IDENTIFICATION, CHARACTERIZATION, AND FUNCTIONAL-ROLE OF PHOSPHODIESTERASE TYPE-IV IN CEREBRAL VESSELS - EFFECTS OF SELECTIVE PHOSPHODIESTERASE INHIBITORS

The role of the phosphodiesterase type IV isozyme (PDE IV) in the regu lation of cerebrovascular tone was investigated in the canine basilar artery in vitro and in vivo. The PDE isozymes extracted from the canin e basilar artery were isolated by diethylaminoethanol (DEAE)-Sepharose affinity chromatography and identified based on sensitivity to isozym e-selective PDE inhibitors. [H-3]cAMP hydrolysis was observed in one m ajor and one minor peak of activity. The predominant peak was inhibite d by the addition of cGMP (25%), siguazodan (26%), rolipram (39%), and the combination of siguazodan and rolipram (95%). Selective PDE IV in hibitors BRL 61063, rolipram, and denbufylline were equieffective inhi bitors of [H-3]ccAMP hydrolysis mediated by PDE IV isolated from the c anine basilar artery [concentrations producing 50% inhibition (IC(50)s ) = 0.21 +/- 0.05 mu M, 0.67 +/- 0.23 mu M, and 0.73 +/- 0.16 mu M, re spectively]. In precontracted isolated ring segments of the canine bas ilar artery, selective PDE IV inhibitors produced potent and complete relaxation (IC(50)s <150 nM). In contrast, zaprinast (a selective PDE V inhibitor) and siguazodan (a selective PDE III inhibitor) produced o nly weak relaxation of the basilar artery (IC(50)s = 4.5 mu M and >10 mu M, respectively). Vasorelaxation produced by PDE IV inhibitors was not altered by removing the endothelium, 1-NAME, or adenosine receptor antagonism. In a canine model of acute cerebral vasospasm, ail three selective PDE IV inhibitors reversed basilar artery spasm-produced by autologous blood without altering mean arterial blood pressure. In con trast, prolonged treatment with BRL 61063 failed to alter the developm ent of basilar spasm in the two hemorrhage canine models of chronic ce rebral vasospasm. Denbufylline-induced relaxation in vitro was also si gnificantly impaired in basilar arteries obtained from the model of ch ronic vasospasm. In conclusion, PDE IV appears to be the predominant i sozyme regulating vascular tone mediated by cAMP hydrolysis in cerebra l vessels. In addition, vasorelaxation modulated by PDE IV is compromi sed in chronic cerebral vasospasm associated with subarachnoid hemorrh age.