Enhancement of tetrodotoxin‐induced axonal blockade by adenosine, adenosine analogues, dibutyryl cyclic AMP and methylxanthines in the frog sciatic nerve

Abstract

The effects of adenosine, adenosine analogues (N6-cyclohexyladenosine (CHA), L-N6-phenylisopropyladenosine (L-PIA), D-N6-phenylisopropyladenosine (D-PIA), N6-methyladenosine and 2-chloroadenosine), adenine, inosine, hypoxanthine, cyclic AMP and its analogue the dibutyryl cyclic AMP (db cyclic AMP), and methylxanthines (theophylline, caffeine and isobutylmethylxanthine (Ibmx) on compound action potentials were investigated in de-sheathed sciatic nerve preparations of the frog. 2 Adenosine and its analogues enhanced, in a concentration-dependent manner, the inhibitory action of tetrodotoxin (TTX) on nerve conduction. The order of potencies was: CHA > D-PIA > L-PIA> N6-methyladenosine > 2-chloroadenosine > adenosine. 3 The adenosine metabolites, inosine and hypoxanthine, were inactive on TTX-induced axonal blockade. Adenine enhanced the inhibitory action of TTX on nerve conduction, but was less effective than adenosine. 4 db Cyclic AMP, but not cyclic AMP, mimicked the inhibitory effect of adenosine on nerve conduction. 5 Methylxanthines did not antagonize the effect of adenosine on TTX-induced axonal block and in high concentrations also mimicked the effect of adenosine on nerve conduction. 6 The possibility of adenosine acting on TTX-induced axonal block through an adenosine receptor positively coupled to adenylate cyclase is discussed.

On the type of receptor involved in the inhibitory action of adenosine at the neuromuscular junction

“…For example the receptors that mediate the effects of adenosine on axons (Ribeiro & Sebastiao, 1984), anococcygeus muscle (Stone, 1983), heart (Hughes & Stone, 1983) and postganglionic neurones (Henon & McAfee, 1983) do not exhibit pharmacological profiles in accordance with the A1/A2 adenosine receptor classification. Also, the electrophysiological actions of adenosine on the central nervous system (Phillis & Wu, 1981;Dunwiddie & Fredholm, 1984) appear to be mediated by a third, as yet unnamed, extracellular receptor which differs in its pharmacological properties from both the Al-and A2-receptors associated with adenylate cyclase.…”

The A3Adenosine Receptor: History and Perspectives

“…The A 3 Receptor: History and Perspectives 75 neuromuscular junction (Ribeiro and Sebastião, 1984). A distinct AR was claimed to exist in the brain that was coupled to Ca 2+ metabolism (Ribeiro and Sebastião, 1986).…”

Inhibitory effects of forskolin and papaverine on nerve conduction partially blocked by tetrodotoxin in the frog sciatic nerve

“…Assuming that each sodium channel is activated in an all or none fashion, 25% of the maximum sodium conductance at the peak of an action potential implies that only 25% of the total number of the voltagesensitive sodium channels need to be activated in order to produce a full action potential (see also Schoffeniels & Dandrifosse, 1980). If this applies to the frog axons, the existence ofspare voltage-dependent sodium channels in the axonal membranes might explain why it is necessary to decrease the amplitude of the action potentials with TTX, a specific blocker of the voltagesensitive sodium channels (Narahashi et al, 1964), in order to detect the inhibitory action ofdibutyryl cyclic AMP, adenosine, methylxanthines (Ribeiro & Sebastiao, 1984), forskolin and papaverine (present work) on nerve conduction.…”

“…In a recent paper Ribeiro & Sebastiao (1984) produced evidence that R-type adenosine receptors positively coupled to adenylate cyclase are present in peripheral axons and suggested that the activation of these receptors causes a decrease in the entry of sodium during the depolarizing phase of the action potential. This idea is based on the findings that adenosine, adenosine analogues, dibutyryl cyclic AMP and theophylline decrease the amplitude of compound action potentials partially inhibited by tetrodotoxin (TTX) (Ribeiro & Sebastiao, 1984), and that adenosine (Roch & Salamin, 1976) and theophylline (Horn & McAffee, 1977) increase cyclic AMP levels in axons.…”

“…This idea is based on the findings that adenosine, adenosine analogues, dibutyryl cyclic AMP and theophylline decrease the amplitude of compound action potentials partially inhibited by tetrodotoxin (TTX) (Ribeiro & Sebastiao, 1984), and that adenosine (Roch & Salamin, 1976) and theophylline (Horn & McAffee, 1977) increase cyclic AMP levels in axons. On the other hand, it has been shown that forskolin, a powerful and specific activator of adenylate cyclase (Seamon et al, 1981) by acting directly at the catalytic subunit ofthe enzyme (see Daly, 1984), increases cyclic AMP levels in frog sciatic nerves (Kilmer & Carlsen, 1984).…”