Mechanism of the cardiovascular activity of laudanosine: comparison with papaverine and other benzylisoquinolines

1. The activity of (+/-)-laudanosine, a benzyltetrahydroisoquinoline alkaloid, was investigated in pithed rats and rat isolated aorta. Its effects on [3H]-(+)-cis-diltiazem and [3H]-nitrendipine binding to rat cerebral cortical membranes, and on the different molecular forms of cyclic nucleotide phosphodiesterases (PDE) isolated from bovine aorta were investigated. 2. The dose-response curve to methoxamine (3-300 micrograms kg-1, i.v.) in normotensive pithed rats was shifted to the right by (+/-)-laudanosine, 3 and 6 mg kg-1. 3. (+/-)-Laudanosine inhibited in a concentration-dependent manner the contractile responses evoked by noradrenaline (NA 1 microM), depolarizing solution (KCl 80 mM) or depolarizing solution plus phentolamine (10 microM) in rat isolated aorta. The alkaloid appeared to be more potent against NA-induced contractions. 4. In CA(2+)-free solution, (+/-)-laudanosine (100 microM) inhibited the contraction evoked by NA and did not modify the phasic contractile response evoked by caffeine. The alkaloid did not modify the refilling of the intracellular CA(2+)-sotres sensitive to NA or caffeine. 5. (+/-)-Laudanosine inhibited [3H]-prazosin binding to cortical membranes and also inhibited [3H]-(+)-cis-diltiazem but with a lower potency. [3H]-nitrendipine binding was not affected by laudanosine. 6. (+/-)-Laudanosine does not have a significant effect on the different forms of PDEs isolated from bovine aorta. In contrast, compounds structurally related to this alkaloid such as papaverine and its derivatives, had a non-selective or more specific inhibitory effect on these PDE forms. These differences can be explained on the basis of their structural features: the planarity of the isoquinoline ring(papaverine) facilitates 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 results suggest that (+/-)-laudanosine has a selective activity as an alpha1-adrenoceptor blocker. Its lack of action on different PDE forms provides us with information about a group of benzylisoquinolines that with small structural changes show a different effect on PDE-forms isolated from vascular smooth muscle.