The effect of S-(+)-boldine on the alpha(1)-adrenoceptor of the guinea-pig aorta

1 The cardiovascular activity of S-(+)-boldine, an aporphine alkaloid structurally related to papaverine, was determined. The work includes functional studies on guinea-pig isolated aorta contracted with noradrenaline, caffeine, KCl or Ca2+, and on guinea-pig trachea contracted with acetylcholine or histamine. 2 S-(+)-boldine inhibited in a concentration-dependent manner the contractile reponse evoked by noradrenaline (10 mu M) in guinea-pig aorta (IC50=1.4+/-0.2 mu M) while the KCI depolarizing solution (60 mM)- or the Ca2+ (1 mM)-induced contractions were only partially affected by boldine up to 300 mu M. In contrast, papaverine relaxed noradrenaline (NA), KCl or Ca2+ induced contractions showing similar IC50 values in all cases. S-(+)-boldine had a greater potency on the contraction elicited by NA whereas papaverine acted in a non-selective manner. 3 S-(+)-boldine was found to be an alpha(1)-adrenoceptor blocking agent in guinea-pig aorta as revealed by its competitive antagonism of noradrenaline-induced vasoconstriction (pA(2) = 5.64 +/- 0.08), and its potency was compared with that of prazosin (pA(2) = 8.56 +/- 0.24), a known potent alpha(1)-adrenoceptor antagonist. In contrast, papaverine caused rightward shifts of the NA concentration-response curves with depression of maximal response indicating that it acts as a non-competitive antagonist. 4 Contraction of guinea-pig aorta induced by caffeine (60 mM) in a Ca2+-containing Krebs solution was not affected by a 60 min incubation period with different doses of S-(+)-boldine (1-300 mu M). Papaverine inhibited partially this caffeine-induced contraction at the maximal dose used (100 mu M) 5 Inositol phosphates formation induced by noradrenaline (10 mu M) in guinea-pig thoracic aorta was inhibited by S-(+)-boldine (30 mu M) but not by papaverine (10 mu M). 6 Contractions of guinea-pig trachea caused by acetylcholine (100 mu M) or histamine (10 mu M) were not modified by S-(+)-boldine (0.1-100 mu M). 7 These results provide evidence that S-(+)-boldine, an aporphine alkaloid, has interesting properties as an alpha(1)-adrenoceptor blocker in vascular smooth muscle, and acts as a competitive antagonist of the alpha 1-adrenoceptor present in the guinea pig aorta.