Pharmacokinetic and alpha 1-adrenoceptor antagonistic properties of two cyanine-type inhibitors of extraneuronal monoamine transport.

ABSTRACT

1,1'-Diethyl-2,2'-cyanine (decynium22) and 1,1'-diisopropyl-2,4'-cyanine (disprocynium24) are highly potent inhibitors of the extraneuronal monamine transporter. When given as i.v. bolus injections (4 mumol kg-1) to anaesthetized rabbits, both drugs elicited a transient fall in blood pressure without altering heart rate. The observed maximum fall in diastolic blood pressure was 59% after decynium22 and 43% after disprocynium24 administration. The pharmacokinetics of decynium22 and disprocynium24 were similar; they were characterized by short half-lives for elimination (8.2 and 4.5 min, respectively) and very high plasma clearances (173 and 180 ml kg-1 min-1, respectively). The mechanism underlying the blood pressure-lowering effect of decynium22 was explored in the isolated incubated rabbit aorta. Decynium22 antagonized the noradrenaline-induced contraction; the pA2 for this interaction was 7.6, and the slope of the corresponding Schild plot was unity. In a membrane preparation from rat myocardium, decynium22 as well as disprocynium24 inhibited the specific binding of [125I]-2-[beta-(4-hydroxy-3-iodophenyl)-ethylaminomethyl]- tetralone (125I-HEAT), a selective ligand to alpha 1-adrenoceptors. The Ki's were 5.3 and 240 mumol l-1 for decynium22 and disprocynium24, respectively. The type of binding inhibition by decynium22 was competitive. It is concluded that the two inhibitors of extraneuronal monoamine transport decynium22 and disprocynium24 lower blood pressure by blocking alpha 1-adrenoceptors. A comparison of their potencies in blocking extraneuronal monoamine transport and alpha 1-adrenoceptors clearly indicates that disprocynium24 is more suitable for studies designed to determine the role of extraneuronal monoamine transport in vivo. Considering its very fast elimination kinetics, disprocynium24 must be administered by constant rate-infusions in order to avoid large fluctuations of plasma levels.