Affinity profile at α1- and α2-adrenoceptor subtypes and in vitro cardiovascular actions of (+)-boldine

Abstract The present study examines the functional and binding affinities of the aporphine alkaloid, (+)-boldine, at different α 1 - and α 2 -adrenoceptor subtypes, namely, α 1A (rat vas deferens and kidney) and its L-like state (rabbit spleen), α 1B (guinea pig spleen, mouse spleen and rabbit aorta), α 1D (rat aorta and pulmonary artery), at possible subtypes of prejunctional α 2 -adrenoceptors in rat and rabbit vas deferens and rat atrium, α 2D in guinea pig ileum, cloned human α 1 -adrenoceptor subtypes A, B and D and α 2 -adrenoceptor subtypes A, B and C as well as rat α 2D -adrenoceptors. Additionally, we investigated its Ca 2+ channel antagonism in vascular and cardiac preparations. (+)-Boldine had higher affinity at α 1 -adrenoceptor subtype A (p A 2 =7.46, p K i =7.21) compared with its L-like state (p A 2 =5.63) or subtype B (p A 2 =5.98– 6.12, p K i =5.79) and subtype D (p A 2 =6.18–6.37, p K i =6.09). Its affinities at α 2 -adrenoceptors in rat and rabbit vas deferens and rat atrium (p A 2 =6.02, 6.36, 6.06, respectively) were identical, but lower at guinea pig ileum α 2D -adrenoceptors (p A 2 =4.38). (+)-Boldine displayed nearly undistinguishable affinity at cloned human α 2 -adrenoceptor subtypes A, B and C (p K i =6.26, 5.79 and 6.35, respectively), whereas its affinity at rat α 2D -adrenoceptors was low (p K i =4.70). In perfused rat kidney, (+)-boldine inhibited K + -evoked vasoconstriction at doses 70-fold higher than diltiazem. In guinea pig Langendorff heart, (+)-boldine (10 −5 –2×10 −4 M) was equieffective in increasing coronary flow and in depressing cardiac force, while lower concentrations already depressed heart rate. In papillary muscles from guinea pig, (+)-boldine (10 −6 –10 −5 M) mainly prolonged the duration of action potential at levels >30% of repolarization. These data reveal that (+)-boldine, except for its moderate selectivity (15 to 25-fold) for α 1A -adrenoceptors, does not discriminate between the α 1 -adrenoceptor subtypes B and D and α 2 -adrenoceptor subtypes A, B and C, at which the drug consistently displays micromolar affinity. In vascular and cardiac preparations, (+)-boldine, although being at least 50-fold weaker than diltiazem, shows Ca 2+ channel antagonistic properties but no specificity for coronary dilatation relative to cardiodepression.