of 2.5 X 10(-4)M. Similarly in the rat vas deferens, contractile responses to exogenously applied alpha, beta-methylene ATP (a more potent P2-purinoceptor agonist) were reduced by only 27.2%. The same concentration of AMP did not affect the contractile responses of the rat vas deferens to noradrenaline. 6. We conclude that the primary mechanism of action of AMP is to inhibit sympathetic neurotransmission by an agonist action at P1-purinoceptors on the sympathetic nerve terminal reducing the release of neurotransmitter, and therefore AMP cannot be used as a selective P2-purinoceptor antagonist.
Dalziel
H H
HH
Department of Physiology and Pharmacology, University of Strathclyde, Glasgow.
Sneddon
P
P
D000200:Action Potentials / Q000187:drug effects; D000249:Adenosine Monophosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000294:innervation; D051381:Rats; D013564:Sympathetic Nervous System / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014649:Vas Deferens / Q000187:drug effects / Q000294:innervation
D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D013806:Theophylline; C028322:8-phenyltheophylline; C002630:alpha,beta-methyleneadenosine 5'-triphosphate