A physiological basis for subclassifying beta-adrenoceptors examined by chemical sympathectomy of guinea-pigs

Abstract

Chemical sympathectomy of guinea-pigs was induced by chronic pretreatment with 6-hydroxydopamine over a 20 day period. Control animals were sham injected with vehicle at the same times. Isolated tissues were removed from the animals and beta-adrenoceptor sensitivity assessed from cumulative concentration-response curves for isoprenaline, followed after wash-out by a partial agonist (salbutamol, ritodrine or prenalterol). The following responses were measured: increases in force and rate of contraction of left and right atria respectively, inhibition of carbachol-induced ileal contractions, relaxation of intrinsic tone of lung strips and tracheal spirals, inhibition of contractions of vas deferens and soleus muscle induced by field stimulation. Left and right atria and ileum from 6-hydroxydopamine-pretreated guinea-pigs exhibited supersensitivity to beta-adrenoceptor stimulation. This was measured as a leftwards shift of the concentration-response curve for isoprenaline and as an elevation of the partial agonist maximum response (relative to isoprenaline), when compared with tissues from sham-injected controls. The supersensitivity was assumed to be due to the loss of endogenous neurotransmitter release by chemical sympathectomy and specific for the beta-adrenoceptor. In contrast, lung strips, vas deferens and soleus muscle were not supersensitive. The responses of these tissues are thought to be mediated via beta 2-adrenoceptors whereas cardiac and ileal responses are beta 1-adrenoceptor mediated. The latter receptor subtype would therefore appear to be under the influence of sympathetic innervation, but since no supersensitivity occurred at beta 2-adrenoceptors these were presumed to be non-innervated but stimulated by circulating adrenaline. These results obtained by use of chemical sympathectomy with 6-hydroxydopamine support the contention that the physiological basis of beta-adrenoceptor subclassification is that the beta 1-subtype are innervated whereas the beta 2-subtype are non-innervated.