Antagonism of the positive chronotropic effect of norepinephrine by purine nucleosides in rat atria.
Adenosine has been shown previously to antagonize the positive chronotropic effects of beta adrenoceptor agonists. In the present study, the effects of adenosine and related compounds were observed on the concentration-effect curve for the positive chronotropic effect of norepinephrine in isolated spontaneously beating rat atria. Adenosine produced both a decrease in the potency of norepinephrine and a decrease in the maximal effect. The decrease in the potency was postulated to be mediated by an action on an external membrane receptor because it was also produced by the potent A1 receptor agonist N6-phenylisopropyladenosine. The effect of N6-phenylisopropyladenosine was antagonized by 8-phenyltheophylline which is known to block external adenosine receptors. When adenosine deaminase was inhibited with erythro-9-(2-hydroxy-3-nonyl)adenine, both effects of adenosine were enhanced markedly suggesting considerable metabolism of exogenous adenosine to inosine under the conditions of this study. Inosine increased rather than decreased the potency of norepinephrine while decreasing its maximal effect. The decrease in the maximal effect of norepinephrine was also produced by 2',5' dideoxyadenosine, 2' deoxyadenosine and S-adenosylhomocysteine but not by N6-phenylisopropyladenosine. This suggests that the decrease in the maximal effect of norepinephrine by adenosine analogs is related to an interaction with an internal site. Adenine had no effect on the concentration-effect curve for norepinephrine. It is suggested that adenosine may regulate cardiac function by antagonizing the chronotropic effect of norepinephrine released upon nerve stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D003839:Deoxyadenosines / Q000494:pharmacology; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects*; D007288:Inosine / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013268:Stimulation, Chemical
D003839:Deoxyadenosines; D010660:Phenylisopropyladenosine; C010192:9-(2-hydroxy-3-nonyl)adenine; D007288:Inosine; D000225:Adenine; D000241:Adenosine; D009638:Norepinephrine