Structural image of catecholamines and drugs of abuse known to contribute to cardiac oxidative stress. 

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... are well recognized regulators of cardiac function but may also elicit cardiotoxic effects. Noradrenaline, adrenaline, and dopamine are biogenic catecholamines derived from the amino acid tyrosine 50 ( Figure 1). Isoproterenol is usually used as a synthetic model for catecholamine toxicity since it has a biogenic amine-like structure and is a β-agonist. ...

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... of Abuse. Amphetamines and cocaine (Figure 1) are cardiotoxicants, as reported by human studies and case reports. The most obvious mechanism for their cardiac toxicity is related to their ability to activate the catecholaminergic system in the central nervous system (CNS) and peripheral organs. ...

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... Catecholamines. Catecholamines are the foremost and probably oldest studied molecules for their cardiac actions. They are well recognized regulators of cardiac function but may also elicit cardiotoxic effects. Noradrenaline, adrenaline, and dopamine are biogenic catecholamines derived from the amino acid tyrosine 50 ( Figure 1). Isoproterenol is usually used as a synthetic model for catecholamine toxicity since it has a biogenic amine-like structure and is a β-agonist. Catecholamine-induced necrosis and fibrosis in the myocardium of human patients was described as early as 1937 in a case of adrenaline misuse in asthma treatment. 1 Also, noradrenaline has been reported to be fatal, namely, after its prolonged infusion for treatment of shock, where focal myocarditis with degeneration of myofibrils and infiltration of leucocytes were observed. 51 Pheochromocytoma patients show similar lesions in the heart, attributed to the high levels of circulating catecholamines. 52 Furthermore, the levels of circulating catecholamines have been described to be high in septic shock. 53 Several pathways are activated after catecholamine stimula- tion that can lead to cardiac toxicity. One of these mechanisms is oxidative stress, although others can be equally or more relevant depending on the situation. Catecholamine-induced oxidative stress has been confirmed in both in vitro and in vivo models. Exposure to catecholamines resulted in increased lipid peroxidation 54,55 and GSSG formation, 17,56,57 and the injury caused by catecholamine exposure was reversed or attenuated by antioxidants. 54,55,58 Malondialdehyde-associated modification of proteins increased in catecholamine-perfused hearts. 59 Dhalla and co-workers found that vitamin E prevented the transition from compensated hypertrophy to failure in guinea pigs with pressure-overload due to aortic constriction caused by catechol- amines. 60 Similarly, dimethylthiourea, a HO • scavenger, prevented chamber dilation and pump dysfunction in infarcted mouse heart. 61 Neri and co-workers showed in the rat heart that the GSH/GSSG ratio significantly decreased and malondialde- hyde levels increased after noradrenaline administration, showing an oxidative stress state of lipid peroxidation in the cardiac tissue, which was not reverted by propranolol (β- antagonist) or prazosin (α 1 -antagonist). 62 The sources of ROS formed upon catecholamine stimulation are most likely multifactorial, as they can result from adrenoceptor stimulation and/or from the enzymatic and nonenzymatic degradation of catecholamines. 1 The activation of α 1 -adrenoceptors, coupled with G-protein G q , triggers NADPH oxidase activity in cardiomyocytes, thus resulting in O ...

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... toxicity of catecholamines and their ability to generate oxidative stress are unquestionable in spite of the multiple mechanisms proposed and the still ongoing discussion regarding the most relevant mechanism. 1,54,94−96 For a wide comprehen- sive review regarding the contribution of the oxidation products of catecholamines and heart pathology, see Costa et al. 1 2.2. Drugs of Abuse. Amphetamines and cocaine (Figure 1) are cardiotoxicants, as reported by human studies and case reports. The most obvious mechanism for their cardiac toxicity is related to their ability to activate the catecholaminergic system in the central nervous system (CNS) and peripheral organs. This catecholaminergic activation leads to the direct lesion of the heart or coronary system as referred in the last section reporting to catecholamines. However, several studies have proven that the direct action of amphetamines and/or their metabolites can trigger cardiotoxicity unrelated to catecholamine release (for a wide review of amphetamines toxicity to target organs, please see Carvalho et al.). 97 2.2.1. Methamphetamine and Amphetamine. Metham- phetamine is easily available on the streets, and most of its clinical complications are related to heart or CNS injuries. Mechanis- tically, amphetamines mainly act on the CNS causing the release of monoamine neurotransmitters, including dopamine, nora- drenaline, and serotonin. 98 In fact, autopsies of deaths attributed to methamphetamine use have shown contraction band necrosis in the myocardium that are clinical signs of catecholamine toxicity, thus corroborating the involvement of biogenic amines on its cardiotoxicity. 99,100 Methamphetamine is well-known to elicit rapid tachycardia in humans that persists for several hours 101,102 with increased systolic and diastolic blood pressures. Cerebral stroke, hemorrhage, and arrhythmias have also been reported to be associated with methamphetamine abuse. 103,104 Postmortem studies on cardiac tissue show that methamphet- amine causes myocardial infarction, cardiomyopathy, and ventricular hypertrophy. 100,105−109 Methamphetamine-elicited oxidative damage in the heart has been studied in animal models but data are still scarce. In rats subjected to four methamphetamine binges [3 mg/kg, intra- venous (i.v.) for 4 days, separated by a 10-day drug-free period], cardiac oxidative stress was detected. 110 Dihydroethedium staining showed that methamphetamine significantly increased the levels of ROS in the left ventricle. Treatment with the SOD mimetic, tempol (2.5 mM), in the drinking water prevented methamphetamine-induced left ventricular dilation and systolic dysfunction. Also, tempol significantly reduced but did not eliminate dihydroethedium staining in the left ventricle. Moreover, tempol did not prevent the diastolic dysfunction. 110 Methamphetamine-induced oxidative damage might be related to the high levels of catecholamines as the result of its interaction with neurotransmitter transporters and the enzymatic degrada- tion system of catecholamines. 97 Another important factor that may contribute to methamphetamine-induced oxidative stress in the heart is inflammation. 99 The heart of rats treated with a methamphetamine binge regimen showed focal inflammatory infiltrates with abundant monocytes and occasional necrotic foci. 111 Inflammatory processes per se lead to the formation of ROS during the "oxidative burst". 112 In summary, mitochondrial dysfunction, the oxidative and nitrosative stress (evaluated by tyrosine nitration), 110 and inflammation 99,111 caused by the methamphetamine-induced catecholamine surge are crucial for the impairment of cardiac function, and it may extend well beyond the acute pharmacodynamic effects of methamphetamine, representing an underlying and potentially progressive degenerative ...