Inhibition of Nitric Oxide Synthase Enhances Cocaine's Developmental Toxicity: Vascular and CNS Effects

Abstract

Ischemia and/or reperfusion injury from free radicals may cause cocaine's toxicity, including its effect upon neurobehavioral development. We previously used salicylate to measure hydroxyl free radicals in chick embryos exposed to cocaine. The combination was more toxic than cocaine alone. We postulated that salicylate enhanced the vasoconstriction and toxicity via inhibition of compensatory processes (eg by inhibition of the synthesis of vasodilatory prostanoids and/or nitric oxide). A nontoxic dose of N(G)-nitro-L-arginine methyl ester (L-NAME) was used to inhibit nitric oxide synthase to test this hypothesis. In one experiment, cocaine was injected every 1.5 h (total dose ¼ 67.5 mg/kg egg) on day 15 of development, 1 h after injection of L-NAME (200 mg/kg egg) to determine viability and hatchability, which are measures of toxicity. Another experiment measured diameters of blood vessels after L-NAME injection, followed by NaCl or cocaine infusion (0.23 mg/egg/min; total dose ¼ 67.5 mg/kg egg) at 15 and 5 min afterwards. Lastly, brains of embryos pretreated with L-NAME before cocaine injections were analyzed for nitric oxide synthase activity. Cocaine decreased viability and hatchability. L-NAME enhanced cocaine's effect upon both parameters. Blood vessel diameters were decreased by cocaine after 15 min of infusion. L-NAME + cocaine caused a decrease in vessel diameter as soon as 5 min into the infusion and was greater with time, compared with other groups. Enzyme activity in brains was decreased only in the L-NAME + cocaine group. Thus, inhibition of nitric oxide synthesis interferes with the embryos' capacity to mount a compensatory vasodilatory response. Neuropsychopharmacology (2007) 32, 940-945.

Cardiovascular and Hepatic Toxicity of Cocaine: Potential Beneficial Effects of Modulators of Oxidative Stress

“…Increased number of circulating endothelial cells (CECs) indicating endothelial dysfunction was recently demonstrated in cocaine abusers [ 88 ]. Furthermore, enhancement of cocaine-induced vasoconstriction was observed after N(G)-nitro-L-arginine methyl ester-induced inhibition of NO synthesis in vitro [ 89 ].…”

MicroRNA-423-5p Mediates Cocaine-Induced Smooth Muscle Cell Contraction by Targeting Cacna2d2

“…Despite the frequency of CV complications in individuals using cocaine, few, if any, studies have explored the molecular mechanisms underlying the effects of cocaine on the CV system beyond its sympathomimetic effect. Although some studies implicated intracellular calcium overload 18 , oxidative stress 19,20 , and mitochondrial dysfunction 21,22 in cocaine-induced cardiotoxicity, these mechanisms were all studied in the context of the effects of catecholamines. Micro (mi) RNAs are small non-coding RNAs that post-transcriptionally regulate gene expression by binding to the 3' UTR of target transcripts leading to translational repression and/or mRNA degradation [23][24][25] .…”

MicroRNA-423-5p Mediates Cocaine-Induced Smooth Muscle Cell Contraction by Targeting Cacna2d2

“…This increase in intracellular calcium concentrations ([Ca 2+ ]i) can be mediated through the engagement of β-adrenergic receptors by catecholamines leading to a cascade of events that result in activation of cAMP-dependent protein kinase (PKA), phosphorylation of Ca 2+ channels and Ca 2+ influx [ 18 , 19 ]. Calcium overload [ 20 ] is just one mechanism that was proposed to be responsible for the cocaine-associated CV complications with additional mechanisms, including oxidative stress [ 21 , 22 ] and mitochondrial dysfunction [ 17 , 23 ]. However, all of these processes were studied in the context of catecholamines.…”