Involvement of monoamine uptake inhibition and local anesthesia in the cardiovascular response to cocaine in conscious rabbits.

The cardiovascular effect of cocaine in rabbits was examined for peripheral and central components and for the contribution of the primary actions of cocaine, i.e., inhibition of the high affinity uptake mechanisms for monoamines and local anesthesia. In pithed rabbits with electrically stimulated sympathetic outflow (2 Hz), cocaine (0.2-5 mg kg-1) lowered the clearance of [3H]norepinephrine from plasma and increased the plasma norepinephrine concentration. Cocaine (0.2 and 1 mg kg-1) increased blood pressure and heart rate, whereas after 5 mg kg-1 heart rate and blood pressure decreased briefly and then recovered. In conscious rabbits, cocaine (0.2 and 1 mg kg-1) reduced renal sympathetic nerve activity and tended to reduce blood pressure and heart rate. Cocaine (5 mg kg-1) increased sympathetic nerve activity, blood pressure and the plasma norepinephrine and epinephrine concentrations. The effects of the lower doses were abolished in animals pretreated with oxaprotiline, but were not changed in animals pretreated with fluvoxamine or SCH 23390 (R-(+)-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol) + sulpiride. The effects of cocaine (5 mg kg-1) were attenuated by SCH 23390 + sulpiride but were not changed after oxaprotiline or fluvoxamine. Procaine (15 mg kg-1) mimicked the effects of cocaine (5 mg kg-1) on blood pressure and renal sympathetic nerve activity. Blood pressure also was increased by lidocaine (6 mg kg-1). It is concluded that cocaine enhances peripheral sympathetic neuro-effector transmission. In conscious rabbits, however, low doses fail to raise blood pressure because they simultaneously depress central sympathetic tone by blockade of the uptake of norepinephrine in the central nervous system. High cocaine doses cause sympathoexcitation in conscious rabbits. The mechanism seems to be dual: blockade of dopamine uptake in the central nervous system and a (peripheral or central) local anesthetic action.