Antagonism to noradrenaline-induced lethality in rats is related to affinity for the alpha1A-adrenoceptor subtype

The potency of several alpha1-adrenoceptor antagonists in preventing the noradrenaline-induced lethality in conscious rats, their binding affinity for the native alpha1A- and alpha1B-adrenoceptors, the recombinant animal alpha1a-, alpha1b- and alpha1d-adrenoceptor subtypes, as well as their functional affinity for the alpha1L-adrenoceptor subtype were evaluated. The potency of the tested compounds as antagonists of noradrenaline-induced lethality was correlated with the affinity for the alpha1A- (and alpha1a-) 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 alpha1-subtypes. These results suggest that the alpha1A-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 alpha1-adrenoceptor subtype.