Suppression of alcohol-induced hypertension by dexamethasone

BACKGROUND. Alcohol consumption is associated with an increased incidence of hypertension and stroke, but the triggering mechanisms are unclear. In animals, alcohol causes activation of the sympathetic nervous system and also stimulates the release of corticotropin-releasing hormone (CRH), which has sympatho-excitatory effects when administered centrally. METHODS. To determine whether alcohol evokes sympathetic activation and whether such activation is attenuated by the inhibition of CRH release, we measured blood pressure, heart rate, and sympathetic-nerve action potentials (using intraneural microelectrodes) in nine normal subjects before and during an intravenous infusion of alcohol (0.5 g per kilogram of body weight over a period of 45 minutes) and for 75 minutes after the infusion. Each subject received two infusions, one after the administration of dexamethasone (2 mg per day) and one after the administration of a placebo for 48 hours. RESULTS. The infusion of alcohol alone evoked a marked (P < 0.001) and progressive increase in the mean (+/- SD) rate of sympathetic discharge, from 16 +/- 3 bursts per minute at base line to 30 +/- 8 bursts per minute at the end of the two-hour period. This sympathetic activation was accompanied during the second hour by an increase in mean arterial pressure of 10 +/- 5 mm Hg (P < 0.001). After the administration of dexamethasone, the alcohol infusion had no detectable sympathetic effect. The dexamethasone-induced suppression of sympathetic activation was associated with a decrease in mean arterial pressure of 7 +/- 6 mm Hg (P < 0.001) during the alcohol infusion and with suppression of the pressor effect during the second hour. CONCLUSIONS. Alcohol induces pressor effects by sympathetic activation that appear to be centrally mediated. It is possible that these alcohol-induced hemodynamic and sympathetic actions could participate in triggering cardiovascular events

Pulmonary Hypertension and Indicators of Right Ventricular Function.

Pulmonary hypertension (PH) is a rare disease, whose underlying mechanisms are not fully understood. It is characterized by pulmonary arterial vasoconstriction and vessels wall thickening, mainly intimal and medial layers. Several molecular pathways have been studied, but their respective roles remain unknown. Cardiac repercussions of PH are hypertrophy, dilation, and progressive right ventricular dysfunction. Multiple echocardiographic parameters are being used, in order to assess anatomy and cardiac function, but there are no guidelines edited about their usefulness. Thus, it is now recommended to associate the best-known parameters, such as atrial and ventricular diameters or tricuspid annular plane systolic excursion. Cardiac catheterization remains necessary to establish the diagnosis of PH and to assess pulmonary hemodynamic state. Concerning energetic metabolism, free fatty acids, normally used to provide energy for myocardial contraction, are replaced by glucose uptake. These abnormalities are illustrated by increased (18)F-fluorodeoxyglucose ((18)F-FDG) uptake on positron emission tomography/computed tomography, which seems to be correlated with echocardiographic and hemodynamic parameters

Separation of Potent and Poorly Functional Human Lung Accessory Cells Based on Autofluorescence

Human alveolar macrophages obtained by bronchoalveolar lavage are usually poor accessory cells in in vitro lymphoprollferation assays. However, we recently described a subpopulation of pulmonary mononuclear cells, obtained from minced and enzyme‐digested lung, which were potent stimulators of allogeneic T‐lymphocyte proliferation. These cells were enriched in loosely adherent mononuclear cell (LAM) fractions, but further study of these accessory cells was hampered by the heterogeneous nature of LAM. It was observed that in the majority of lung tissue sections, most alveolar macrophages were autofluorescent, whereas most interstitial HLA‐DR positive cells were not. Therefore autofluorescence was utilized to fractionate LAM in an attempt to remove alveolar macrophages and selectively purify interstitial accessory cells. LAM were separated by flow cytometry using forward and side scatter to exclude lymphocytes, and red autofluorescence to obtain brightly autofluorescent (A pos) and relatively nonautofluorescent (A neg) mononuclear cells. Although both populations contained over 80% HLA‐DR positive cells, A pos cells were poor accessory cells, whereas A neg cells were extremely potent stimulators of a mixed leukocyte reaction at all stimulator ratios tested. When A pos cells were added to A neg cells, T‐cell proliferation was markedly suppressed in the majority of experiments. Morphologically, A pos cells appeared similar to classical alveolar macrophages with 95% of the cells being large and intensely nonspecific esterase positive. In contrast, the majority of A neg were smaller, B‐cell antigen‐negative, nonspecific esterase negative, and had a distinctive morphology on Wright‐stained smears. We conclude that fractionation of LAM based on autofluorescence is a powerful tool to isolate and characterize lung mononuclear cells that act either as stimulators or as suppressors of immune responses in the lung.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141667/1/jlb0458.pd

Mononuclear Cells From Human Lung Parenchyma Support Antigen‐Induced T Lymphocyte Proliferation

We have previously demonstrated that there is a subpopulation of loosely adherent pulmonary mononuclear cells that can be isolated from minced and enzyme‐digested lung tissue with a potent capacity to stimulate allogeneic T lymphocyte proliferation. We now demonstrate that these cells are also capable of stimulating an autologous mixed leukocyte reaction (AMLR) and presenting antigen to autologous T lymphocytes. These loosely adherent mononuclear cells (LAM) were more effective than either alveolar macrophages or monocytes as antigen‐presenting cells. Depletion of phagocytic or Fc receptor‐positive cells from the LAM population enhanced the stimulation of an reaction AMLR while preserving antigen‐induced T lymphocyte proliferation. These results indicate that there are nonphagocytic, Fc receptor‐negative accessory cells in human lung parenchyma capable of activating resting T cells in an AMLR and supporting antigen‐specific T lymphocyte proliferation. The identity of these cells is uncertain, but the data strongly suggest that the cell is not a classical monocyte‐derived macrophage. These antigen‐presenting cells may be critical in the initiation of immune responses within the lung.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141257/1/jlb0336.pd

Contribution of connexins to the function of the vascular wall

Gap junction channels provide an enclosed conduit for direct exchanges of signalling molecules, including ions and small metabolites between cells. This system of communication allows cells to monitor the functional state of their neighbours, and is rapidly modulated to continuously adapt to the immediate needs of groups of coupled cells. In the major arteries, endothelial cells may express three connexins isotypes, namely Connexin 37 (Cx37), Cx40 and Cx43, whereas the underlying smooth muscle cells may express Cx37, Cx40, Cx43 and Cx45. Moreover, myoendothelial gap junctions have also been shown to be involved in the regulation of vascular tone. This review highlights the regulation of vessel connexins in response to injury, as observed during experimental hypertension or wound repair, as well as the consequences of loss of one connexin in different transgenic null mice. In view of the major endocrine role of the kidney in the control of blood pressure, we also discuss the distribution of connexins in the kidney vasculature. Cx40 is present between endothelial cells of vessels and glomeruli, as well as between renin-secreting cells, the modified smooth muscle cells which form the wall of the terminal part of afferent arterioles. Modulation of Cx40 expression in a model of renin-dependent hypertension suggests that this connexin may be implicated in the function of renin-secreting cells. Finally, to address the possible regulation of connexin expression by fluid pressure, we summarize the effects of elevated transmural urine pressure on bladder Cx43 expression

Insulin resistance in mice lacking neuronal nitric oxide synthase is related to an alpha-adrenergic mechanism.

BACKGROUND: nitric oxide (NO) plays an important role in the regulation of cardiovascular and glucose homeostasis. Mice lacking the gene encoding the neuronal isoform of nitric oxide synthase (nNOS) are insulin-resistant, but the underlying mechanism is unknown. nNOS is expressed in skeletal muscle tissue where it may regulate glucose uptake. Alternatively, nNOS driven NO synthesis may facilitate skeletal muscle perfusion and substrate delivery. Finally, nNOS dependent NO in the central nervous system may facilitate glucose disposal by decreasing sympathetic nerve activity. METHODS: in nNOS null and control mice, we studied whole body glucose uptake and skeletal muscle blood flow during hyperinsulinaemic clamp studies in vivo and glucose uptake in skeletal muscle preparations in vitro. We also examined the effects of alpha-adrenergic blockade (phentolamine) on glucose uptake during the clamp studies. RESULTS: as expected, the glucose infusion rate during clamping was roughly 15 percent lower in nNOS null than in control mice (89 (17) vs 101 (12) [-22 to -2]). Insulin stimulation of muscle blood flow in vivo, and intrinsic muscle glucose uptake in vitro, were comparable in the two groups. Phentolamine, which had no effect in the wild-type mice, normalised the insulin sensitivity in the mice lacking the nNOS gene. CONCLUSIONS: insulin resistance in nNOS null mice was not related to defective insulin stimulation of skeletal muscle perfusion and substrate delivery or insulin signaling in the skeletal muscle cell, but to a sympathetic alpha-adrenergic mechanism

Echocardiographic Confirmation of Mitral Valve Prolapse: A New Finding on Radionuclide Ventriculography- A Case Report

A prominent filling defect was depicted on a radionuclide ventriculogram in a patient with mitral regurgitation. This defect was later shown, by cardiac ultrasound, to be due to mitral valve prolapse into the left ventricle during diastole. This case illustrates that mitral valve prolapse should be added to the list of clinical entities that can result in an intraventricular defect on a radionu clide ventriculogram.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67208/2/10.1177_000331978904000209.pd

Inhaled nitric oxide for high-altitude pulmonary edema

BACKGROUND. Pulmonary hypertension is a hallmark of high-altitude pulmonary edema and may contribute to its pathogenesis. When administered by inhalation, nitric oxide, an endothelium-derived relaxing factor, attenuates the pulmonary vasoconstriction produced by short-term hypoxia. METHODS. We studied the effects of inhaled nitric oxide on pulmonary-artery pressure and arterial oxygenation in 18 mountaineers prone to high-altitude pulmonary edema and 18 mountaineers resistant to this condition in a high altitude laboratory (altitude, 4559 m). We also obtained lung-perfusion scans before and during nitric oxide inhalation to gain further insight into the mechanism of action of nitric oxide. RESULTS. In the high-altitude laboratory, subjects prone to high-altitude pulmonary edema had more pronounced pulmonary hypertension and hypoxemia than subjects resistant to high-altitude pulmonary edema. Arterial oxygen saturation was inversely related to the severity of pulmonary hypertension (r=-0.50, P=0.002). In subjects prone to high-altitude pulmonary edema, the inhalation of nitric oxide (40 ppm for 15 minutes) produced a decrease in mean (+/-SD) systolic pulmonary-artery pressure that was three times larger than the decrease in subjects resistant to such edema (25.9+/-8.9 vs. 8.7+/-4.8 mm Hg, P<0.001). Inhaled nitric oxide improved arterial oxygenation in the 10 subjects who had radiographic evidence of pulmonary edema (arterial oxygen saturation increased from 67+/-10 to 73+/-12 percent, P=0.047), whereas it worsened oxygenation in subjects resistant to high-altitude pulmonary edema. The nitric oxide-induced improvement in arterial oxygenation in subjects with high-altitude pulmonary edema was accompanied by a shift in blood flow in the lung away from edematous segments and toward nonedematous segments. CONCLUSIONS. The inhalation of nitric oxide improves arterial oxygenation in high-altitude pulmonary edema, and this beneficial effect may be related to its favorable action on the distribution of blood flow in the lungs. A defect in nitric nitric oxide synthesis may contribute to high-altitude pulmonary edema

Imaging angiogenesis in atherosclerosis in large arteries with 68Ga-NODAGA-RGD PET/CT: relationship with clinical atherosclerotic cardiovascular disease.

Integrin alpha-V-beta-3 (αvβ3) pathway is involved in intraplaque angiogenesis and inflammation and represents a promising target for molecular imaging in cardiovascular diseases such as atherosclerosis. The aim of this study was to assess the clinical correlates of arterial wall accumulation of <sup>68</sup> Ga-NODAGA-RGD, a specific α <sub>v</sub> β <sub>3</sub> integrin ligand for PET. The data of 44 patients who underwent <sup>68</sup> Ga-NODAGA-RGD PET/CT scans were retrospectively analyzed. Tracer accumulation in the vessel wall of major arteries was analyzed semi-quantitatively by blood-pool-corrected target-to-background ratios. Tracer uptake was compared with clinically documented atherosclerotic cardiovascular disease, cardiovascular risk factors and calcified plaque burden. Data were compared using the Mann-Whitney U test, Pearson correlation and Spearman correlation. <sup>68</sup> Ga-NODAGA-RGD arterial uptake was significantly higher in patients with previous clinically documented atherosclerotic cardiovascular disease (mean TBR 2.44 [2.03-2.55] vs. 1.81 [1.56-1.96], p = 0.001) and showed a significant correlation with prior cardiovascular or cerebrovascular event (r = 0.33, p = 0.027), BMI (ρ = 0.38, p = 0.01), plaque burden (ρ = 0.31, p = 0.04) and hypercholesterolemia (r = 0.31, p = 0.04). <sup>68</sup> Ga-NODAGA-RGD holds promise as a non-invasive marker of disease activity in atherosclerosis, providing information about intraplaque angiogenesis