The Effect of α1-Acid Glycoprotein on the Pharmacological Activity of α1-Adrenergic Antagonists in Rabbit Aortic Strips

Abstract

Abstract The pharmacological activity of three α1-adrenergic antagonists, prazosin, tiodazosin and WB4101 has been studied in the presence and absence of 20 μ m α1-acid glycoprotein (AAG) in rabbit aortic strips, and measured as the ability to increase the EC50 value of the α1-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 < 0·002), at 122 Nm unbound tiodazosin, 39% lower (P < 0·01), and at 25·6 Nm unbound WB4101, 68% lower (P < 0·002). Albumin showed no ability to modify the α1-adrenergic blocking activity of prazosin (P > 0·1). 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 μm AAG. AAG significantly decreased prazosin's ability to reduce α1adrenergic stimulation of calcium influx (P < 0·05), while it had no effect on prazosin's ability to decrease α1-adrenergic-stimulated formation of inositol phosphate. These results suggest that the effect of AAG on adrenoceptors appears to act selectively via α1a-receptors. Consistent with these observations was the observation that WB4101, a selective α1a-antagonist was more affected by AAG than was prazosin or tiodazosin.