The anti-adrenergic effect of adenosine and its blockade by pertussis toxin: a comparative study in myocytes isolated from guinea-pig, rat and failing human hearts.
1. In intact ventricular preparation, adenosine has been shown to reduce the beta-adrenoceptor-induced increase in contraction (the anti-adrenergic effect). In the present study we have investigated this effect of adenosine on isolated ventricular myocytes from failing human heart and normal guinea-pig and rat heart. 2. Adenosine in the absence of beta-adrenoceptor-mediated stimulation had no effect on contraction in human and guinea-pig myocytes but produced a variable effect in rat myocytes. 3. 8-Cyclopentyl 1,3-dipropylxanthine (CPX), a selective A1-receptor antagonist, antagonised the anti-adrenergic effect of adenosine in guinea-pig myocytes. 4. The anti-adrenergic effect of adenosine was greater in guinea-pig than rat myocytes and even more pronounced in cells isolated from failing human heart. 5. Pertussis toxin-pretreatment at 35 degrees C of guinea-pig and human myocytes abolished the anti-adrenergic effect of adenosine. Longer exposure to higher concentrations of pertussis toxin was required for complete abolition in human compared to guinea-pig cells. 6. These results support the suggestion that the adenosine receptors mediating the anti-adrenergic effect of adenosine are of the A1 subtype and are coupled to the inhibitory guanine nucleotide binding protein, Gi/Go. 7. Pertussis toxin pretreatment increased the sensitivity of guinea-pig myocytes to isoprenaline in the absence of adenosine; the EC50 value was decreased by a factor of 10. This suggests that Gi may exert a tonic inhibitory effect on the beta-adrenoceptor/adenylate cyclase interaction in normal myocardium.
Brown
L A
LA
Department of Cardiac Medicine, National Heart & Lung Institute, London.
Humphrey
S M
SM
Harding
S E
SE
D000241:Adenosine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists; D000818:Animals; D002303:Cardiac Output, Low / Q000503:physiopathology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology; D037342:Pertussis Toxin; D051381:Rats; D013045:Species Specificity; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin; D000241:Adenosine; D007545:Isoproterenol