The anti‐adrenergic effect of adenosine and its blockade by pertussus toxin: a comparative study in myocytes isolated from guinea‐pig, rat and failing human hearts

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Abstract
In intact ventricular preparations, adenosine has been shown to reduce the β‐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. Adenosine in the absence of β‐adrenoceptor‐mediated stimulation had no effect on contraction in human and guinea‐pig myocytes but produced a variable effect in rat myocytes. 8‐Cyclopentyl 1,3‐dipropylxanthine (CPX), a selective A1‐receptor antagonist, antagonised the anti‐adrenergic effect of adenosine in guinea‐pig myocytes. 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. Pertussis toxin‐pretreatment at 35°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. 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. 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 β‐adrenoceptor/adenylate cyclase interaction in normal myocardium.