Selective β 1 ‐adrenoceptor blockade enhances the activity of the stimulatory G‐protein in human atrial myocardium

Chronic selective β 1 ‐adrenoceptor (β 1 AR) blocker treatment enhances the sensitivity of β 2 ‐adrenoceptor (β 2 AR) in human heart (Hall et al ., 1990; 1991). To clarify the mechanism of the cross‐sensitization between β 1 AR and β 2 AR, we determined whether the stimulatory G‐protein (G s α) function is increased in atria from β 1 AR‐blocker treated patients compared with non‐β‐blocked patients, and investigated whether this change is caused by an alteration of post‐translational modification of G s α protein. G s α function was determined by reconstitution of human atrial G s α into S49 cyc − cell membranes. In the reconstitution system, GTP γ S stimulated cyclic AMP generation in a dose‐dependent manner. Upon 10 −4 M GTP γ S stimulation, G s α activity in the β 1 AR‐blocker, atenolol, treated group (78.2±10.3 pmol cyclic AMP mg −1  min −1  10 −3 ) was 65% higher than that in non‐β‐blocked patients (47.3±6.3 pmol cyclic AMP mg −1  min −1  10 −3 , n =15, P =0.02). Isoelectric point (pI) values of G s α were measured by two dimensional gel electrophoresis (2D‐E) and the amount of each isoform quantified by image analysis of a Western blot of the gel using specific antibody. Multiple isoforms of G s α were detected by 2D‐E with different pI values. There were no significant differences between the groups of patients in either pI values or the proportions of the acidic isoforms of G s α to the main basic form ( n =12, P >0.05). The results suggest that chronic β 1 AR‐blockade enhances G s α function in human atrium, and this may account in part for the hypersensitivity of β 2 AR and other G s ‐coupled receptors during β 1 AR‐blockade. The increased G s α function is unlikely to be caused directly by blockade of protein kinase A phosphorylation of G s α protein.British Journal of Pharmacology (1999) 128 , 135–141; doi: 10.1038/sj.bjp.0702750