In microvessels of patients with coronary artery disease (CAD), flow-mediated dilation (FMD) is largely dependent upon the endothelium-derived hyperpolarizing factor HO. The goal of this study is to examine the influence of age and presence or absence of disease on the mechanism of FMD. Human coronary or adipose arterioles (~150 µm diameter) were prepared for videomicroscopy. The effect of inhibiting COX [indomethacin (Indo) or NOS (L-NAME), eliminating HO (polyethylene glycol-catalase (PEG-CAT)] or targeting a reduction in mitochondrial ROS with scavengers/inhibitors [Vitamin E (Vitamin E); phenylboronic acid (PBA)] was determined in children aged 0-18 years; young adults 19-55 years; older adults >55 years without CAD, and similarly aged adults with CAD. Indo eliminated FMD in children and reduced FMD in younger adults. This response was mediated mainly by PGI, as the prostacyclin-synthase-inhibitor trans-2-phenyl cyclopropylamine reduced FMD in children and young adults. L-NAME attenuated dilation in children and younger adults and eliminated FMD in older adults without CAD, but had no effect on vessels from those with CAD, where mitochondria-derived HO was the primary mediator. The magnitude of dilation was reduced in older compared to younger adults independent of CAD. Exogenous treatment with a sub-dilator dose of NO blocked FMD in vessels from subjects with CAD, while prolonged inhibition of NOS in young adults resulted in a phenotype similar to that observed in disease. The mediator of coronary arteriolar FMD evolves throughout life from prostacyclin in youth, to NO in adulthood. With the onset of CAD, NO-inhibitable release of HO emerges as the exclusive mediator of FMD. These findings have implications for use of pharmacological agents, such as nonsteroidal anti-inflammatory agents in children and the role of microvascular endothelium in cardiovascular health.

We examined whether survival of different rat strains administered anthrax lethal toxin is genetically determined. A reproducible test population of first filial generation hybrid rats was bred based on the susceptibility of progenitors to anthrax lethal toxin and to maximize genetic diversity across the strains. These rats were then tested with varying doses of anthrax lethal toxin. We found that all 'sensitive' strains died within 2 h following systemic administration of 240 mg/kg lethal toxin, while one strain survived following a five times higher dose (1.4 mg/kg). The ability of lethal toxin to lyse macrophage cultures derived from the bone marrow of these strains corresponded with in vivo results. We conclude that a rat test population can detect strain differences in response to anthrax lethal toxin. Survival is influenced by the host genome background and is likely due to a single gene with a recessive mode of inheritance.

Hydrogen peroxide (H2O2) has been show to be an endothelial derived factor that derived from the endothelium regulates vascular tone and tissue blood flow. In previous studies, inhibition of the endogenous H2O2 scavenger, catalase, increased the sensitivity of H2O2‐ induced dilation in an endothelium‐dependent manner in human adipose microvessels. Since ROS and their scavengers may be upregulated in disease, the purpose of this study was to determine if catalase modulation of H2O2 dilation is greater in the coronary and peripheral microcirculation of patients with coronary artery disease (CAD).Methods: Arterioles (∼150 μm ID) obtained at surgery from patients with or without CAD (atrial appendage and visceral adipose), were prepared for videomicroscopy. Vasomotor responses to exogenous H2O2 (10–10 to 10–3 M) were evaluated in the presence and absence of the catalase inhibitor 3‐amino‐1,2,4‐triazole (ATZ (4x10–2M)). Results: H2O2 dilated adipose [ED50=7.62x10‐6M, n=7] and coronary arterioles [ED50=8.63x10–6M] from CAD patients. Adipose tissue with CAD were not affected by inhibition of catalase with ATZ [ED50=4.31x10–6M, n=7]. Treatment with ATZ did not enhance dilation to H2O2 in any of the tissues tested. (with CAD [ED50=4.19x10–6M]; without CAD [ED50=1.08x10–5M]). Conclusions: H2O2 signaling is less modulated by endogenous catalase in subjects with than those without CAD.

BackgroundAcetylcholine (ACH) dose‐dependently constricts human coronary atrial arterioles (HCA) but dilates ventricular arterioles in patients with coronary disease. Whether NO mechanisms participate in Ach‐induced dilation in atrial arterioles remains unclear. Since CAD and its risk factors generate ROS that can quench NO, we hypothesized that acetylcholine‐induced dilation can be restored in HCA by restoring redox balance and supporting exogenous NO synthesis.MethodsArterioles (~150 μm) from patients with coronary artery disease were prepared for videomicroscopy. HCA's were pre‐incubated with indomethacin (10‐5), sepiapterin (10‐4), L‐Arginine (10‐3), and Peg‐SOD (300units/ml) for 30 minutes. After preconstruction with endothelin‐1, vasomotor responses to exogenous ACH (10‐9 to 10‐4 M) were evaluated in control or in the presence and absence of N‐nitro‐L‐arginine methyl ester (L‐name; 10‐4)).ResultsACH dilated pretreated compared to control intact arterioles [%max dilation (MD): 80±8% vs. ‐36.4±7%]. Treatment with L‐name abolished dilation (MD:‐0.5±9%).ConclusionsReducing endogenous oxidative stress and providing NOS substrate converts an , ACH‐induced constriction to an NO ‐dependent vasodilation in HCA. There may be a greater sensitivity to ROS in endothelium of atrial vs. ventricular arterioles.