The effect of alpha 1-acid glycoprotein on the pharmacological activity of alpha 1-adrenergic antagonists in rabbit aortic strips.

The pharmacological activity of three alpha 1-adrenergic antagonists, prazosin, tiodazosin and WB4101 has been studied in the presence and absence of 20 microM alpha 1-acid glycoprotein (AAG) in rabbit aortic strips, and measured as the ability to increase the EC50 value of the alpha 1-adrenergic agonist phenylephrine. For all three drugs, the presence of AAG diminished the pharmacological activity when compared with equivalent unbound concentrations in the absence of AAG. In the presence of AAG the EC50 value of phenylephrine at 5.69 nM unbound prazosin was on average 47% lower than in the absence of AAG (P less than 0.002), at 122 nM unbound tiodazosin, 39% lower (P less than 0.01), and at 25.6 nM unbound WB4101, 68% lower (P less than 0.002). Albumin showed no ability to modify the alpha 1-adrenergic blocking activity of prazosin (P greater than 0.7). The EC50 value for phenylephrine in the absence of antagonists was not affected by AAG. The effect of AAG on the antagonistic activity of prazosin was concentration-dependent with a maximum suppression of prazosin activity of 79% and with a half-maximum concentration of 1.1 microM AAG. AAG significantly decreased prazosin's ability to reduce alpha 1-adrenergic stimulation of calcium influx (P less than 0.05), while it had no effect on prazosin's ability to decrease alpha 1-adrenergic-stimulated formation of inositol phosphate. These results suggest that the effect of AAG on adrenoceptors appears to act selectively via alpha 1 a-receptors. Consistent with these observation was the observation that WB4101, a selective alpha 1a-antagonist was more affected by AAG than was prazosin or tiodazosin.