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The authors reflect on the physiological functions of angiotensin II through its type 1 and type 2 receptors. The authors highlight the counterregulatory interactions of the two receptors in the cardiovascular system. The authors point out the potential role of these interactions in the antihypertensive and/or vasoprotective effects of angiotensin type 1 receptor blockers. The authors explain the mechanisms by which angiotensin II increase reactive oxygen species production.

Epidemiological studies have shown that obesity and cigarette smoking (CS) are major cardiovascular (CV) risk factors and when coexisting in the same individuals have additive/synergistic effects upon CVD development. We have shown that stable compounds of CS (ATVB 2004) as well as nicotine, in concentrations found in smoker’s plasma, promote atherosclerotic CVD (AJP 2013). Here we studied in Sprague Dawley (SD) rats with diet -induced obesity the mechanisms involved in nicotine enhancement of CVD. SD rats (N=6-7 each group) were fed either a high fat (HF) or a standard chow (SCH) diet with or without nicotine (100 mg/kg/day in the drinking water) for 20 weeks. The HF rats developed central obesity, characterized by increased body weight gain (22%) and abdominal fat weight (53%), increased plasma levels of cholesterol (33%), non-esterified free fatty acids (68%), insulin (15%) glucose (12%)and systolic blood pressure (SBP: 146 ± 5 vs. 131 ± 5 mmHg SCH rats, p<0.05). Nicotine further increased SBP in obese HF rats (158 ± 4 mmHg, p<0.05) but not in lean SCH rats. Nicotine significantly increased O2- production in both obese (1689 ± 87 count/min/mg) and lean rats (1074 ± 105 count/min/mg) and further impaired EDR (Emax: 74 ± 5%) in obese HF rats. Nicotine also increased the expression of the macrophage marker ED1 in the aortas of obese HF rats. In peritoneal macrophages from obese HF rats TNFα, IL1β and CD36 were increased, and were further significantly increased in nicotine-treated obese HF rats. Using PCR array for inflammatory cytokines and receptor signaling pathway we found that the aortas from obese HF rats showed 2-4 fold increases in expression of several chemokines and interleukin genes expression; nicotine further increased the expression of 11 pro-inflammatory genes in the aortas from obese HF rats. Our results suggest that nicotine dramatically aggravates the CV effects of diet -induced obesity by increasing oxidative stress, vascular inflammation and endothelial dysfunction. Clinically chronic inhalation of nicotine, as that delivered by E-cigarettes, by individuals unable to quit the habit may have an important pro-atherogenic effect, particularly in obese subjects. [ABSTRACT FROM AUTHOR]

In hypertension aortic (Ao) stiffness is a main determinant of increased systolic (SBP) and pulse- pressure (PP). Brachial and Ao SBP and PP often differ; Ao pressures predict cardiovascular events more accurately than brachial pressures. It is surmised that increased pressure-workload is cause and effect of Ao stiffening but the mechanisms involved are poorly understood. Rho Kinase is a master regulator of vascular tone and remodeling: In endothelium Rho kinase decreases eNOS expression and NO production. In VSMC Ang II/ AT1R specifically activates Rho Kinase via phosphorylation of Jak2 /Arhgef1 which phosphorylates (inhibits) myosin light chain phosphatase (MYPT1) thereby promoting vasoconstriction. Groups (n= 6) of Dahl SS (DS) rats fed either 0.5% or 4% NaCl diets for 10 weeks were matched with SHR of similar age (6 and 16weeks old) and SBP (147+8 & 211+7). Hypertensive DS rats, but not SHR showed increased Ao weight/length (17%, P<0.05) and left ventricle weight/ body weight ratios (16%, P<0.05). Compared to normotensive DS, Ao AT1Rs in hypertensive DS rose 230% accompanied by increased pJak2/Jak2 (3.5 fold) and pMYPT1/MYPT1 (3.95 fold) all p<0.05. Switch of hypertensive DS to a 0.5 % NaCl diet for 4 additional weeks did not reduce either SBP or the activated Ang l1/Rho Kinase pathways. The ARB Candesartan prevented Angll/AT1-Jak2-Rho Kinase activation in hypertensive DS fed 4% NaCl diet and normalized SBP, LVH and Ao weight/length in hypertensive DS switched to a 0,5% NaCl diet. Hypertensive SHR did not show Ao upregulation of AT1Rs or activation of the Angll/Jak2-Rho Kinase pathway. These studies show for the first time that in low renin salt sensitive hypertension there is specific Ao activation of the Ang II/Jak2-Rho Kinase pathway that is independent of the severity of SBP.Clinically the variable end-organ disease observed in individuals with similar severity of hypertension may be linked, at least in part, to genetically conditioned differences in Angll/AT1R, Jak-2 activation in response to high dietary salt. These novel studies extend and complement previous studies by us and others implicating abnormal bioactivity of NO and aldosterone in salt sensitive hypertension and unravel a new and intricate pathway in which Rho Kinase plays a pivotal role. [ABSTRACT FROM AUTHOR]

Objective: Endothelial dysfunction is an early manifestation of cigarette smoke (CS) toxicity. We have previously demonstrated that CS impairs nitric oxide (NO)-mediated endothelial function via increased generation of superoxide anion (O2*). In these studies, we investigated whether stable compounds present in CS activate specific pathways responsible for the increased endothelial O2* production., Methods and Results: Short exposure of bovine pulmonary artery endothelial cells (BPAECs), human pulmonary artery endothelial cells, and rat pulmonary arteries to CS extracts (CSEs) resulted in a large increase in O2* production (20-fold, 3-fold, and 2-fold increase, respectively; P<0.05 versus control), which was inhibited by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors diphenyleneiodinium, apocynin, and gp91 docking sequence-tat peptide but not by oxypurinol, the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester, or the mitochondrial respiration inhibitor rotenone. Exposure of BPAECs to acrolein, a stable thiol-reactive agent found in CS, increased O2* production 5-fold, which was prevented by prior inhibition of NADPH oxidase., Conclusions: These studies demonstrate that thiol-reactive stable compounds in CS can activate NADPH oxidase and increase endothelial O2* production, thereby reducing NO bioactivity and resulting in endothelial dysfunction. Clinically, these studies may contribute to the development of agents able to mitigate CS-mediated vascular toxicity.