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

The present study examines the functional and binding affinities of the aporphine alkaloid, (+)-boldine, at different α1- and α2-adrenoceptor subtypes, namely, α1A (rat vas deferens and kidney) and its L-like state (rabbit spleen), α1B (guinea pig spleen, mouse spleen and rabbit aorta), α1D (rat aorta and pulmonary artery), at possible subtypes of prejunctional α2-adrenoceptors in rat and rabbit vas deferens and rat atrium, α2D in guinea pig ileum, cloned human α1-adrenoceptor subtypes A, B and D and α2-adrenoceptor subtypes A, B and C as well as rat α2D-adrenoceptors. Additionally, we investigated its Ca2+ channel antagonism in vascular and cardiac preparations. (+)-Boldine had higher affinity at α1-adrenoceptor subtype A (pA2=7.46, pKi=7.21) compared with its L-like state (pA2=5.63) or subtype B (pA2=5.98– 6.12, pKi=5.79) and subtype D (pA2=6.18–6.37, pKi=6.09). Its affinities at α2-adrenoceptors in rat and rabbit vas deferens and rat atrium (pA2=6.02, 6.36, 6.06, respectively) were identical, but lower at guinea pig ileum α2D-adrenoceptors (pA2=4.38). (+)-Boldine displayed nearly undistinguishable affinity at cloned human α2-adrenoceptor subtypes A, B and C (pKi=6.26, 5.79 and 6.35, respectively), whereas its affinity at rat α2D-adrenoceptors was low (pKi=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 α1A-adrenoceptors, does not discriminate between the α1-adrenoceptor subtypes B and D and α2-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 Ca2+ channel antagonistic properties but no specificity for coronary dilatation relative to cardiodepression.