Role of cyclic AMP in the release of noradrenaline from isolated rat atria. Effect of pretreatment with clenbuterol.
The possible role of cyclic AMP (cAMP) on tritium overflow evoked by stimulation of the cardio-accelerant nerves was studied in rat atria preincubated with [3H]-noradrenaline. Addition of the activator of adenylate cyclase forskolin (1 mumol/l), or of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX, 100 mumol/l), did not affect both basal and evoked overflow. However, in the presence of the alpha 2-adrenoceptor antagonist yohimbine (0.03 mumol/l) both forskolin and IBMX increased the stimulation-induced transmitter overflow by 49% and 141%, respectively (compared to yohimbine 0.03 mumol/l). Thus, in rat atria the cAMP-dependent facilitation of noradrenaline release is only present when the autoinhibition exerted by activation of prejunctional alpha 2-adrenoceptors is blocked. Propranolol (0.1 mumol/l) that did not produce any effect on noradrenaline release markedly reduced the facilitatory response induced by forskolin in the presence of yohimbine. When rats were pretreated with the beta 2-adrenoceptor agonist clenbuterol (0.3 mg.kg-1, s.c., twice daily, 14 days), a treatment which desensitizes beta-adrenoceptor-mediated facilitation of noradrenaline release (Kazanietz and Enero 1989), the facilitatory effect of forskolin and IBMX in the presence of yohimbine was abolished. The results indicate that in rat atria the effect of forskolin and IBMX on noradrenaline release are only to be observed after blockade of presynaptic alpha 2-adrenoceptor autoinhibition. beta-adrenoceptor blockade or clenbuterol pretreatment decreases the facilitatory response to forskolin and hence prejunctional beta-adrenoceptor-mediated enhancement of noradrenaline release is linked to the stimulation of adenylate cyclase.
Kazanietz
M G
MG
Cátedra de Farmacología, Facultad de Farmacia y Bioquímica, UBA., Instituto de Investigaciones Farmacológicas, CONICET, Argentina.
Enero
M A
MA
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002976:Clenbuterol / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D004558:Electric Stimulation; D006321:Heart / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015016:Yohimbine / Q000494:pharmacology
D005576:Colforsin; D015016:Yohimbine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D015056:1-Methyl-3-isobutylxanthine; D009638:Norepinephrine; D002976:Clenbuterol