BETA-ADRENOCEPTOR SUBTYPES MEDIATING THE METABOLIC EFFECTS OF BRL-35135 IN MAN

1. The aim of the present study was to evaluate the metabolic response s produced in man by the beta(3)-adrenoceptor agonist BRL 35135, and t o determine which of these responses are beta(3)-, rather than beta(1) - or beta(2)-, mediated.2. Eight normal male subjects received single oral doses of BRL 35135 (8 mg) or the selective beta(2)-adrenoceptor a gonist salbutamol (8 mg) after pretreatment with placebo, bisoprolol ( 5 mg) as a selective beta(1)-antagonist or nadolol (20 mg) to block be ta(1)- and beta(2)-, but not beta(3)-adrenoceptors. 3. BRL 35135 and s albutamol produced a significant fall in serum potassium concentration compared with placebo, in keeping with beta(2)-adrenoceptor stimulati on. Both drugs also produced a significant increase in serum glucose, insulin and lactate concentrations, which mirrored the hypokalaemic re sponse, being unaffected by selective beta(1)-blockade (bisoprolol), b ut completely blocked by nadolol. BRL 35135 (but not salbutamol) also produced a significant rise in serum free fatty acid and glycerol conc entrations, which appeared to be beta(2)-mediated. 4. A significant in crease in basal metabolic rate occurred with both BRL 35135 and salbut amol. In the case of salbutamol, this effect appeared to be mediated s olely by beta(2)-adrenoceptors, whereas BRL 35135 produced a thermogen ic response which could only be partially accounted for by a combinati on of beta(1)- and beta(2)-adrenoceptor stimulation. 5. These results infer the possibility of thermogenic beta(3)-adrenoceptors in man, alt hough these do not appear to be involved in the control of carbohydrat e or fat metabolism.