title: Affinity profile at alpha(1)- and alpha(2)-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 alpha(1)- and alpha(2)-adrenoceptor subtypes, namely, alpha(1A) (rat vas deferens and kidney) and its L-like state (rabbit spleen), alpha(1B) (guinea pig spleen, mouse spleen and rabbit aorta), alpha(1D) (rat aorta and pulmonary artery), at possible subtypes of prejunctional alpha(2)-adrenoceptors in rat and rabbit vas deferens and rat atrium, alpha(2D) in guinea pig ileum, cloned human alpha(1)-adrenoceptor subtypes A, B and D and alpha(2)-adrenoceptor subtypes A, B and C as well as rat alpha(2D)-adrenoceptors. Additionally, we investigated its Ca(2+) channel antagonism in vascular and cardiac preparations. (+)-Boldine had higher affinity at alpha(1)-adrenoceptor subtype A (pA(2)=7.46, pK(i)=7.21) compared with its L-like state (pA(2)=5.63) or subtype B (pA(2)=5.98- 6.12, pK(i)=5.79) and subtype D (pA(2)=6.18-6.37, pK(i)=6.09). Its affinities at alpha(2)-adrenoceptors in rat and rabbit vas deferens and rat atrium (pA(2)=6.02, 6.36, 6.06, respectively) were identical, but lower at guinea pig ileum alpha(2D)-adrenoceptors (pA(2)=4.38). (+)-Boldine displayed nearly undistinguishable affinity at cloned human alpha(2)-adrenoceptor subtypes A, B and C (pK(i)=6.26, 5.79 and 6.35, respectively), whereas its affinity at rat alpha(2D)-adrenoceptors was low (pK(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 x 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 alpha(1A)-adrenoceptors, does not discriminate between the alpha(1)-adrenoceptor subtypes B and D and alpha(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.
authors.affiliation: Department of Pharmacology, Byk Gulden, D-78467, Konstanz, Germany. manfrid.eltze@byk.de
authors.forename: Manfrid
authors.initials: M
authors.lastname: Eltze
authors.forename: Thomas
authors.initials: T
authors.lastname: Grebe
authors.forename: Martin C
authors.initials: MC
authors.lastname: Michel
authors.forename: Peter
authors.initials: P
authors.lastname: Czyborra
authors.forename: Brigitte
authors.initials: B
authors.lastname: Ullrich
mesh_terms: D000818:Animals; D001060:Aporphines / Q000494:pharmacology*; D001665:Binding Sites; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects*; D002460:Cell Line; D006224:Cricetinae; D004594:Electrophysiology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009928:Organ Specificity; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*
chemical_list: D001060:Aporphines; D002317:Cardiovascular Agents; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; C011686:boldine