Antagonism to noradrenaline-induced lethality in rats is related to affinity for the alpha sub(1A)-adrenoceptor subtype

The potency of several alpha sub(1)-adrenoceptor antagonists in preventing the noradrenaline-induced lethality in conscious rats, their binding affinity for the native alpha sub(1A)- and alpha sub(1B)-adrenoceptors, the recombinant animal alpha sub(1a)-, alpha sub(1b)- and alpha sub(1d)-adrenoceptor subtypes, as well as their functional affinity for the alpha sub(1L)-adrenoceptor subtype were evaluated. The potency of the tested compounds as antagonists of noradrenaline-induced lethality was correlated with the affinity for the alpha sub(1A)- (and alpha sub(1a)-) adrenoceptor subtype, but not with the affinity for the other subtypes. On the contrary, the hypotensive effects of the compounds, assessed in anesthetized rats, were not clearly related with the affinity for any of the alpha sub(1)-subtypes. These results suggest that the alpha sub(1A)-subtype plays a determining role in preventing lethality induced by noradrenaline in the rats, and that this activity is unrelated to the hypotensive effect of the compounds, which cannot be clearly correlated with affinity for a particular alpha sub(1)-adrenoceptor subtype.