In vivo selectivity of prazosin but not of WB4101 for postsynaptic alpha-1 adrenoceptors

The relative selectivities of phentolamine, prazosin and WB4101 for pre- and postsynaptic alpha adrenoceptors were studied in vitro in the perfused cat spleen and in vivo in the anesthetized dog. In the perfused cat spleen, the effect of alpha adrenoceptor antagonists was determined on the stimulation-evoked release of [³H]norepinephrine and on the responses to sympathetic nerve stimulation. Prazosin was shown to be the most selective alpha-1 adrenoceptor antagonist tested. Phentolamine was 5 times and WB4101 approximately 60 times more potent in blocking the alpha-1 postsynaptic adrenoceptors, compared to their relative effects on presynaptic alpha-2 adrenoceptors. In the anesthetized dog, the presynaptic effect of drugs was assessed by using the antagonism of the clonidine-induced inhibition of the tachycardia elicited by electrical stimulation of the ansa subclavia. The antagonism of the clonidine-induced contraction of the nictitating membrane was taken as an estimate of the postsynaptic alpha adrenoceptor activity of the blocking agents. By using this experimental model, prazosin was shown to be over 100 times more effective in blocking postsynaptic alpha-1 adrenoceptors than in blocking presynaptic alpha-2 adrenoceptors. On the other hand, phentolamine was equipotent in blocking pre- and postsynaptic alpha adrenoceptors, whereas WB4101 was only 4 times more effective in preferentially blocking the alpha-1 postsynaptic adrenoceptors. The results obtained with phentolamine and prazosin indicate that with these methods there is quite a good correlation between the in vitro and in vivo assessment of selectivity for pre- and postsynaptic alpha adrenoceptors. The lack of selectivity of WB4101 observed in vivo suggests that either tissue and species differences or metabolism of WB4101 to a less selective compound may explain this difference between in vitro and in vivo results. In conclusion, the reported in vitro selectivity of WB4101, unlike that of prazosin, cannot be demonstrated in vivo under these experimental conditions; consequently, great care must be taken when extrapolating in vitro selectivity data to in vivo situations.