CARDIAC EFFECTS OF THE BETA(3)-ADRENOCEPTOR AGONIST BRL35135 IN MAN

1 The aim of the present study was to evaluate the cardiac effects of the beta3-adrenoceptor agonist BRL35135, and determine whether beta3-r eceptors are involved in mediating chronotropic or inotropic responses in man 2 Eight normal males received single oral doses of BRL35135 8 mg (BRL) or the selective beta2-adrenoceptor agonist salbutamol 8 mg ( SAL), after pretreatment with either placebo (PL), bisoprolol 5 mg (B5 ) as a selective beta1-adrenoceptor antagonist, or nadolol 20 mg (N20) to block beta1- and beta2- but not beta3-receptors. 3 Both BRL and SA L produced a significant increase in postural finger tremor in keeping with beta2-adrenoceptor stimulation, and this response was totally ab olished by pretreatment with N20. 4 Significant increases in systolic blood pressure and Doppler stroke distance occurred with BRL and SAL w hich were unaffected by pretreatment with B5 and completely blocked by N20, in keeping with beta2-mediated effects. 5 BRL and SAL produced s ignificant chronotropic and minute distance responses which were unaff ected by beta1-adrenoceptor blockade. However, whereas N20 blocked the se responses to SAL, a small but significant response occurred with BR L in comparison with placebo despite complete blockade of co-existing beta2-mediated effects. Compared with PL, the mean responses to N20/BR L, and the 95% confidence interval for the differences between the mea ns were 7.4 beats min-1 [3.2 to 11.6] (P = 0.002) for heart rate, and 208.8 cm [38.3 to 379.3] (P = 0.02) for minute distance responses. 6 T hese results suggest that BRL35135 produces most, if not all of its ca rdiac effects by beta2-adrenoceptor stimulation, although the possibil ity exists that a component of its chronotropic response is mediated b y beta3-receptors.