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BACKGROUND: Endothelin-1 (ET1) is a potent vasoconstrictor peptide with pro-mitogenic and pro-inflammatory properties and is therefore of interest in the development of endothelial dysfunction, endothelium-dependent flow-related remodeling, and hypertension-related remodeling. ET1 can be formed through cleavage of big ET1 by endothelin-converting enzyme (ECE) and neutral endopeptidase (NEP).METHOD: We investigated whether the dual NEP/ECE inhibitor SOL1 improves resistance artery function and structure in 12 weeks old spontaneously hypertensive rats (SHRs) and whether arterial structural responses to decreased (-90%) or increased (+100%) blood flow are impaired in young SHRs. To this end two groups of SHRs received chronic 4-week treatment at two different time points (4-8 and 8-12 weeks) prior to the experiment. We compared in-vitro effects of cyclo-oxygenase inhibition (1 μmol/l indomethacine), nitric oxide synthase inhibition (100 μmol/l N(ω)-L-nitro arginine methyl ester), and stimulation of the endothelium by 0.001-10 μmol/l acetylcholine (ACh) in isolated third-order mesenteric arteries of SHRs and aged-matched Wistar-Kyoto (WKY) rats.RESULTS: SOL1 had no effect on blood pressure in SHRs or WKY rats. ACh caused biphasic effects in mesenteric arteries of SHRs. The contractile component (endothelium-derived contractile factor) was absent in WKY and abolished by acute indomethacin administration or chronic SOL1 treatment. Endothelium-derived nitric oxide-type responses did not differ in both strains and were not influenced by SOL1 treatment. Endothelium-derived hyperpolarizing factor-type responses were severely impaired in SHRs as compared to WKY rats and were normalized by chronic SOL1 treatment. In first-order mesenteric arteries, outward flow-induced remodeling was impaired in SHRs. Chronic SOL1 treatment did not restore this response.CONCLUSION: Thus chronic SOL1 treatment during the development of hypertension in SHRs has no effect on blood pressure but improves several aspects of endothelium-dependent vasomotor responses but not arterial remodeling.

It has been previously demonstrated that the morning rise (MoR) of blood pressure (BP) may predict major cardiovascular events in hypertensive patients. Structural alterations of small resistance arteries, as evaluated by the tunica media to internal lumen ratio (M/L) of subcutaneous small resistance arteries, may also predict cardiovascular events. Because an increased M/L may amplify the effect of hypertensive stimuli, the present study aimed to evaluate the possible relationships between MoR and M/L in a population of hypertensive patients.Sixty-four patients with essential hypertension were included in the present study. All patients were submitted to a biopsy of subcutaneous fat. Small resistance arteries were dissected and mounted on an isometric myograph, and the M/L was measured. In addition, MoR was calculated from ambulatory blood pressure monitoring (ABPM) according to four previously published different methods (MoR1 to MoR4).A statistically significant correlation was observed between M/L and MoR1 (r = 0.52, P0.001), MoR2 (r = 0.32, P0.01), MoR3 (r = 0.25, P0.05) and MoR4 (r = 0.27, P0.05), as well as between internal diameter of subcutaneous small arteries and MoR1 (r = -0.45, P0.001) and MoR2 (r = -0.28, P0.05).Our results indicate that subcutaneous small artery structure is related to MoR, possibly because an altered vascular structure may amplify BP changes or, vice versa, because a greater MoR may further damage peripheral vasculature.

Hydrogen peroxide (H2O2) plays a key role in the control of resistance artery (RA) tone and is hypothesized as an endothelial-derived hyperpolarizing factor.In this study, we investigated the effects of the same concentration of exogenous H2O2 on mouse mesenteric RA tone induced by intraluminal pressure, G-protein coupled receptor activation and KCl. RAs were cannulated in an arteriograph in the absence or presence of vasoconstrictors.RA developed myogenic tone (MT) in response to stepwise pressure increases. Under phenylephrine, H2O2 induced a dose-dependent (1-50 micromol/l) vasodilation with maximum dilation at 50 micromol/l. H2O2 at 50 micromol/l induced a full dilation of RA under MT or contraction by phenylephrine that was independent of nitric oxide synthase, cyclooxygenase, endothelium and potassium channels iberiotoxin and apamin sensitive. The Ca2+ channel inhibitor, nimodipine, significantly blocked MT and also the contraction to phenylephrine and KCl. Under these conditions, H2O2 had no effect on RA diameter. Under KCl, the same concentration of H2O2 induced a potent vasoconstriction. This contraction involved p38 mitogen-activated protein-kinase activation but not ERK1/2.These findings provide the first evidence showing that the same and low concentrations of H2O2 can act as a relaxing factor but also as a vasoconstrictor under conditions in which hyperpolarization is compromised.

Precapillary resistance arteries from spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive rats (WKY) were found to contain three inositol lipids and to produce five inositol phosphate peaks. These were assessed by a highly sensitive procedure which involved the separation of radiolabelled inositol-containing components by anion-exchange high-performance liquid chromatography. Basal levels of radiolabelled inositol lipids were found to be significantly increased in SHR at 5 weeks of age, and also increased at 12 weeks, although this was only statistically significant for glycerophosphoinositol. At 5 weeks of age, exposure to a maximal concentration of noradrenaline brought about a significant increase in lipid radioactivity in WKY and in glycerophosphoinositol and glycerophosphoinositol 4-phosphate in SHR. The levels of these lipids remained significantly raised in the SHR at this time. At 12 weeks of age, exposure to noradrenaline produced reductions in radioactivity associated with inositol lipids. These new levels were elevated in SHR and significant for glycerophosphoinositol 4-phosphate. Basal levels of four inositol phosphates were not different between the two rat strains at 5 weeks of age. Inositol 1,3,4-trisphosphate was only present at minute levels and could not be measured. At 12 weeks of age, basal radiolabelling of inositol phosphates was not different between the two strains. The application of noradrenaline caused age-dependent changes in arterial inositol-containing compounds in both strains, which resulted in increased levels of inositol 1,4,5-trisphosphate in young SHR and also in adult rats in which the blood pressure level had become established.(ABSTRACT TRUNCATED AT 250 WORDS)