MECHANISM OF THE CARDIOVASCULAR ACTIVITY OF LAUDANOSINE - COMPARISON WITH PAPAVERINE AND OTHER BENZYLISOQUINOLINES

1 The activity of (+/-)-laudanosine, a benzyltetrahydrdisoquinoline al kaloid, was investigated in pithed rats and rat isolated aorta. Its ef fects on [H-3]-prazosin, [H-3]-(+)-cis-diltiazem and [H-3]-nitrendipin e binding to rat cerebral cortical membranes, and on the different mol ecular forms of cyclic nucleotide phosphodiesterases (PDE) isolated fr om bovine aorta were investigated. 2 The dose-response curve to methox amine (3-300 mu g kg(-1), i.v.) in normotensive pithed rats was shifte d to the right by (+/-)-laudanosine, 3 and 6 mg kg(-1). 3 (+/-)-Laudan osine inhibited in a concentration-dependent manner the contractile re sponses evoked by noradrenaline (NA 1 mu M), depolarizing solution (KC l 80 mM) or depolarizing solution plus phentolamine (10 mu M) in rat i solated aorta. The alkaloid appeared to be more potent against NA-indu ced contractions. 4 In Ca2+-free solution, (+)-laudanosine (100 mu M) inhibited the contraction evoked by NA and did not modify the phasic c ontractile response evoked by caffeine. The alkaloid did not modify th e refilling of the intracellular Ca2+-stores sensitive to NA or caffei ne. 5 (+/-)-Laudanosine inhibited [H-3]-prazosin binding to cortical m embranes and also inhibited [H-3]-(+)cis-diltiazem but with a lower po tency. [H-3]-nitrendipine binding was not affected by laudanosine. 6 ( +)-Laudanosine does not have a significant effect on the different for ms of PDEs isolated from bovine aorta. In contrast, compounds structur ally related to this alkaloid such as papaverine and its derivatives, had a non-selective or more specific inhibitory effect on these PDE fo rms. These differences can be explained on the basis of their structur al features: the planarity of the isoquinoline ring (papaverine) facil itates the interaction with receptor sites, and the different position of the benzyl group does not modify the activity unless this position leads to the presence of a chiral centre (laudanosine). 7 These resul ts suggest that (+/-)-laudanosine has a selective activity as an alpha (1)-adrenoceptor blocker. Its lack of action on different PDE forms pr ovides us with information about a group of benzylisoquinolines that w ith small structural changes show a different effect on PDE-forms isol ated from vascular smooth muscle.