Vasoconstriction Caused by Cocaine is Enhanced by Sodium Salicylate: Is Inducible Nitric Oxide Synthase mRNA Related?

Abstract

We have previously found that sodium salicylate (NaSal), injected into chicken eggs at nontoxic doses used for quantifying hydroxyl free radicals in hearts and brains of embryos, caused or exacerbated hemorrhages and dramatically reduced hatchability when combined with cocaine (Coc). It has also been reported that inducible nitric oxide synthase (iNOS) gene expression is altered in brain in response to vascular damage and inflammation. In this study we measured diameters of membrane-bound blood vessels (BV) before and after pretreatment with saline (NaCl) or NaSal (100 mg/kg egg), followed by infusion of either NaCl or Coc HCl (total of 67.5 mg/kg egg) during 15 min. Brains and hearts of the embryos were then analyzed for iNOS messenger RNA (mRNA) concentrations. Coc caused vasoconstriction that was significant 5 min postinfusion (5 min PI) of the entire dose (ie after 67.5 mg/kg egg). Significant vasoconstriction was evident within 5 min in the group injected with NaSal followed by infusion with Coc (ie after 22.5 mg Coc/kg egg). Expression of iNOS mRNA was significantly increased only in the brains of the group exposed to NaSal plus Coc, and the increase was inversely related to BV diameter. These data are discussed in relation to effects of salicylate upon prostanoid synthesis and/or nitric oxide synthesis via iNOS inhibition and their possible relationship to Coc-associated cerebral vascular and/or cardiovascular events in abusing humans.

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

“…Cocaine by itself caused significant vasoconstriction compared to controls (ie NaCl + NaCl) and the L-NAME + NaCl group, but not until 15 min into the infusion and we have previously reported this vasoactive property of cocaine in this model (Mendoza-Baumgart et al, 2004;Schrott et al, 2002;Zhang et al, 1998). In addition, cocaine's vasoconstrictor action has been known for decades.…”

“…A two-factor repeated measures ANOVA and factorial ANOVAs for each of the four times after infusions were started, followed by preplanned contrasts were used for group comparisons, where appropriate. Based on previous studies (Mendoza-Baumgart et al, 2004;Schrott et al, 2002;Zhang et al, 1998), showing the vasoconstrictive effect of cocaine upon the chicks' extraembryonic vasculature, a unidirectional Dunnett's test was used as the preplanned contrast to compare blood vessel diameters of each treated group against the control group. Because of the possibility that the baseline diameters were partially influenced by constitutive synthase activity and nitric oxide production, we also compared vessel diameters in the L-NAME + NaCl group with other groups using the protected least significant difference (PLSD) test.…”

“…Treatment groups (n ¼ 8/group) consisted of: NaCl + NaCl, NaCl + cocaine, L-NAME + NaCl, and L-NAME + cocaine. The procedure and equipment used are described in detail elsewhere (Zhang et al, 1998;Mendoza-Baumgart et al, 2004). Briefly, the eggshell above the aircell was removed and the chorioallantoic membrane was made transparent with a drop of mineral oil so as to visualize, record, and measure the apparent diameter of extraembryonic vitelline blood vessels before, during, and after infusion of NaCl or cocaine in eggs previously injected with NaCl or L-NAME.…”

“…We also reported that salicylate, in combination with cocaine, can exacerbate cocaine's toxic effect upon younger (ie E12) chicken embryos, manifest as hemorrhages and reduced hatchability in the presence of hydroxyl free radicals . Recently, we demonstrated that salicylate enhanced the vasoconstrictive effect of cocaine and that the degree of vasoconstriction was inversely related to embryonic brain-inducible nitric oxide synthase mRNA concentration (Mendoza-Baumgart et al, 2004). We hypothesized that this enhanced vascular and other toxic effects of cocaine by salicylate was owing to the blockade of compensatory mechanisms, such as production of prostacylin and/or nitric oxide, which are both powerful vasodilators (Shimokawa et al, 1988;Vane and Botting, 1998;Ignarro, 2002).…”

The role of the NADPH oxidase derived brain oxidative stress in the cocaine-related death associated with excited delirium: A literature review

“…Increased expression of HSP70 gene in the brain -Response to hyperthermia (>39 C) and ischemic stimuli -Cytoprotection and cellular assembly -Rapid response to altered redox state -Redox status dependent regulatory activity on several organs -Biomaker for the identification of excited delirium as cause of death -Biomarker of post-drug survival time and/or interventions by medical and law enforcement personnel -Biomarker of an adaptive response to limit cocaine-induced ischemic neurotoxicity (Mash et al, 2009;Riezzo et al, 2010;Lind et al, 2005;Johnson et al, 2012;Kubo et al, 1998;Xiao et al, 2002;Chen et al, 2011) Increased expression of HSP90 gene in the brain (Ang and Tergaonkar, 2007;Dello Russo et al, 2009;Yao et al, 2010;Block et al, 2007) Decreased NF-kB activity in the frontal cortex -Altered behaviour in cocaine-treated rats -Reduced GSH concentration in hippocampus -Reduced glutathione peroxidase activity in hippocampus -Impairement of memory retrieval of experiences acquired prior to cocaine administration (Muriach et al, 2010) Increased nitrotyrosine expression -Role in oxidative myocardial damage in human cocainerelated cardiomyopathy -Role in MDMA-induced neurotoxicity -Protein nitrosylation mediated directly by NADPH oxidase via activation of specific p38 and ERK1/2 (Xiao et al, 2005;Tanabe et al, 2012;Darwish et al, 2007;Frustaci et al, 2015;James et al, 2003;Sautin et al, 2007) Increased i-NOS expression and functioning -Development of neuropathological alterations in rodent models of neurological disorders -Development of neuropathological alterations in cocaineabuse -Role in the cocaine-induced locomotor sensitization and kindling -Synergistic effect with activated microglia NADPH oxidase in inducing neuronal death -Synergistic effect with NADPH oxidase-dependent redox signalling in microvascular endothelial cells (Chang et al, 2002;Torreilles et al, 1999;Emerit et al, 2004;Hald and Lotharius, 2005;Mendoza-Baumgart et al, 2004;Portugal-Cohen et al, 2010;Park et al, 2001;Mander and Brown, 2005;…”