High salt intake shifts the mechanisms of flow-induced dilation in the middle cerebral arteries of Sprague-Dawley rats.

The goal of the present study was to examine the effect of 1 wk of high salt (HS) intake and the role of oxidative stress in changing the mechanisms of flow-induced dilation (FID) in isolated pressurized middle cerebral arteries of male Sprague-Dawley rats ( n = 15-16 rats/group). Reduced FID in the HS group was restored by intake of the superoxide scavenger tempol (HS + tempol in vivo group). The nitric oxide (NO) synthase inhibitor Nω-nitro-l-arginine methyl ester, cyclooxygenase inhibitor indomethacin, and selective inhibitor of microsomal cytochrome P-450 epoxidase activity N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide significantly reduced FID in the low salt diet-fed group, whereas FID in the HS group was mediated by NO only. Cyclooxygenase-2 mRNA (but not protein) expression was decreased in the HS and HS + tempol in vivo groups. Hypoxia-inducible factor-1α and VEGF protein levels were increased in the HS group but decreased in the HS + tempol in vivo group. Assessment by direct fluorescence of middle cerebral arteries under flow revealed significantly reduced vascular NO levels and increased superoxide/reactive oxygen species levels in the HS group. These results suggest that HS intake impairs FID and changes FID mechanisms to entirely NO dependent, in contrast to the low-salt diet-fed group, where FID is NO, prostanoid, and epoxyeicosatrienoic acid dependent. These changes were accompanied by increased lipid peroxidation products in the plasma of HS diet-fed rats, increased vascular superoxide/reactive oxygen species levels, and decreased NO levels, together with increased expression of hypoxia-inducible factor-1α and VEGF. NEW & NOTEWORTHY High-salt (HS) diet changes the mechanisms of flow-induced dilation in rat middle cerebral arteries from a combination of nitric oxide-, prostanoid-, and epoxyeicosatrienoic acid-dependent mechanisms to, albeit reduced, a solely nitric oxide-dependent dilation. In vivo reactive oxygen species scavenging restores flow-induced dilation in HS diet-fed rats and ameliorates HS-induced increases in the transcription factor hypoxia-inducible factor-1α and expression of its downstream target genes.

Urodilatin reverses the detrimental influence of bradykinin in acute ischemic stroke.

Occlusion of cerebral arteries leads to ischemic stroke accompanied by subsequent brain edema. Bradykinin (BK) is involved in the formation of cerebral edema, and natriuretic peptides (NPs) potentially have beneficial effects on brain edema formation via a still unknown mechanism. The aim of this study was clarifying the mechanisms of action of NPs on BK signaling, and their interactive effects after ischemic brain injury. We used a mouse model for stroke, the middle cerebral artery (MCA) occlusion. Brain lesion and edema were measured by microcomputerized tomography volumetric measurements. To determine the effects of NPs on the BK signaling pathway in the MCAs we measured changes in vessel diameter and membrane potentials in endothelial cells. To determine the effects of NPs on BK signaling pathway in isolated astrocytes and neurons, membrane potentials and intercellular Ca2+ concentrations were measured. Urodilatin inhibited and when applied together with BK, reduced the formation of the ischemic lesion via activation of G-Protein-Signaling Protein Type 4 at the cellular (atrocities, neurons) and blood vessel (endothelial cells and isolated MCA) level as well as in in vivo experiments. The results of this study show the existence of a natural antagonist of BK in the brain, and the possible use of NPs in the treatment of stroke.

Hyperbaric oxygenation affects the mechanisms of acetylcholine-induced relaxation in diabetic rats.

The effects of hyperbaric oxygenation (HBO2) on acetylcholine-induced vasorelaxation (AChIR) were evaluated in male Sprague-Dawley (SD) rats randomized into four groups: healthy controls (Ctrl), diabetic rats (DM), and control and diabetic rats that underwent hyperbaric oxygenation (Ctrl+HBO2 and DM+HBO2). AChIR was measured in aortic rings, with L-NAME, indomethacin, or MS-PPOH and a combination of inhibitors. mRNA expression of eNOS, iNOS, COX-1 and COX-2 was assessed by qPCR, and protein expression of CYP4A(1-3) by Western blot. Plasma antioxidative capacity and systemic oxidative stress were determined with the ferric reducing ability of plasma (FRAP) and thiobarbituric acid-reactive substances (TBARS) assays, respectively. AChIR was preserved in all groups of rats, but mediated with different mechanisms. In all experimental groups of rats, AChIR was mediated mainly by NO, with the contribution of CYP450 vasodilator metabolites. This effect was the most prominent in the DM+HBO2 group of rats. The TBARS was significantly higher in both DM and DM+HBO2 groups compared to respective controls. eNOS expression was upregulated in the DM+HBO2 group compared to other groups, COX-1 expression was upregulated in the DM+HBO2 group compared to the control. CYP450-4A1 / A2/A3protein expression was significantly higher expressed in both hyperbaric groups compared to their respective controls. In conclusion, HBO2 affected all three vasodilator pathways and shifted AChIR to CYP450 enzymes pathway.

Different roles of sex steroid hormones in the pathogenesis of vascular dysfunction and the development of cardiovascular disease in men and women.

In this review an overview of current literature on the topic of the relation between sex steroid hormones and cardiovascular diseases (CVDs) is presented. The influence of the mentioned hormones on the three levels has been analyzed: their interaction with the blood vessel receptors, their modulation of the vascular function, and finally their role in the pathogenesis of CVDs. This review is focused not only on already known facts of the protective role of estrogens and the inceptive role of testosterone, but attempts to give examples of their opposite effects on vascular function and development of CVDs.

The effect of hyperbaric oxygen therapy on blood vessel function in diabetes mellitus.

Prolonged untreated diabetes mellitus leads to microangiopathy, tissue hypoxia and ischemic lesions; it increases the risk for stroke and exacerbates brain tissue damage following ischemia. Patients exhibit advanced atherosclerosis in coronary and cerebral arteries as well as enhanced vascular responsiveness to vasoconstrictors, an attenuated response to vasodilators and impaired autoregulation of cerebral blood flow. Altered endothelial function of arterioles and an impaired vasomotor function of resistance vessels could contribute to altered regulation of regional blood flow and insufficient tissue perfusion in diabetes mellitus. Hyperbaric oxygen therapy is shown to contribute to the healing of ischemic ulcerations in diabetic patients and to improvement of several other pathologic conditions. However, information about the mechanism of how this therapy works is still very limited. We postulate that hyperbaric oxygen therapy has an effect on vascular function by modulating mechanisms of vascular responses to various dilator and constrictor agonists in cerebral resistance vessels, leading to restored vascular reactivity. In accordance to this, the therapy affects production of vasodilators and vasoconstrictors, as well as the vessel-sensitivity to these factors. Furthermore, we hypothesize that hyperbaric oxygen therapy would restore cerebral blood flow regulation that is impaired in diabetics, whereas in contrast to that, chronic intermittent hypoxia would lead to impaired cerebral blood flow. These proposed mechanisms would, if confirmed, represent a valuable advancement in the understanding of this subject.