Cocaine synergism with alpha agonists in rat aorta: Computational analysis reveals an action beyond reuptake inhibition

BackgroundCocaine has long been known to increase blood pressure, but the degree and mechanism of vasoconstricting action remain poorly understood. Here we examine the interaction between cocaine and alpha-adrenoceptor agonists, with the action of reuptake inhibition minimized.MethodsCocaine was administered to isolated rings of rat thoracic aorta, alone and in combination with three different adrenoceptor agonists: phenylephrine, methoxamine, and norepinephrine. Synergy analysis begins with the predicted additive effect of the combination of two agonists, based upon dose equivalence theory. This case where one agonist (cocaine) has no effect when administered alone requires only a t-test to demonstrate that a departure from additivity has occurred.ResultsAt doses where cocaine alone produced no vasoconstriction, it potentiated the vasoconstriction produced by all three alpha agonists, a clear indication of synergism between cocaine and these agents. Higher doses of cocaine in combination with alpha adrenoceptor agents gave an inverted-U shaped (hormetic) dose–effect curve, i.e., dose-related relaxation at higher doses. The hormetic dose–effect relation was analyzed using computational methodology based on dose equivalence to derive the unknown second component of action that causes relaxation.ConclusionsCocaine exhibits both vasoconstricting and vasorelaxant effects. This relaxing component, possibly related to activation of myosin light chain phosphatase, was quantified as a dose–effect curve. Most important is the synergism between cocaine and alpha-adrenoceptor stimulation which cannot be explained as an action due to reuptake inhibition, and has not been previously described.