Cardiovascular diseases are a leading cause of morbidity and mortality in most developed countries of the world. Pharmaceuticals, illicit drugs, and toxins can significantly contribute to the overall cardiovascular burden and thus deserve attention. The present article is a systematic overview of drugs that may induce distinct cardiovascular toxicity. The compounds are classified into agents that have significant effects on the heart, blood vessels, or both. The mechanism(s) of toxic action are discussed and treatment modalities are briefly mentioned in relevant cases. Due to the large number of clinically relevant compounds discussed, this article could be of interest to a broad audience including pharmacologists and toxicologists, pharmacists, physicians, and medicinal chemists. Particular emphasis is given to clinically relevant topics including the cardiovascular toxicity of illicit sympathomimetic drugs (e.g., cocaine, amphetamines, cathinones), drugs that prolong the QT interval, antidysrhythmic drugs, digoxin and other cardioactive steroids, beta‐blockers, calcium channel blockers, female hormones, nonsteroidal anti‐inflammatory, and anticancer compounds encompassing anthracyclines and novel targeted therapy interfering with the HER2 or the vascular endothelial growth factor pathway.

Background Little is known about the impact of type 2 diabetes mellitus (DM) on coronary arteriole remodeling. The aim of this study was to determine the mechanisms that underlie coronary arteriole structural remodeling in type 2 diabetic (db/db) mice. Methods and Results Passive structural properties of septal coronary arterioles isolated from 12- and 16-wk-old diabetic db/db and control mice were assessed by pressure myography. Coronary arterioles from 12-wk-old db/db mice were structurally similar to age-matched controls. By 16-wks of age, coronary wall thickness was increased in db/db arterioles (p < 0.01), while luminal diameter was reduced (Control: 118±5μm; db/db: 102±4μm, p < 0.05), augmenting the wall-to-lumen ratio by 58% (Control: 5.9±0.6; db/db: 9.5±0.4, p < 0.001). Inward hypertrophic remodeling was accompanied by a 56% decrease in elastic modulus (p < 0.05, indicating decreased vessel coronary wall stiffness) and a ~30% reduction in coronary flow reserve in diabetic mice. Interestingly, aortic pulse wave velocity and femoral artery incremental modulus were increased (p < 0.05) in db/db mice, indicating macrovascular stiffness. Molecular tissue analysis revealed increased elastin-to-collagen ratio in diabetic coronaries when compared to control and a decrease in the same ratio in the diabetic aortas. Conclusions These data show that coronary arterioles isolated from type 2 diabetic mice undergo inward hypertrophic remodeling associated with decreased stiffness and increased elastin-to-collagen ratio which results in a decreased coronary flow reserve. This study suggests that coronary microvessels undergo a different pattern of remodeling from macrovessels in type 2 DM.

D9 -Tetrahydrocannabinol (D 9 -THC), the primary psychoactive component in marijuana, is FDA approved to ameliorate AIDS-associated wasting. Because cannabinoid receptors are expressed on cells of the immune system, chronic D 9 -THC use may impact HIV disease progression. We examined the impact of chronic D 9-THC administration (0.32 mg/kg im, 2Âdaily), starting 28 days prior to inoculation with simian immunodeficiency virus (SIV mac251 ; 100 TCID 50 /ml, iv), on immune and metabolic indicators of disease during the initial 6 month asymptomatic phase of infection in rhesus macaques. SIV mac251 inoculation resulted in measurable viral load, decreased lymphocyte CD4 þ /CD8 þ ratio, and increased CD8 þ proliferation. D 9 -THC treatment of SIV-infected animals produced minor to no effects in these parameters. However, chronic D 9 -THC administration decreased early mortality from SIV infection ( p ¼ 0.039), and this was associated with attenuation of plasma and CSF viral load and retention of body mass ( p ¼ NS). In vitro, D 9 -THC (10 mm) decreased SIV (10 TCID 50 ) viral replication in MT4-R5 cells. These results indicate that chronic D 9 -THC does not increase viral load or aggravate morbidity and may actually ameliorate SIV disease progression. We speculate that reduced levels of SIV, retention of body mass, and attenuation of inflammation are likely mechanisms for D 9 -THC-mediated modulation of disease progression that warrant further study.T he cannabinoids including cannabidiol, cannabinol, and D 9 -tetrahydrocannabinol (D 9 -THC) exert their effects by binding to two major subtypes of cannabinoid receptor, CB1 and CB2.1 The CB1 receptor is preferentially expressed in the brain where it mediates neurobehavioral effects. The CB2 receptor is expressed primarily in peripheral tissues, particularly in immune cells where they have been shown to affect cytokine production, lymphocyte phenotype, function and survival, cell-mediated immunity, and balance of Th1/ Th2 cells.2 With the advent of highly active antiretroviral therapy (HAART), human immunodeficiency virus (HIV) infection has become a chronic disease frequently coexisting with chronic use of drugs of abuse, including marijuana. Using a well-established nonhuman primate model of HIV disease, we examined the impact of chronic intramuscular D 9 -THC (provided by the National Institute on Drug Abuse, Research Technical Branch, Rockville, MD) administration on the early phase of simian immunodeficiency virus (SIV) infection in age-matched (4-6 years old) and body weight-matched healthy male Indian-derived rhesus macaques. Chronic administration of D 9 -THC [or 0.05 ml/kg vehicle (VEH)] was initiated prior to SIV with 0.18 mg/kg, a dose that eliminated responding in a complex operant behavioral task in almost all of the subjects. The dose was subsequently increased for each subject to 0.32 mg/kg, over

A large body of evidence indicates that the central nervous system plays an essential role in the pathogenesis of hypertension. However, in many cases the specific brain regions involved and the mechanisms by which these regions promote hypertension are not known. In recent years, research in this and other laboratories has attempted to determine the mechanisms by which neural and humoral signals arising in response to pathological conditions (often occurring in the periphery) interact with the central nervous system to produce hypertension. In this article, we illustrate the coupling of peripheral and central factors in the pathogenesis of hypertension by examining the central actions of angiotensin II and mineralocorticoids in the expression of renal hypertension and mineralocorticoid-salt hypertension, respectively. We also review recent data from this laboratory illustrating the involvement of medullary vasomotor centers in the development of neurogenic hypertension after sinoaortic deafferentation and in the maintenance of hypertension in the spontaneously hypertensive rat.

Particular matter (PM) is emitted during thermal decomposition of waste. During this process, aromatic compounds chemisorb to the surface of metal-oxide-containing PM, forming a surface-stabilized environmentally persistent free radical (EPFR). We hypothesized that EPFR-containing PM redox cycle to produce ROS and that this redox cycle is maintained in biological environments. To test our hypothesis, we incubated model EPFRs with the fluorescent probe dihydrorhodamine (DHR). Marked increases in DHR fluorescence were observed. Using a more specific assay, hydroxyl radicals (•OH) were also detected, and their level was further increased by co-treatment with thiols or ascorbic acid (AA), known components of epithelial lining fluid. Next, we incubated our model EPFR in bronchoalveolar lavage fluid (BALF) or serum. Detection of EPFRs and •OH verified that PM generate ROS in biological fluids. Moreover, incubation of pulmonary epithelial cells with EPFR-containing PM increased •OH levels compared to PM lacking EPFRs. Finally, measurements of oxidant injury in neonatal rats exposed to EPFRs by inhalation suggested that EPFRs induce an oxidant injury within lung lining fluid and that the lung responds by increasing antioxidant levels. In summary, our EPFR-containing PM redox cycle to produce ROS, and these ROS are maintained in biological fluids and environments. Moreover, these ROS may modulate toxic responses of PM in biological tissues such as the lung.

Methamphetamine (METH) abuse is often characterized by a repeated pattern of frequent drug administrations (binge) followed by a period of abstinence. The effect of this pattern of METH use on cardiovascular function has not been characterized. Radiotelemetry was used to record the cardiovascular responses elicited during three successive METH binges (3 mg/kg, b.i.d. for 4 days) in conscious rats. Each binge was followed by a 10-day METH-free period. The effects of METH administration on vascular reactivity, Bezold-Jarisch reflex function, and cardiac morphology were also evaluated. The pressor responses elicited by the first three doses of METH in the second and third binges were significantly larger than those elicited by the corresponding doses in the first binge. The heart rate (HR) responses elicited by METH were similar within and among the three binges. Ten days after the last binge, the depressor responses elicited by the i.v. injection of sodium nitroprusside, isoproterenol, and acetylcholine were significantly smaller than those elicited before each binge. The arterial pressure and HR responses elicited by phenylephrine were unchanged. Bezold-Jarisch reflex function evoked by i.v. serotonin (10 g/kg) was significantly altered. The hearts from treated rats showed focal inflammatory infiltrates with abundant monocytes and occasional necrotic foci. These results indicate that this binge pattern of METH administration can significantly alter cardiovascular function and cardiovascular reflex function and produce serious cardiac pathology.

Activator of G protein signaling (AGS)-3 plays functional roles in cell division, synaptic plasticity, addictive behavior, and neuronal development. As part of a broad effort to define the extent of functional diversity of AGS3-regulated-events in vivo, we generated AGS3 null mice. Surprisingly, AGS3 null adult mice exhibited unexpected alterations in cardiovascular and metabolic functions without any obvious changes in motor skills, basic behavioral traits, and brain morphology. AGS3 null mice exhibited a lean phenotype, reduced fat mass, and increased nocturnal energy expenditure. AGS3 null mice also exhibited altered blood pressure control mechanisms. These studies expand the functional repertoire for AGS3 and other G protein regulatory proteins providing unexpected mechanisms by which G protein systems may be targeted to influence obesity and cardiovascular function.

This study identifies a novel endogenous pathway by which the renal nerves participate in the degradation of cardioprotective NP. Furthermore, removal of the influence of the renal nerves on kidney function attenuates renal neprilysin activity, augments circulating NP levels, reduces myocardial fibrosis, and improves LV function in the setting of HF.