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: Prior research points to the importance of psychostimulants in improving self-control. However, the neural substrates underlying such improvement remain unclear. Here, in a pharmacological functional MRI study of the stop signal task, we show that methylphenidate (as compared with placebo) robustly decreased stop signal reaction time (SSRT), an index of improved control, in cocaine-dependent patients (a population in which inhibitory control is impaired). Methylphenidate-induced decreases in SSRT were positively correlated with inhibition-related activation of left middle frontal cortex (MFC) and negatively with activation of the ventromedial prefrontal cortex (vmPFC) in whole brain linear regressions. Inhibition-related MFC but not vmPFC activation distinguished individuals with short and long SSRT in 36 demographically matched healthy individuals, whereas vmPFC but not MFC activation, along with improvement in SSRT, was correlated with a previously implicated biomarker of methylphenidate response (systolic blood pressure). These results implicate a specific neural (i.e., vmPFC) mechanism whereby stimulants improve inhibitory control. Altered ventromedial prefrontal activation and increased blood pressure may represent useful CNS and peripheral biomarkers in individualized treatment with methylphenidate for patients with cocaine dependence.Proceedings of the National Academy of Sciences 08/2010; 107(32):14455-9. · 9.74 Impact Factor
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ABSTRACT: Several drugs can cause hypertension and/or blunt the effect of antihypertensive treatment. They can exacerbate a previously well controlled hypertension and/or render it resistant to therapy. Accordingly, drugs represent a common cause of resistance of hypertension to treatment. Identification of drug-related hypertension can be achieved with a thorough medical history targeted to ascertain concurrent therapies that are prescribed for conditions other than cardiovascular diseases. This can avoid prescribing a more aggressive antihypertensive treatment and may prevent embarking in costly and sometimes invasive diagnostic procedures. Drugs that commonly raise blood pressure include NSAIDs, steroids, oestroprogestinic agents, immunosuppressants, erythropoietin, inhibitors of angiogenesis, anti-HIV agents, and also some high-density lipoprotein-raising agents. As withdrawal of the offending drug is often impracticable, knowledge of the mechanism(s) by which each drug exerts its pressor effects may help selecting the most effective treatment. Purpose of this review is to examine the most common causes of resistant hypertension that are due to drugs or abuse of substances along with their underlying pathophysiological mechanisms. The strategy for selecting the most appropriate treatment and the reasons for 'a call of action' of research in this area are also examined.Journal of hypertension 12/2011; 29(12):2295-309. · 4.02 Impact Factor
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ABSTRACT: Every year more than 500,000 patients present to the emergency department with cocaine-associated complications, most commonly chest pain. Many of these patients undergo extensive work-up and treatment. Much of the evidence regarding cocaine's cardiovascular effects, as well as the current management of cocaine-associated chest pain and acute coronary syndromes, is anecdotally derived and based on studies written more than 2 decades ago that involved only a few patients. Newer studies have brought into question many of the commonly held theories and practices regarding the etiology, diagnosis, and treatment of this common clinical scenario. However, there continues to be a paucity of prospective, randomized trials addressing this topic as it relates to clinical outcomes. We searched PubMed for English-language articles from 1960 to 2011 using the keywords cocaine, chest pain, coronary arteries, myocardial infarction, emergency department, cardiac biomarkers, electrocardiogram, coronary computed tomography, observation unit, β-blockers, benzodiazepines, nitroglycerin, calcium channel blockers, phentolamine, and cardiomyopathy; including various combinations of these terms. We reviewed the abstracts to confirm relevance, and then full articles were extracted. References from extracted articles were also reviewed for relevant articles. In this review, we critically evaluate the limited historical evidence underlying the current teachings on cocaine's cardiovascular effects and management of cocaine-associated chest pain. We aim to update the reader on more recent, albeit small, studies on the emergency department evaluation and clinical and pharmacologic management of cocaine-associated chest pain. Finally, we summarize recent guidelines and review an algorithm based on the current best evidence.Mayo Clinic Proceedings 12/2011; 86(12):1198-207. · 5.79 Impact Factor