Alpha-1 adrenoceptor selectivity of phenoxybenzamine in the rat kidney

The dose-dependent selectivity of an irreversible binding antagonist, phenoxybenzamine (POB), for renal alpha-1 adrenoceptors, was biochemically and physiologically characterized. Receptors were quantified with the radioligands [3H]prazosin and [3H]rauwolscine for alpha-1 and alpha-2 adrenoceptors, respectively. Alpha-1 adrenoceptor function was quantified by the shift of the norepinephrine and phenylephrine pressor response in vivo and the vasoconstrictor response in the isolated perfused kidney preparation. A renal alpha-2 adrenoceptor response was demonstrated by showing that epinephrine could reverse the effect of vasopressin on water and sodium in the presence of beta blockade and alpha-1 destruction by POB. Doses of POB from 0.1 to 10.0 mg/kg progressively reduced [3H]prazosin binding to renal alpha-1 adrenoceptors until there was no specific binding at the 10.0-mg/kg dose. At this dose more than 60% of [3H]rauwolscine binding to renal alpha-2 adrenoceptors was still present. POB 1.0 mg/kg/hr decreased specific binding to renal alpha-1 adrenoceptors by approximately 40% (P less than .05) but reduced the alpha-1 adrenoceptor-induced vasoconstriction in the nonrecirculating isolated perfused kidney to 10 to 20% of the control. This was the maximal dose of POB studied which did not affect the alpha-2 adrenoceptor-induced antagonism of vasopressin. Higher doses of POB (3.0 mg/kg/hr) demonstrated some alpha-2 adrenoceptor binding as indicated by an attenuation of the antagonism by alpha-2 adrenoceptors. Thus, POB displays selectivity for renal alpha-1 over alpha-2 adrenoceptors. Our data indicate that a dose of 1.0 mg/kg/hr of POB will leave alpha-2 adrenoceptors intact while functionally incapacitating alpha-1 adrenoceptors to 10 to 20% of the control value.