The new pathway nitrate-nitrite-nitric oxide (NO) has emerged as a physiological alternative to the classical enzymatic pathway for NO formation from l-arginine. Nitrate is converted to nitrite by commensal bacteria in the oral cavity and the nitrite formed is then swallowed and reduced to NO under the acidic conditions of the stomach. In this study, we tested the hypothesis that increases in gastric pH caused by omeprazole could decrease the hypotensive effect of oral sodium nitrite. We assessed the effects of omeprazole treatment on the acute hypotensive effects produced by sodium nitrite in normotensive and L-NAME-hypertensive free-moving rats. In addition, we assessed the changes in gastric pH and plasma levels of nitrite, NO(x) (nitrate+nitrite), and S-nitrosothiols caused by treatments. We found that the increases in gastric pH induced by omeprazole significantly reduced the hypotensive effects of sodium nitrite in both normotensive and L-NAME-hypertensive rats. This effect of omeprazole was associated with no significant differences in plasma nitrite, NO(x), or S-nitrosothiol levels. Our results suggest that part of the hypotensive effects of oral sodium nitrite may be due to its conversion to NO in the acidified environment of the stomach. The increase in gastric pH induced by treatment with omeprazole blunts part of the beneficial cardiovascular effects of dietary nitrate and nitrite.

Hypertension induces vascular alterations that are associated with up-regulation of matrix metalloproteinases (MMPs). While these alterations may be blunted by doxycycline, a non-selective MMPs inhibitor, no previous study has examined the effects of different doses of doxycycline on these alterations. This is important because doxycycline has been used at sub-antimicrobial doses, and the use of lower doses may prevent the emergence of antibiotic-resistant microorganisms. We studied the effects of doxycycline at 3, 10 and 30 mg ⁄ kg per day on the vascular alterations found in the rat two kidneyone clip (2K1C) hypertension (n = 20 rats ⁄ group). Systolic blood pressure (SBP) was monitored during 4 weeks of treatment.We assessed endothelium-dependent and independent relaxations. Quantitative morphometry of structural changes in the aortic wall was studied, and aortic MMP-2 levels ⁄ proteolytic activity were determined by gelatin and in situ zymography, respectively. All treatments attenuated the increases in SBP in hypertensive rats (195.4 € 3.9 versus 177.2 € 6.2, 176.3 € 4.5, and 173 € 5.1 mmHg in 2K1C hypertensive rats treated with vehicle, or doxycycline at 3, 10, 30 mg ⁄ kg per day, respectively (all p < 0.01). However, only the highest dose prevented 2K1C-induced reduction in endothelium-dependent vasorelaxation (p < 0.05), vascular hypertrophy and increases in MMP-2 levels (all p < 0.05). In conclusion, our results suggest that relatively lower doses of doxycycline do not attenuate the vascular alterations found in the 2K1C hypertension model, and only the highest dose of doxycycline affects MMPs and vascular structure. Our results support the idea that the effects of doxycycline on MMP-2 and vascular structure are pressure independent.Hypertension is a major cardiovascular disease that is associated with vascular remodelling characterized by degradation and reorganization of extracellular matrix in the vessel wall [1]. Vascular remodelling is an adaptive response to elevation of arterial pressure to normalize the wall tension [2] and has been clearly described in experimental models of hypertension, including the 2-kidney, 1-clip (2K1C) Goldblatt model, which involves the activation of the renin-angiotensin-aldosterone axis [3,4].Metalloproteinases (MMPs) are zinc-containing enzymes that play important roles in cardiovascular diseases [5]. Upregulated MMPs promote excessive degradation of extracellular matrix and are involved in pathological vascular remodelling [6], which includes vascular smooth muscle cell migration and proliferation in the arterial wall [7]. In fact, increased expression and activity of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) have been consistently implicated in vascular remodelling associated with hypertension in patients [8,9] and animal models [10][11][12][13][14][15][16]. We have recently found evidence suggesting that enhanced aortic MMP-2 levels and activity may underlie the impaired endothelial-dependent vasorelaxation, arterial wall hypertrophy, and excessive c...

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Extraskeletal myxoid chondrosarcoma is a rare mesenchymal soft-tissue malignancy of putative chondrocytic differentiation. Occasional overt cartilage formation, positivity for S-100 protein, and ultrastructural analysis have supported this view. However, most extraskeletal myxoid chondrosarcomas do not show chondroid tissue formation, and S-100 protein is found much less commonly than has been reported. Both these observations cast doubt on the histogenetic classification of extraskeletal myxoid chondrosarcoma as a chondroblastic entity. Mostly using matrix proteins as markers of mesenchymal cell differentiation, we investigated the biochemical matrix composition and cellular phenotype of the tumor cells in representative specimens from 14 extraskeletal myxoid chondrosarcomas. In all but one tumor specimen, which showed histomorphologically overt cartilage formation, only occasional staining for the proteoglycan aggrecan was found. Specimens from two tumors showed presence of collagen type II, and none was positive for collagen type X. Instead, collagen types I, III, and VI were diffusely positive. Also, S-100 protein was largely absent. Our results suggest that the basic cellular phenotype of extraskeletal myxoid chondrosarcoma is not chondrocytic or prechondrocytic and that extraskeletal myxoid chondrosarcoma is not a chondrosarcomatous entity. Extraskeletal myxoid chondrosarcoma consists most likely of primitive mesenchymal cells with focal, multidirectional differentiation. Chondrocytic differentiation is an unusual facet in the spectrum of differentiation patterns exhibited by these lesions.

We report the negative ion photoelectron spectroscopy of the hydroxymethoxide anion, H2C(OH)O−. The photoelectron spectra show that 3.49 eV photodetachment produces two distinct electronic states of the neutral hydroxymethoxy radical (H2C(OH)O⋅). The H2C(OH)O⋅ ground state (X̃ 2A) photoelectron spectrum exhibits a vibrational progression consisting primarily of the OCO symmetric and asymmetric stretches, the OCO bend, as well as combination bands involving these modes with other, lower frequency modes. A high-resolution photoelectron spectrum aids in the assignment of several vibrational frequencies of the neutral H2C(OH)O⋅ radical, including an experimental determination of the H2C(OH)O⋅ 2ν12 overtone of the H–OCO torsional vibration as 220(10) cm−1. The electron affinity of H2C(OH)O⋅ is determined to be 2.220(2) eV. The low-lying Ã 2A excited state is also observed, with a spectrum that peaks ∼0.8 eV above the X̃ 2A state origin. The Ã 2A state photoelectron spectrum is a broad, partially resolved band. Quantum chemical calculations and photoelectron simulations aid in the interpretation of the photoelectron spectra. In addition, the gas phase acidity of methanediol is calculated to be 366(2) kcal mol−1, which results in an OH bond dissociation energy, D0(H2C(OH)O–H), of 104(2) kcal mol−1, using the experimentally determined electron affinity of the hydroxymethoxy radical.

Functional correlates of α₁-adrenoceptors were studied in thoracic aorta and carotid arteries from Wistar rats, at maturation (3- and 8-week-old) and aging (17- and 29-week-old) phases, using phenylephrine (PHE) and KCl. PHE and KCl effects on rat aorta did not differ with age. A reduction in maximal contractions to PHE or KCl occurred in carotid arteries during maturation. Concentration-inhibition curves to the alkylating agent chloroethylclonidine or WB4101 suggested at all ages studied a predominance of α_1B-adrenoceptors in aorta. However, α_1A-adrenoceptors may account for some activity in aortas of 29-week-old rats. In carotid arteries α_1D-adrenoceptors account for functional correlates at all ages studied. The results indicate that maturation or aging affects vascular responsiveness or predominant receptor subtype differently in aorta and carotid arteries with intact endothelium.

We report high-resolution photoelectron spectra of the simplest carbanions, CH₃⁻ and CD₃⁻. The vibrationally resolved spectra are dominated by a long progression in the umbrella mode (ν₂) of ˙CH₃ and ˙CD₃, indicating a transition from a pyramidal C(3v) anion to the planar D(3h) methyl radical. Analysis of the spectra provides electron affinities of ˙CH₃ (0.093(3) eV) and ˙CD₃ (0.082(4) eV). These results enable improved determination of the corresponding gas-phase acidities: Δ(acid)H(0K)°(CH₄) = 414.79(6) kcal/mol and Δ(acid)H(0K)°(CD₄) = 417.58(8) kcal/mol. On the basis of the photoelectron anisotropy distribution, the electron is photodetached from an orbital with predominant p-character, consistent with the sp³-hybridized orbital picture of the pyramidal anion. The double-well potential energy surface along the umbrella inversion coordinate leads to a splitting of the vibrational energy levels of the umbrella mode. The inversion splittings of CH₃⁻ and CD₃⁻ are 21(5) and 6(4) cm⁻¹, respectively, and the corresponding anion umbrella vibrational frequencies are 444(13) and 373(12) cm⁻¹, respectively. Quantum mechanical calculations reported herein show good agreement with the experimental data and provide insight regarding the electronic potential energy surface of CH₃⁻.

Anion photoelectron spectra of deprotonated indole have been obtained utilizing several photon energies. The slow electron velocity-map imaging spectrum of indolide allows for the determination of the electron affinity (EA) of indolyl, 2.4315 ± 0.0017 eV. The equilibrium geometry of indolide was shown to minimally distort upon photodetachment with only ring distortion vibrational modes of A' symmetry becoming significantly excited. Photoelectron spectra of indolide accessing the electronic ground state of indolyl displayed a photon energy dependence due to electron autodetachment. Combining the EA of indolyl with the previous work studying the dissociation energy of H-indolyl allows for a new independent measure of ΔHN-H ≤ 348.7 kcal/mol, which improves the previous measurement of the gas phase acidity. The anion photoelectron spectrum of deprotonated indoline consisted of a featureless broad band extending from ∼1.3 eV to 1.7 eV electron binding energy. The congested nature of the spectrum is likely due to the presence of multiple isomers of deprotonated indoline, including ring-opened structures.