PHARMACOKINETIC ALPHA(1)-ADRENOCEPTOR ANTAGONISTIC PROPERTIES OF 2 CYANINE-TYPE INHIBITORS OF EXTRANEURONAL MONOAMINE TRANSPORT

1,1'-Diethyl-2,2'-cyanine (decynium22) and 1,1'-diisopropyl-2,4'-cyani ne (disprocynium24) are highly potent inhibitors of the extraneuronal monoamine transporter. When given as i.v. bolus injections (4 mu mol k g(-1)) to anaesthetized rabbits, both drugs elicited a transient fall in blood pressure without altering heart rate. The observed maximum fa ll 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-liv es for elimination (8.2 and 4.5 min, respectively) and very high plasm a clearances (173 and 180 ml kg(-1) min(-1), respectively). The mechan ism underlying the blood pressure-lowering effect of decynium22 was ex plored in the isolated incubated rabbit aorta. Decynium22 antagonized the noradrenaline-induced contraction; the pA(2) for this interaction was 7.6, and the slope of the corresponding Schild plot was unity. Zn a membrane preparation from rat myocardium, decynium22 as well as disp rocynium24 inhibited the specific binding of -hydroxy-3-iodophenyl)-et hylaminomethyl]-tetralone (I-125-HEAT), a selective ligand to alpha(1) -adrenoceptors. The K-i's were 5.3 and 240 nmol l(-1) for decynium22 a nd disprocynium24, respectively. The type of binding inhibition by dec ynium22 was competitive. It is concluded that the two inhibitors of ex traneuronal monoamine transport decynium22 and disprocynium24 lower bl ood 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 f or studies designed to determine the role of extraneuronal monoamine t ransport in vivo. Considering its very fast elimination kinetics, disp rocynium24 must be administered by constant rate-infusions in order to avoid large fluctuations of plasma levels.