ENDOTHELIUM-DEPENDENT RELAXATION OF RAT AORTA BY BUTEIN, A NOVEL CYCLIC AMP-SPECIFIC PHOSPHODIESTERASE INHIBITOR

Butein, isolated from Dalbergia odorifera T. Chen, caused endothelium- dependent relaxation of rat aorta precontracted with phenylephrine. Th is effect was abolished in endothelium-denuded aorta and in endotheliu m-intact aorta in the presence of N-G-monomethyl-L-arginine, oxyhemogl obin and methylene blue, whereas the effect was unaltered by indometha cin or charybdotoxin, These results indicate that the vasorelaxant eff ect of butein depended on the endothelium and was mediated by endothel ium-derived relaxing factor (EDRF). Incubation of endothelium-intact a orta with butein increased not only cAMP but also cGMP content. Four p hosphodiesterase forms were isolated by diethylaminoethyl (DEAE)-Sepha cel chromatography from rat aorta. cAMP-specific phosphodiesterase (ty pe IV) activity was potently inhibited by butein with an IC50 of 10.4 +/- 0.4 mu M. In contrast, phosphodiesterase I, III and V activities w ere inhibited by butein above 100 mu M. Adenylate cyclase and guanylat e cyclase activities were unchanged by butein. These results suggest t hat the increase of cAMP formation elicited by butein is due to the in hibition of cAMP-specific phosphodiesterase. The specific phosphodiest erase IV inhibitor (rolipram) and V inhibitor (zaprinast) both produce d endothelium-dependent relaxations, whereas the phosphodiesterase III inhibitor (trequinsin) produced relaxation of rat aorta independent o f the endothelium. In the presence of a functional endothelium, relaxa tions produced by butein were significantly potentiated by isoprenalin e, forskolin, trequinsin and sodium nitroprusside. It is concluded tha t butein, a novel cAMP-specific phosphodiesterase inhibitor, produced relaxation of rat aorta, an effect dependent on an intact endothelium. The relaxant effect of butein was markedly enhanced by cGMP-elevating agents. These results indicated that cGMP enhances cAMP-mediated rela xation possibly through the inhibition of the cGMP-inhibited cAMP phos phodiesterase.