| 1. |
- Edvinsson, Marie-Louise, et al.
(författare)
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Characterization of Relaxant Responses to Natriuretic Peptides in the Human Microcirculation In Vitro and In Vivo
- 2016
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Ingår i: Microcirculation. - : Wiley. - 1073-9688. ; 23:6, s. 438-446
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Tidskriftsartikel (refereegranskat)abstract
- Objective: We characterized the vasodilatory effects of ANP, BNP, and CNP in human subcutaneous arterioles in vitro and the cutaneous microcirculation in vivo. Methods: The in vitro experiments were performed using wire myography and the responses were characterized by the use of inhibitors for nitric oxide (L-NAME), prostaglandin synthesis (indomethacin), or the endothelium-derived hyperpolarization factor. In vivo, the vasorelaxant effect of iontophoretically administrated BNP or CNP was measured with a noninvasive laser Doppler technique. Involvement of nitric oxide or prostaglandins was assessed by L-NAME or indomethacin given by iontophoresis. Results: In vitro all three peptides showed significant vasodilatation with the efficacy order: CNP > BNP = ANP. The BNP-induced vasodilatation, but not that of ANP or CNP, was significantly reduced by pretreatment with indomethacin or L-NAME. In vivo administration of BNP induced a marked vasodilatory response that was attenuated by local pretreatment of L-NAME. Indomethacin by itself resulted in increased cutaneous perfusion. Conclusions: NPs are potent vasodilators in the human subcutaneous circulation. The response to BNP differs from that of the other peptides as it seems dependent on cyclooxygenase products and nitric oxide.
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| 2. |
- Rehnström, Mimmi, et al.
(författare)
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Ovariectomy Reduces Vasocontractile Responses of Rat Middle Cerebral Arteries After Focal Cerebral Ischemia
- 2022
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Ingår i: Journal of Cardiovascular Pharmacology. - 1533-4023. ; 79:1, s. 122-128
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: Effects of sex hormones on stroke outcome are not fully understood. A deleterious consequence of cerebral ischemia is upregulation of vasoconstrictor receptors in cerebral arteries that exacerbate stroke injury. Here, we tested the hypothesis that female sex hormones alter vasocontractile responses after experimental stroke in vivo or after organ culture in vitro, a model of vasocontractile receptor upregulation. Female rats with intact ovaries and ovariectomized (OVX) females treated with 17β-estradiol, progesterone, or placebo were subjected to transient, unilateral middle cerebral artery occlusion followed by reperfusion (I/R). The maximum contractile response, measured my wire myography, in response to the endothelin B receptor agonist sarafotoxin 6c was increased in female arteries after I/R, but the maximum response was significantly lower in arteries from OVX females. Maximum contraction mediated by the serotonin agonist 5-carboxamidotryptamine was diminished after I/R, with arteries from OVX females showing a greater decrease in maximum contractile response. Contraction elicited by angiotensin II was similar in all arteries. Neither estrogen nor progesterone treatment of OVX females affected I/R-induced changes in endothelin B- and 5-carboxamidotryptamine-induced vasocontraction. These findings suggest that sex hormones do not directly influence vasocontractile alterations that occur after ischemic stroke; however, loss of ovarian function does impact this process.
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| 3. |
- Ahnstedt, Hilda, et al.
(författare)
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Cytokines and growth factors modify the upregulation of contractile endothelin ET(A) and ET(B) receptors in rat cerebral arteries after organ culture.
- 2012
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1708. ; 205:2, s. 266-278
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Experimental cerebral ischemia and organ culture of cerebral arteries induce an increased endothelin ET(B) receptor-mediated contraction. The aim of the present study was to examine if cytokines and growth factors, known to be activated in ischemia, can influence the expression and function of endothelin receptors after organ culture. Methods: Rat middle cerebral arteries were cultured for 24 h at 37°C in humidified 5% CO(2) and air in culture medium alone, or with tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), platelet-derived growth factor (PDGF), epidermal growth factor (EGF) or basic fibroblast growth factor (bFGF). Concentration-response curves were obtained for sarafotoxin 6c (ET(B) receptor agonist) and endothelin-1 (here ET(A) receptor agonist, because of ET(B) receptor desensitization). The receptor mRNA expression was examined by real-time PCR and the protein expression by immunohistochemistry and Western blot. Results: TNF-α (100 ng/ml) and EGF (20 ng/ml) potentiated the ET(B) receptor-mediated contraction (increase in pEC(50) without change in E(max) ). bFGF (10 ng/ml) and IL-1β (10 ng/ml) induced an enhanced ET(A) receptor-mediated contraction. bFGF (10 ng/ml) significantly increased the ET(B) mRNA level, and EGF (20 ng/ml) increased the ET(A) receptor protein. Increased ET(B) receptor mRNA and protein level also were observed after treatment with IL-1β (10 ng/ml). Conclusion: The present study show that TNF-α, IL-1β, EGF and bFGF can modify the expression and function of endothelin receptors during organ culture. Since there is similar receptor upregulation in experimental stroke, the effect of cytokines and growth factors on endothelin receptor upregulation is an interesting aspect to study in vivo.
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| 4. |
- Ahnstedt, Hilda, et al.
(författare)
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Human cerebrovascular contractile receptors are upregulated via a B-Raf/MEK/ERK-sensitive signaling pathway.
- 2011
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Ingår i: BMC Neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Cerebral ischemia results in a rapid increase in contractile cerebrovascular receptors, such as the 5-hydroxytryptamine type 1B (5-HT1B), angiotensin II type 1 (AT1), and endothelin type B (ETB) receptors, in the vessel walls within the ischemic region, which further impairs local blood flow and aggravates tissue damage. This receptor upregulation occurs via activation of the mitogen-activated protein kinase pathway. We therefore hypothesized an important role for B-Raf, the first signaling molecule in the pathway. To test our hypothesis, human cerebral arteries were incubated at 37°C for 48 h in the absence or presence of a B-Raf inhibitor: SB-386023 or SB-590885. Contractile properties were evaluated in a myograph and protein expression of the individual receptors and activated phosphorylated B-Raf (p-B-Raf) was evaluated immunohistochemically. RESULTS: 5-HT1B, AT1, and ETB receptor-mediated contractions were significantly reduced by application of SB-590885, and to a smaller extent by SB-386023. A marked reduction in AT1 receptor immunoreactivity was observed after treatment with SB-590885. Treatment with SB-590885 and SB-386023 diminished the culture-induced increase of p-B-Raf immunoreactivity. CONCLUSIONS: B-Raf signaling has a key function in the altered expression of vascular contractile receptors observed after organ culture. Therefore, specific targeting of B-Raf might be a novel approach to reduce tissue damage after cerebral ischemia by preventing the previously observed upregulation of contractile receptors in smooth muscle cells.
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| 5. |
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| 6. |
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| 7. |
- Ahnstedt, Hilda, et al.
(författare)
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Male-female differences in upregulation of vasoconstrictor responses in human cerebral arteries.
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:4
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Tidskriftsartikel (refereegranskat)abstract
- Male-female differences may significantly impact stroke prevention and treatment in men and women, however underlying mechanisms for sexual dimorphism in stroke are not understood. We previously found in males that cerebral ischemia upregulates contractile receptors in cerebral arteries, which is associated with lower blood flow. The present study investigates if cerebral arteries from men and women differ in cerebrovascular receptor upregulation.
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| 8. |
- Ahnstedt, Hilda, et al.
(författare)
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U0126 attenuates cerebral vasoconstriction and improves long-term neurologic outcome after stroke in female rats.
- 2015
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 35:3, s. 454-460
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Tidskriftsartikel (refereegranskat)abstract
- Sex differences are well known in cerebral ischemia and may impact the effect of stroke treatments. In male rats, the MEK1/2 inhibitor U0126 reduces ischemia-induced endothelin type B (ETB) receptor upregulation, infarct size and improves acute neurologic function after experimental stroke. However, responses to this treatment in females and long-term effects on outcome are not known. Initial experiments used in vitro organ culture of cerebral arteries, confirming ERK1/2 activation and increased ETB receptor-mediated vasoconstriction in female cerebral arteries. Transient middle cerebral artery occlusion (tMCAO, 120 minutes) was induced in female Wistar rats, with U0126 (30 mg/kg intraperitoneally) or vehicle administered at 0 and 24 hours of reperfusion, or with no treatment. Infarct volumes were determined and neurologic function was assessed by 6-point and 28-point neuroscores. ETB receptor-mediated contraction was studied with myograph and protein expression with immunohistochemistry. In vitro organ culture and tMCAO resulted in vascular ETB receptor upregulation and activation of ERK1/2 that was prevented by U0126. Although no effect on infarct size, U0126 improved the long-term neurologic function after experimental stroke in female rats. In conclusion, early prevention of the ERK1/2 activation and ETB receptor-mediated vasoconstriction in the cerebral vasculature after ischemic stroke in female rats improves the long-term neurologic outcome.Journal of Cerebral Blood Flow & Metabolism advance online publication, 10 December 2014; doi:10.1038/jcbfm.2014.217.
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| 9. |
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| 10. |
- Edvinsson, Lars, et al.
(författare)
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Differential localization and characterization of functional calcitonin gene-related peptide receptors in human subcutaneous arteries.
- 2014
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1716 .- 1748-1708. ; 210:4, s. 811-822
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Tidskriftsartikel (refereegranskat)abstract
- Calcitonin gene-related peptide (CGRP) and its receptor are widely distributed within the circulation and the mechanism behind its vasodilation not only differs from one animal species to another but is also dependent on the type and size of vessel. The present study examines the nature of CGRP-induced vasodilation, characteristics of the CGRP receptor antagonist telcagepant and localization of the key components calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) of the CGRP receptor in human subcutaneous arteries.
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