scholarly journals Angiotensin-(1-7) and low-dose angiotensin II infusion reverse salt-induced endothelial dysfunction via different mechanisms in rat middle cerebral arteries

2010 ◽  
Vol 299 (4) ◽  
pp. H1024-H1033 ◽  
Author(s):  
Matthew J. Durand ◽  
Gábor Raffai ◽  
Brian D. Weinberg ◽  
Julian H. Lombard
Keyword(s):  
Endothelial Dysfunction ◽  
Receptor Antagonist ◽  
Intravenous Infusion ◽  
Low Dose ◽  
Cerebral Arteries ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Resistance Arteries ◽  
Mas Receptor ◽  
Middle Cerebral Arteries

The goals of this study were to 1) determine the acute effect of ANG-(1-7) on vascular tone in isolated middle cerebral arteries (MCAs) from Sprague-Dawley rats fed a normal salt (NS; 0.4% NaCl) diet, 2) evaluate the ability of chronic intravenous infusion of ANG-(1-7) (4 ng·kg−1·min−1) for 3 days to restore endothelium-dependent dilation to acetylcholine (ACh) in rats fed a high-salt (HS; 4% NaCl) diet, and 3) determine whether the amelioration of endothelial dysfunction by ANG-(1-7) infusion in rats fed a HS diet is different from the protective effect of low-dose ANG II infusion in salt-fed rats. MCAs from rats fed a NS diet dilated in response to exogenous ANG-(1-7) (10−10–10−5 M). Chronic ANG-(1-7) infusion significantly reduced vascular superoxide levels and restored the nitric oxide-dependent dilation to ACh (10−10–10−5 M) that was lost in MCAs of rats fed a HS diet. Acute vasodilation to ANG-(1-7) and the restoration of ACh-induced dilation by chronic ANG-(1-7) infusion in rats fed a HS diet were blocked by the Mas receptor antagonist [d-ALA( 7 )]-ANG-(1-7) or the ANG II type 2 receptor antagonist PD-123319 and unaffected by ANG II type 1 receptor blockade with losartan. The restoration of ACh-induced dilation in MCAs of HS-fed rats by chronic intravenous infusion of ANG II (5 ng·kg−1·min−1) was blocked by losartan and unaffected by d-ALA. These findings demonstrate that circulating ANG-(1-7), working via the Mas receptor, restores endothelium-dependent vasodilation in cerebral resistance arteries of animals fed a HS diet via mechanisms distinct from those activated by low-dose ANG II infusion.

Abstract 357: Cerebral Arterial Endothelial Dysfunction in the Post-Cardiac Arrest Period

Circulation ◽  
2019 ◽  
Vol 140 (Suppl_2) ◽  
Author(s):  
Frederik B Hansen ◽  
Goncalo Esteves ◽  
Niels Secher ◽  
Bo Lofgren ◽  
Ulf Simonsen ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Endothelial Dysfunction ◽  
Cerebral Arteries ◽  
Channel Blockers ◽  
Sprague Dawley ◽  
No Donor ◽  
Sprague Dawley Rats ◽  
Middle Cerebral Arteries ◽  
Cerebral Vasodilation ◽  
Synthase Inhibitor

Introduction: Cardiac arrest (CA) has a poor prognosis due to brain injury that progresses over time. Endothelial dysfunction may play an important role in the impairment of the cerebral circulation after CA. Aims: To investigate 1) whether endothelial dysfunction is present in cerebral arteries, and 2) if the altered endothelial function is caused by increased activity of calcium-activated potassium (K ca ) channels. Methods: Male Sprague-Dawley rats (403g±24g) were anaesthetized, intubated and ventilated. Four groups were examined; two CA groups observed for either 2 hours (2h-CA, n=10) or 4 hours (4h-CA, n=10) and two corresponding sham groups (2h-sham, n=10; 4h-sham, n=10). Following 7 minutes of asphyxial CA, the rats were resuscitated using adrenaline, ventilation, and chest compressions. Middle cerebral arteries were isolated and examined in wire-myographs. Results: Cerebral vasodilation was significantly enhanced in response to bradykinin in arteries from 4h-CA rats when compared to 4h-sham rats (4h-sham: E max 58% (5.57 of 9.69) ± 6% vs 4h-CA: E max 84% (6.16 of 7.32) ± 4%, p=0.007). Likewise, vasodilation induced by NS309 (K Ca -channel activator) was increased in CA rats when compared to sham rats. In the presence of L-NAME (NO synthase inhibitor), bradykinin induced vasodilation was significantly augmented in 4h-CA rats when compared to 4h-sham rats, whereas SNP (NO donor) induced vasodilation was similar between groups. In the presence of L-NAME and K Ca -channel blockers (UCL1684 and ICA-17043), bradykinin induced vasodilation was abolished in cerebral arteries in all four groups. Conclusion: Our findings demonstrate an enhanced endothelial-dependent vasodilation in cerebral arteries in the post-cardiac arrest period. The increased vasodilatory response may be explained by increased endothelial K Ca -channel activity and bioavailability of NO, and may contribute to dysregulation of cerebral blood flow after CA.

scholarly journals Acute and chronic angiotensin-(1–7) restores vasodilation and reduces oxidative stress in mesenteric arteries of salt-fed rats

2011 ◽  
Vol 301 (4) ◽  
pp. H1341-H1352 ◽  
Author(s):  
Gábor Raffai ◽  
Matthew J. Durand ◽  
Julian H. Lombard
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Oxidant Stress ◽  
Chronic Administration ◽  
Mesenteric Arteries ◽  
Ang Ii ◽  
Vascular Relaxation ◽  
Sprague Dawley ◽  
Mas Receptor ◽  
Sprague Dawley Rats

This study determined the effect of ANG-(1–7) on salt-induced suppression of endothelium-dependent vasodilatation in the mesenteric arteries of male Sprague-Dawley rats. Chronic intravenous infusion of ANG-(1–7), oral administration of the nonpeptide mas receptor agonist AVE-0991, and acute preincubation of the arteries with ANG-(1–7) and AVE-0991 all restored vasodilator responses to both ACh and histamine that were absent in the arteries of rats fed a high-salt (4% NaCl) diet. The protective effects of ANG-(1–7) and AVE-0991 were inhibited by acute or chronic administration of the mas receptor antagonist A-779, the ANG II type 2 (AT2) receptor blocker PD-123319, or N-nitro-l-arginine methyl ester, but not the ANG II type 1 receptor antagonist losartan. Preincubation with the antioxidant tempol or the nitric oxide (NO) donor diethylenetriamine NONOate and acute and chronic administration of the AT2 receptor agonist CGP-42112 mimicked the protective effect of ANG-(1–7) to restore vascular relaxation. Acute preincubation with ANG-(1–7) and chronic infusion of ANG-(1–7) ameliorated the elevated superoxide levels in rats fed a high-salt diet, but the expression of Cu/Zn SOD and Mn SOD enzyme proteins in the vessel wall was unaffected by ANG-(1–7) infusion. These results indicate that both acute and chronic systemic administration of ANG-(1–7) or AVE-0991 restore endothelium-dependent vascular relaxation in salt-fed Sprague-Dawley rats by reducing vascular oxidant stress and enhancing NO availability via mas and AT2 receptors. These findings suggest a therapeutic potential for mas/AT2 receptor activation in preventing the vascular oxidant stress and endothelial dysfunction associated with elevated dietary salt intake.

Chronic intermittent hypoxia alters NE reactivity and mechanics of skeletal muscle resistance arteries

2006 ◽  
Vol 100 (4) ◽  
pp. 1117-1123 ◽  
Author(s):  
Shane A. Phillips ◽  
E. B. Olson ◽  
Julian H. Lombard ◽  
Barbara J. Morgan
Keyword(s):  
Skeletal Muscle ◽  
Intermittent Hypoxia ◽  
Chronic Intermittent Hypoxia ◽  
Physiological Salt Solution ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Resistance Arteries ◽  
Sprague Dawley Rats ◽  
Resting Tone ◽  
Wall Distensibility

Although arterial dilator reactivity is severely impaired during exposure of animals to chronic intermittent hypoxia (CIH), few studies have characterized vasoconstrictor responsiveness in resistance arteries of this model of sleep-disordered breathing. Sprague-Dawley rats were exposed to CIH (10% inspired O2 fraction for 1 min at 4-min intervals; 12 h/day) for 14 days. Control rats were housed under normoxic conditions. Diameters of isolated gracilis muscle resistance arteries (GA; 120–150 μm) were measured by television microscopy before and during exposure to norepinephrine (NE) and angiotensin II (ANG II) and at various intraluminal pressures between 20 and 140 mmHg in normal and Ca2+-free physiological salt solution. There was no difference in the ability of GA to constrict in response to ANG II ( P = 0.42; not significant; 10−10–10−7 M). However, resting tone, myogenic activation, and vasoconstrictor responses to NE ( P < 0.001; 10−9–10−6 M) were reduced in CIH vs. controls. Treatment of rats with the superoxide scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (tempol; 1 mM) in the drinking water restored myogenic responses and NE-induced constrictions of CIH rats, suggesting that elevated superoxide production during exposure to CIH attenuates vasoconstrictor responsiveness to NE and myogenic activation in skeletal muscle resistance arteries. CIH also leads to an increased stiffness and reduced vessel wall distensibility that were not correctable with oral tempol treatment.

The arterial depressor response to chronic low-dose angiotensin II infusion in female rats is estrogen dependent

2012 ◽  
Vol 302 (1) ◽  
pp. R159-R165 ◽  
Author(s):  
Amanda K. Sampson ◽  
Lucinda M. Hilliard ◽  
Karen M. Moritz ◽  
Merlin C. Thomas ◽  
Chris Tikellis ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Arterial Pressure ◽  
Low Dose ◽  
Renin Angiotensin System ◽  
Female Rats ◽  
Ang Ii ◽  
Pressure Regulation ◽  
Estrogen Replacement ◽  
Sprague Dawley ◽  
Arterial Pressure Regulation

The complex role of the renin-angiotensin-system (RAS) in arterial pressure regulation has been well documented. Recently, we demonstrated that chronic low-dose angiotensin II (ANG II) infusion decreases arterial pressure in female rats via an AT2R-mediated mechanism. Estrogen can differentially regulate components of the RAS and is known to influence arterial pressure regulation. We hypothesized that AT2R-mediated depressor effects evident in females were estrogen dependent and thus would be abolished by ovariectomy and restored by estrogen replacement. Female Sprague-Dawley rats underwent ovariectomy or sham surgery and were treated with 17β-estradiol or placebo. Mean arterial pressure (MAP) was measured via telemetry in response to a 2-wk infusion of ANG II (50 ng·kg−1·min−1 sc) or saline. MAP significantly decreased in females treated with ANG II (−10 ± 2 mmHg), a response that was abolished by ovariectomy (+4 ± 2 mmHg) and restored with estrogen replacement (−6 ± 2 mmHg). Cardiac and renal gene expression of components of the RAS was differentially regulated by estrogen, such that overall, estrogen shifted the balance of the RAS toward the vasodilatory axis. In conclusion, estrogen-dependent mechanisms offset the vasopressor actions of ANG II by enhancing RAS vasodilator pathways in females. This highlights the potential for these vasodilator pathways as therapeutic targets, particularly in women.

scholarly journals Myogenic Vasoconstriction Requires Canonical Gq/11 Signaling of the Angiotensin II Type 1a Receptor in the Murine Vasculature

2020 ◽  
Author(s):  
Yingqiu Cui ◽  
Mario Kassmann ◽  
Sophie Nickel ◽  
Chenglin Zhang ◽  
Natalia Alenina ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Signaling Pathways ◽  
G Protein ◽  
Cerebral Arteries ◽  
Myogenic Tone ◽  
Myogenic Response ◽  
Ang Ii ◽  
Resistance Arteries ◽  
Renal Vasculature ◽  
Downstream Signaling

AbstractBackgroundThe myogenic response is an inherent vasoconstrictive property of resistance arteries to keep blood flow constant in response to increases in intravascular pressure. Angiotensin II (Ang II) type 1 receptors (AT1R) are broadly distributed, mechanoactivated receptors, which have been proposed to transduce myogenic vasoconstriction. However, the AT1R subtype(s) involved and their downstream G protein- and β-arrestin-mediated signaling pathways are still elusive.ObjectiveTo characterize the function of AT1aR and AT1bR in the regulation of the myogenic response of resistance size arteries and possible downstream signaling cascades mediated by Gq/11 and/or β-arrestins.MethodsWe used Agtr1a-/-, Agtr1b-/- and tamoxifen-inducible smooth muscle-specific AT1aR knockout mice (SM-Agtr1a mice). FR900359, [Sar1, Ile4, Ile8] Ang II (SII) and TRV120055 were used as selective Gq/11 protein inhibitor and biased agonists to activate non-canonical β-arrestin and canonical Gq/11 signaling of the AT1R, respectively.ResultsMyogenic and Ang II-induced vasoconstrictions were diminished in the perfused renal vasculature of Agtr1a-/- and SM-Agtr1a mice. Similar results were observed in isolated pressurized mesenteric and cerebral arteries. Myogenic tone and Ang II-induced vasoconstrictions were normal in arteries from Agtr1b-/- mice. The Gq/11 blocker FR900359 decreased myogenic tone and Ang II vasoconstrictions while selective biased targeting of AT1R β-arrestin signaling pathways had no effects.ConclusionThe present study demonstrates that myogenic arterial constriction requires Gq/11-dependent signaling pathways of mechanoactivated AT1aR but not G protein-independent, noncanonical alternative signaling pathways in the murine mesenteric, cerebral and renal circulation.

Abstract MP29: Activation Of Transient Receptor Potential Melastatin 2 (trpm2) Cation Channel Contributes To Nox4-induced Protective Effects In Endothelial Cells.

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Rheure Alves-Lopes ◽  
Karla B Neves ◽  
Adam Harvey ◽  
Augusto C Montezano ◽  
Rhian M Touyz
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Protective Effects ◽  
Ang Ii ◽  
Vascular Relaxation ◽  
Resistance Arteries ◽  
Transient Receptor Potential Melastatin

NOX4-induced H 2 O 2 production promotes vasodilation and is cardiovascular protective. H 2 O 2 also regulates TRPM2, a redox-sensitive channel that regulates Ca 2 influx. eNOS is a Ca 2+ -dependent enzyme, and hypertension-associated endothelial dysfunction involves eNOS inactivation. As NOX4-derived H 2 O 2 regulates TRPM2 and consequently Ca 2+ influx, we questioned whether downregulation of the H 2 O 2 -TRPM2-Ca 2+ axis in endothelial cells may contributes to impaired vascular relaxation in hypertension. WT and TTRhRen hypertensive mice were crossed with Nox4 KO mice. Vascular function was studied in mesenteric resistance arteries by wire myography. Ca 2+ influx was assessed by fluorescence microscopy in aortic endothelial cells, eNOS activation and TRPM2 expression were assessed by immunoblotting and immunohistochemistry, respectively. Blood pressure in TTRhRen (130.3±7.0 mmHg) and TTRhRen/NOX4 KO mice (141.3±18 mmHg) was significantly increased compared to control mice (98.1±8.0 mmHg). Endothelium-dependent relaxation was impaired in TTRhRen mice (Emax: WT 83.5±4.03 vs TTRhRen 59.1±3.5), effects worsened by NOX4 KO (37.9±5.4), p<0.05. Activation of TRPM2 with ADPR, improved vascular relaxation in TTRhRen/NOX4 KO mice (75.9±7.7); an effect also achieved with H 2 O 2 incubation (74.2±15.4), p<0.05. Ang II stimulated H 2 O 2 generation (% of control: 138.23±9.04) followed by Ca 2+ influx (AUC - Ca 2+ : 19401.25±1940.21), an important regulator of eNOS. These processes were reduced by TRPM2 inhibition (AUC - Ca 2+ : 8-br-cADPR 15232.2±1052.0; Olaparib 14260±843.2 and 2-APB 13095.2±277.4, p<0.05) and by the NOX1/4 inhibitor GKT137831 (AUC - Ca 2+ : Ang II 107357±1940.2 vs GKT 15067.5±255.6, p<0.05). Activation of eNOS (Ser1177) by Ang II in endothelial cells was blocked by PEG-catalase, GKT137831, and the TRPM2 inhibitor 8-br-cADPR. TRPM2 inhibitors also increased MAPK expression in endothelial cells. In conclusion, endothelial dysfunction in TTRhRen/NOX4 KO mice involves impaired TRPM2 activation. Reduced bioavailability of H 2 O 2 due to Nox4 downregulation is a major driver of this process. We identify a new axis in endothelial cells involving Nox4-H 2 O 2 -mediated activation of TRPM2-Ca 2+ -eNOS signalling which is vasoprotective.

scholarly journals Angiotensin-(1-7) Protects against the Development of Aneurysmal Subarachnoid Hemorrhage in Mice

2015 ◽  
Vol 35 (7) ◽  
pp. 1163-1168 ◽  
Author(s):  
Kenji Shimada ◽  
Hajime Furukawa ◽  
Kosuke Wada ◽  
Yuan Wei ◽  
Yoshiteru Tada ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Protective Effect ◽  
Receptor Antagonist ◽  
Intracranial Aneurysms ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Cerebral Arteries ◽  
Aneurysm Rupture ◽  
Dependent Manner ◽  
Aneurysmal Rupture ◽  
Mas Receptor

Angiotensin-(1-7) (Ang-(1-7)) can regulate vascular inflammation and remodeling, which are processes that have important roles in the pathophysiology of intracranial aneurysms. In this study, we assessed the effects of Ang-(1-7) in the development of intracranial aneurysm rupture using a mouse model of intracranial aneurysms in which aneurysmal rupture (i.e., aneurysmal subarachnoid hemorrhage) occurs spontaneously and causes neurologic symptoms. Treatment with Ang-(1-7) (0.5 mg/kg/day), Mas receptor antagonist (A779 0.5 mg/kg/day or 2.5 mg/kg/day), or angiotensin II type 2 receptor (AT2R) antagonist (PD 123319, 10 mg/kg/day) was started 6 days after aneurysm induction and continued for 2 weeks. Angiotensin-(1-7) significantly reduced the rupture rate of intracranial aneurysms without affecting the overall incidence of aneurysms. The protective effect of Ang-(1-7) was blocked by the AT2R antagonist, but not by the Mas receptor antagonist. In AT2R knockout mice, the protective effect of Ang-(1-7) was absent. While AT2R mRNA was abundantly expressed in the cerebral arteries and aneurysms, Mas receptor mRNA expression was very scarce in these tissues. Angiotensin-(1-7) reduced the expression of tumor necrosis factor-α and interleukin-1β in cerebral arteries. These findings indicate that Ang-(1-7) can protect against the development of aneurysmal rupture in an AT2R-dependent manner.

Elevated salt intake impairs dilation of rat skeletal muscle resistance arteries via ANG II suppression

2000 ◽  
Vol 278 (2) ◽  
pp. H500-H506 ◽  
Author(s):  
David S. Weber ◽  
Julian H. Lombard
Keyword(s):  
Salt Intake ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Resistance Arteries ◽  
Dietary Salt ◽  
Short Term ◽  
Dietary Salt Intake ◽  
Sprague Dawley Rats ◽  
Camp And Cgmp ◽  
Prostacyclin Analog

Vasodilator responses were assessed in resistance arteries (100–200 μm) isolated from the gracilis muscle of normotensive rats after changes in dietary salt intake. Sprague-Dawley rats were maintained on either a high-salt (HS) diet (4.0% NaCl) or a low-salt (LS) diet (0.4% NaCl) for 4–8 wk (chronic) or 3 days (short-term) with water ad libitum. One group of short-term HS rats received a continuous intravenous infusion of a low dose (5 ng ⋅ kg− 1 ⋅ min− 1) of ANG II to prevent the ANG II suppression that occurs with HS diet. Short-term and chronic HS diet eliminated arterial dilation in response to ACh and reduced[Formula: see text] (30–40 mmHg) and the stable prostacyclin analog iloprost. ANG II infusion preserved the response to these vasodilator stimuli in short-term HS animals. Dilator responses to sodium nitroprusside and forskolin were unaffected by HS diet. These findings suggest that ANG II suppression during HS diet impairs vascular relaxation mechanisms upstream from the cAMP and cGMP second messenger systems.

scholarly journals Angiogenesis after Stroke is Correlated with Increased Numbers of Macrophages: The Clean-up Hypothesis

2001 ◽  
Vol 21 (10) ◽  
pp. 1223-1231 ◽  
Author(s):  
Panya S. Manoonkitiwongsa ◽  
Catherine Jackson-Friedman ◽  
Paul J. McMillan ◽  
Robert L. Schultz ◽  
Patrick D. Lyden
Keyword(s):  
Microvessel Density ◽  
Focal Cerebral Ischemia ◽  
Cerebral Arteries ◽  
Sprague Dawley ◽  
Regional Cerebral Blood ◽  
Ischemic Brain ◽  
Sprague Dawley Rats ◽  
Middle Cerebral Arteries ◽  
The Brain ◽  
Left Middle

Brain cells manufacture and secrete angiogenic peptides after focal cerebral ischemia, but the purpose of this angiogenic response is unknown. Because the maximum possible regional cerebral blood flow is determined by the quantity of microvessels in each unit volume, it is possible that angiogenic peptides are secreted to generate new collateral channels; other possibilities include neuroprotection, recovery/regeneration, and removal of necrotic debris. If the brain attempts to create new collaterals, microvessel density should increase significantly after ischemia. Conversely, if angiogenic-signaling molecules serve some other purpose, microvessel densities may increase slightly or not at all. To clarify, the authors measured microvessel densities with quantitative morphometry. Left middle cerebral arteries of adult male Sprague–Dawley rats were occluded with intraluminal nylon suture for 4 hours followed by 7, 14, 19, or 30 days of reperfusion. Controls received no surgery or suture occlusion. Changes in microvessel density and macrophage numbers were measured by light microscopic morphometry using semiautomated stereologic methods. Microvessel density increased only in the ischemic margin adjacent to areas of pannecrosis and was always associated with increased numbers of macrophages. Ischemic brain areas without macrophages displayed no vascularity changes compared with normal animals. These data suggest that ischemia-induced microvessels are formed to facilitate macrophage infiltration and removal of necrotic brain.

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