Cardiovascular Effects of Dopamine and Some Methylated and Fluorinated Derivatives in Pithed Normotensive Rats

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Abstract
The cardiovascular effects of dopamine, (R)-.alpha.-methyldopamine, (S)-.alpha.-methyldopamine, (R)-.alpha.-fluoromethyldopamine, (R,S)-.alpha.-difluoromethyldopamine and (R)-.alpha.-fluoromethyltryamine were characterized in the pithed normotensive rat. The activity on .alpha.1-adrenoceptors in the resistance vessels of the pithed rat was identified by prazosin antagonism, on .alpha.2-adrenoceptors by rauwolscine antagonism, on .beta.1-adrenoceptors by chronotropic effects sensitive to atenolol antagonism and on vascular .beta.2-adrenoceptors by potentiation of pressor responses by ICI 118,551 [erythro-DL-1-(7-methylindan-4-yloxy)-3-isopropylamino-butan-2-ol]. Indirect sympathomimetic effects were studied by reserpine pretreatment and the influence of neuronal uptake by the effect of cocaine on the chronotropic effects of the agents. The .alpha.-methyl substitution induces pronounced .beta.2-agonistic properties especially for the (S)-enantiomer, which also displays some selectivity for .alpha.2-adrenoceptors. This selectivity is diminished by the substitution of 1 fluorine atom in the methyl group. The introduction of 2 fluorine atoms leads to a reduction in potency on all adrenoceptors studied.