Mechanism of the blood pressure--raising effect of cocaine in humans.
ABSTRACT Although the sympathomimetic actions and cardiovascular complications of cocaine are ascribed to inhibition of norepinephrine (NE) reuptake, this hypothesis has not been tested in humans. We asked (a) whether cocaine can inhibit NE reuptake in the human peripheral circulation and (b) whether the NE-mediated peripheral vasoconstriction is the main mechanism mediating blood pressure-raising effect of cocaine.
In 15 healthy cocaine-naive subjects, we measured blood pressure, forearm blood flow, and forearm venous NE concentration during administration of (a) intrabrachial cocaine (0.15 and 15 mg), which produced no systemic neurohormonal effects, and (b) intranasal cocaine (2 mg/kg). Intrabrachial cocaine (0.15 mg) increased venous forearm NE concentration by 82% and vascular resistance by 71% (P<0.01). Increasing the intrabrachial cocaine dose by 100-fold to match the venous cocaine level of massive cocaine overdose caused a small additional increase in venous forearm NE concentration without causing significant additional vasoconstriction. Although intranasal cocaine (2 mg/kg) matched the venous cocaine concentrations caused by 0.15 mg of intrabrachial cocaine, venous NE concentration was unchanged as sympathetic nerve activity (SNA) decreased reflexively as the result of an increase in blood pressure. When SNA was restored to baseline by blunting the cocaine-induced rise in blood pressure (baroreflex activation) with nitroprusside, venous NE concentration increased to the same level caused by intrabrachial cocaine.
In healthy cocaine-naive individuals, cocaine can inhibit NE reuptake in the human peripheral circulation. However, this mechanism does not contribute importantly to the blood pressure-raising effect of cocaine because activation of baroreceptor reflexes decreases SNA, the neural stimulus for NE release.
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ABSTRACT: Many previous studies suggest the potential of psychostimulants in improving cognitive functioning. Our earlier pharmacological brain imaging study showed that intravenous methylphenidate (MPH) improves inhibitory control by altering cortico-striato-thalamic activations in cocaine-dependent (CD) individuals. Here we provide additional evidence for the effects of MPH in restoring cerebral activations during cognitive performance. Ten CD individuals performed a stop signal task (SST) during functional magnetic resonance imaging (fMRI) in two sessions, in which either MPH (0.5mg/kg body weight) or saline was administered intravenously. In the SST, a frequent go signal instructs participants to make a speeded response and a less frequent stop signal instructs them to withhold the response. Our previous work described increased activation of the precuneus/posterior cingulate cortex and ventromedial prefrontal cortex-regions of the default mode network (DMN)-before participants committed a stop error in healthy control but not CD individuals (Bednarski et al., 2011). The current results showed that, compared to saline, MPH restored error-preceding activations of DMN regions in CD individuals. The extent of the changes in precuneus activity was correlated with MPH-elicited increase in systolic blood pressure. These findings suggest that the influence of MPH on cerebral activations may extend beyond cognitive control and provide additional evidence warranting future studies to investigate the neural mechanisms and physiological markers of the efficacy of agonist therapy in cocaine dependence.Psychiatry research. 08/2013;
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ABSTRACT: Cocaine is a major cause of acute coronary syndrome (ACS), especially in young adults; however, the mechanistic underpinning of cocaine-induced ACS remains limited. Previous studies in animals and in patients undergoing cardiac catheterization suggest that cocaine constricts coronary microvessels, yet direct evidence is lacking. We used myocardial contrast echocardiography (MCE) to test the hypothesis that cocaine causes vasoconstriction in the human coronary microcirculation. Measurements were performed at baseline and after a low non-intoxicating dose of intranasal cocaine (2 mg/kg) in 10 healthy cocaine-naïve young men (median age 32 years). Post-destruction time-intensity MCE kinetic data were fit to the equation: y = A(1-e(-βt)) to quantify functional capillary blood volume (A), microvascular flow velocity (β), and myocardial perfusion (A x β). Heart rate (HR), mean arterial pressure (MAP), and LV work (two-dimensional echocardiography) were measured before and 45 minutes after cocaine. Cocaine increased MAP (+14±2 mmHg; mean ± SE), HR (+8±3 beats/min), and LV work (+50±18 mmHg•mL(-1)•bpm(-1)). Despite increasing these determinants of myocardial oxygen demand, myocardial perfusion decreased by 30% (103.7±9.8 to 75.9±10.8 a.u/s, p<0.01) due mainly to decreased capillary blood volume (133.9±5.1 to 111.7±7.7 a.u., p<.05) with no significant change in microvascular flow velocity (0.8±0.1 to 0.7±0.1 a.u.). In healthy cocaine-naïve young adults, a low-dose cocaine challenge evokes a sizeable decrease in myocardial perfusion. Moreover, the predominant effect is to decrease myocardial capillary blood volume rather than microvascular flow velocity, suggesting a specific action of cocaine to constrict terminal feed arteries.Circulation 06/2013; · 14.95 Impact Factor
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ABSTRACT: During cocaine-induced hepatotoxicity, lipid accumulation occurs prior to necrotic cell death in the liver. However, the exact influences of cocaine on the homeostasis of lipid metabolism remain largely unknown. In this study, the progression of subacute hepatotoxicity, including centrilobular necrosis in the liver and elevation of transaminase activity in serum, was observed in a three-day cocaine treatment, accompanying the disruption of triacylglycerol (TAG) turnover. Serum TAG level increased on day 1 of cocaine treatment but remained unchanged afterwards. In contrast, hepatic TAG level was elevated continuously during three days of cocaine treatment and was better correlated with the development of hepatotoxicity. Lipidomic analyses of serum and liver samples revealed time-dependent separation of the control and cocaine-treated mice in multivariate models, which was due to the accumulation of long-chain acylcarnitines together with the disturbances of many bioactive phospholipid species in the cocaine-treated mice. An in vitro function assay confirmed the progressive inhibition of mitochondrial fatty acid oxidation after the cocaine treatment. Cotreatment of fenofibrate significantly increased the expression of peroxisome proliferator-activated receptor α (PPARα)-targeted genes and the mitochondrial fatty acid oxidation activity in the cocaine-treated mice, resulting in the inhibition of cocaine-induced acylcarnitine accumulation and other hepatotoxic effects. Overall, the results from this lipidomics-guided study revealed that the inhibition of fatty acid oxidation plays an important role in cocaine-induced liver injury.The Journal of Lipid Research 08/2012; 53(11):2318-30. · 4.73 Impact Factor