scholarly journals Peroxynitrite Decomposition with FeTMPyP Improves Plasma-Induced Vascular Dysfunction and Infarction during Mild but not Severe Hyperglycemic Stroke

2012 ◽  
Vol 32 (6) ◽  
pp. 1035-1045 ◽  
Author(s):  
Sara Morales Palomares ◽  
Ira Gardner-Morse ◽  
Julie G Sweet ◽  
Marilyn J Cipolla
Keyword(s):  
Vascular Dysfunction ◽  
Cerebral Arteries ◽  
Stroke Outcome ◽  
Cerebrovascular Function ◽  
Middle Cerebral Arteries ◽  
Male Wistar Rats ◽  
Physiologic Saline ◽  
Severe Ischemia

We investigated mechanisms by which circulating factors during hyperglycemic (HG) stroke affect cerebrovascular function and the role of peroxynitrite in stroke outcome. Middle cerebral arteries (MCAs) were isolated from male Wistar rats and perfused with plasma from rats that were hyperglycemic for 5 to 6 days by streptozotocin and underwent either MCA occlusion (HG MCAO) or Sham surgery (HG Sham) compared with MCA perfused with physiologic saline (No plasma). Myogenic responses and endothelial function were compared in untreated MCA ( n=8/group) or with inhibitors of NADPH oxidase (apocynin; n=8), peroxynitrite (FeTMPyP; n=8) or endothelin-1 (ET-1)A (BQ-123; n=8). Finally, animals were treated in vivo before reperfusion after mild (<68% cerebral blood flow (CBF) decrease) or severe (>68% CBF decrease) MCAO with FeTMPyP ( n=12) or vehicle ( n=12) and CBF and infarction measured. The HG MCAO plasma increased tone in MCA versus No plasma ( P<0.05) that was reversed by FeTMPyP, but not by apocynin or BQ-123. The HG Sham plasma also increased tone in MCA ( P<0.05) that was reversed by BQ-123 only. In vivo, FeTMPyP was neuroprotective during mild, but not severe ischemia. These results show that circulating factors in plasma can affect cerebrovascular function through peroxynitrite generation and ET-1. In addition, peroxynitrite decomposition improves stroke outcome acutely during mild, but not severe HG ischemia.

scholarly journals Introgression of Brown Norway CYP4A genes on to the Dahl salt-sensitive background restores vascular function in SS-5BN consomic rats

2012 ◽  
Vol 124 (5) ◽  
pp. 333-342 ◽  
Author(s):  
Kathleen M. Lukaszewicz ◽  
John R. Falck ◽  
Vijaya L. Manthati ◽  
Julian H. Lombard
Keyword(s):  
Vascular Function ◽  
Vascular Dysfunction ◽  
Cerebral Arteries ◽  
Dienoic Acid ◽  
Brown Norway ◽  
No Donor ◽  
Middle Cerebral Arteries ◽  
No Bioavailability ◽  
Relaxation Responses

The present study tested the hypothesis that the Dahl SS (salt-sensitive) rat has vascular dysfunction due, in part, to the up-regulation of the CYP4A/20-HETE (cytochrome P450 ω-hydroxylase 4A)/20-hydroxyeicosatetraenoic acid) system. To assess the role of vascular 20-HETE, SS rats were compared with SS-5BN consomic rats, carrying CYP4A alleles on chromosome 5 from the normotensive BN (Brown Norway) introgressed on to the SS genetic background. Cerebral arteries from SS-5BN rats had less CYP4A protein than arteries from SS rats fed either NS (normal-salt, 0.4% NaCl) or HS (high-salt, 4.0% NaCl) diet. ACh (acetylcholine)-induced dilation of MCAs (middle cerebral arteries) from SS and SS-5BN rats was present in SS-5BN rats fed on either an NS or HS diet, but absent in SS rats. In SS rats fed on either diet, ACh-induced dilation was restored by acute treatment with the CYP4A inhibitor DDMS (N-methyl-sulfonyl-12,12-dibromododec-11-enamide) or the 20-HETE antagonist 20-HEDE [20-hydroxyeicosa-6(Z),15(Z)-dienoic acid]. The restored response to ACh in DDMS-treated SS rats was inhibited by L-NAME (NGnitro-L-arginine methyl ester) and unaffected by indomethacin or MS-PPOH [N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide]. Vascular relaxation responses to the NO donor C5FeN6Na2O were intact in both SS and SS-5BN rats and unaffected by the acute addition of DDMS, indicating that the vascular dysfunction of the SS rat is due to a reduced bioavailability of NO instead of failure of the VSMCs (vascular smooth muscle cells) to respond to the vasodilator. Superoxide levels in cerebral arteries of SS-5BN rats [evaluated semi-quantitatively by DHE (dihydroethidium) fluorescence] were lower than those in the arteries of SS rats. These findings indicate that SS rats have an up-regulation of the CYP4A/20-HETE pathway resulting in elevated ROS (reactive oxygen species) and reduced NO bioavailability causing vascular dysfunction.

scholarly journals Dihydropyridine-Insensitive Calcium Currents Contribute to Function of Small Cerebral Arteries

2010 ◽  
Vol 30 (6) ◽  
pp. 1226-1239 ◽  
Author(s):  
Ivana Y Kuo ◽  
Anthie Ellis ◽  
Victoria AL Seymour ◽  
Shaun L Sandow ◽  
Caryl E Hill
Keyword(s):  
Cerebral Arteries ◽  
Calcium Currents ◽  
Adult Rat ◽  
Cerebrovascular Function ◽  
Middle Cerebral Arteries ◽  
Voltage Dependent ◽  
Basilar Arteries ◽  
Voltage Dependent Calcium Channels ◽  
Patch Clamp Electrophysiology

Although dihydropyridines are widely used for the treatment of vasospasm, their effectiveness is questionable, suggesting that other voltage-dependent calcium channels (VDCCs) contribute to control of cerebrovascular tone. This study therefore investigated the role of dihydropyridine-insensitive VDCCs in cerebrovascular function. Using quantitative PCR and immunohistochemistry, we found mRNA and protein for L-type (CaV1.2) and T-type (CaV3.1 and CaV3.2) channels in adult rat basilar and middle cerebral arteries and their branches. Immunoelectron microscopy revealed both L- and T-type channels in smooth muscle cell (SMC) membranes. Using patch clamp electrophysiology, we found that a high-voltage-activated calcium current, showing T-type channel kinetics and insensitivity to nifedipine and nimodipine, comprised ∼20% of current in SMCs of the main arteries and ∼45% of current in SMCs from branches. Both components were abolished by the T-type antagonists mibefradil, NNC 55-0396, and efonidipine. Although nifedipine completely blocked vasoconstriction in pressurized basilar arteries, a nifedipine-insensitive constriction was found in branches and this increased in magnitude as vessel size decreased. We conclude that a heterogeneous population of VDCCs contributes to cerebrovascular function, with dihydropyridine-insensitive channels having a larger role in smaller vessels. Sensitivity of these currents to nonselective T-type channel antagonists suggests that these drugs may provide a more effective treatment for therapy-refractory cerebrovascular constriction.

Role of Methylglyoxal in Diabetic Cardiovascular and Kidney Diseases: Insights from Basic Science for Application into Clinical Practice

2018 ◽  
Vol 24 (26) ◽  
pp. 3072-3083 ◽  
Author(s):  
Sowndramalingam Sankaralingam ◽  
Angham Ibrahim ◽  
MD Mizanur Rahman ◽  
Ali H. Eid ◽  
Shankar Munusamy
Keyword(s):  
Therapeutic Strategy ◽  
Kidney Diseases ◽  
Vascular Dysfunction ◽  
Dicarbonyl Compound ◽  
Renal Complications ◽  
Lysine Residues ◽  
Patients With Diabetes ◽  
Prevalence Of Diabetes Mellitus

Background: The incidence and prevalence of diabetes mellitus are increasing globally at alarming rates. Cardiovascular and renal complications are the major cause of morbidity and mortality in patients with diabetes. Methylglyoxal (MG) - a highly reactive dicarbonyl compound – is increased in patients with diabetes and has been implicated to play a detrimental role in the etiology of cardiovascular and renal complications. Derived from glucose, MG binds to arginine and lysine residues in proteins, and the resultant end products serve as surrogate markers of MG generation in vivo. Under normal conditions, MG is detoxified by the enzyme glyoxalase 1 (Glo1), using reduced glutathione as a co-factor. Elevated levels of MG is known to cause endothelial and vascular dysfunction, oxidative stress and atherosclerosis; all of which are risk factors for cardiovascular diseases. Moreover, MG has also been shown to cause pathologic structural alterations and impair kidney function. Conversely, MG scavengers (such as N-acetylcysteine, aminoguanidine or metformin) or Nrf2/Glo1 activators (such as trans-resveratrol / hesperetin) are shown to be useful in preventing MG-induced cardiovascular and renal complications in diabetes. However, clinical evidence supporting the MG lowering properties of these agents are limited and hence, need further investigation. Conclusion: Reducing MG levels directly using scavengers or indirectly via activation of Nrf2/Glo1 may serve as a novel and potent therapeutic strategy to counter the deleterious effects of MG in diabetic complications.

Effects of ischemia and myogenic activity on active and passive mechanical properties of rat cerebral arteries

2002 ◽  
Vol 283 (6) ◽  
pp. H2268-H2275 ◽  
Author(s):  
Rebecca J. Coulson ◽  
Naomi C. Chesler ◽  
Lisa Vitullo ◽  
Marilyn J. Cipolla
Keyword(s):  
Contractile Activity ◽  
Cerebral Arteries ◽  
Biomechanical Properties ◽  
Short Term ◽  
Mechanical Stiffness ◽  
Middle Cerebral Arteries ◽  
Male Wistar Rats ◽  
Myogenic Activity ◽  
Activity Dependent

Passive (papaverine induced) and active (spontaneous pressure induced) biomechanical properties of ischemic and nonischemic rat middle cerebral arteries (MCAs) were studied under pressurized conditions in vitro. Ischemic (1 h of occlusion), contralateral, and sham-operated control MCAs were isolated from male Wistar rats ( n = 22) and pressurized using an arteriograph system that allowed control of transmural pressure (TMP) and measurement of lumen diameter and wall thickness. Three mechanical stiffness parameters were computed: overall passive stiffness (β), pressure-dependent modulus changes ( E inc,p), and smooth muscle cell (SMC) activity-dependent changes ( E inc,a). The β-value for ischemic vessels was increased compared with sham vessels (13.9 ± 1.7 vs. 9.1 ± 1.4, P < 0.05), indicating possible short-term remodeling due to ischemia. E inc,p increased with pressure in the passive vessels ( P < 0.05) but remained relatively constant in the active vessels for all vessel types, indicating that pressure-induced SMC contractile activity (i.e., myogenic reactivity) in cerebral arteries leads to the maintenance of a constant elastic modulus within the autoregulatory pressure range. E inc,a increased with pressure for all conditions, signifying that changes in stiffness are influenced by SMC activity and vascular tone.

scholarly journals Hepatic Encephalopathy-Associated Cerebral Vasculopathy in Acute-on-Chronic Liver Failure: Alterations on Endothelial Factor Release and Influence on Cerebrovascular Function

2020 ◽  
Vol 11 ◽  
Author(s):  
Laura Caracuel ◽  
Esther Sastre ◽  
María Callejo ◽  
Raquel Rodrigues-Díez ◽  
Ana B. García-Redondo ◽  
...  
Keyword(s):  
Hepatic Encephalopathy ◽  
Liver Failure ◽  
Cerebral Arteries ◽  
Chronic Liver ◽  
Chronic Liver Failure ◽  
Cerebrovascular Function ◽  
Liver Decompensation ◽  
Middle Cerebral Arteries ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

The acute-on-chronic liver failure (ACLF) is a syndrome characterized by liver decompensation, hepatic encephalopathy (HE) and high mortality. We aimed to determine the mechanisms implicated in the development of HE-associated cerebral vasculopathy in a microsurgical liver cholestasis (MHC) model of ACLF. Microsurgical liver cholestasis was induced by ligating and extracting the common bile duct and four bile ducts. Sham-operated and MHC rats were maintained for eight postoperative weeks Bradykinin-induced vasodilation was greater in middle cerebral arteries from MHC rats. Both Nω-Nitro-L-arginine methyl ester and indomethacin diminished bradykinin-induced vasodilation largely in arteries from MHC rats. Nitrite and prostaglandin (PG) F1α releases were increased, whereas thromboxane (TX) B2 was not modified in arteries from MHC. Expressions of endothelial nitric oxide synthase (eNOS), inducible NOS, and cyclooxygenase (COX) 2 were augmented, and neuronal NOS (nNOS), COX-1, PGI2 synthase, and TXA2S were unmodified. Phosphorylation was augmented for eNOS and unmodified for nNOS. Altogether, these endothelial alterations might collaborate to increase brain blood flow in HE.

Functional heterogeneity of endothelial P2 purinoceptors in the cerebrovascular tree of the rat

1999 ◽  
Vol 277 (3) ◽  
pp. H893-H900 ◽  
Author(s):  
Junping You ◽  
T. David Johnson ◽  
Sean P. Marrelli ◽  
Robert M. Bryan
Keyword(s):  
Cerebral Arteries ◽  
No Synthase ◽  
Third Order ◽  
Selective Agonist ◽  
Middle Cerebral Arteries ◽  
Spontaneous Tone ◽  
A Minor ◽  
Calcium Activated Potassium Channel ◽  
Dose Dependent

The effects of stimulating P2Y1 or P2Y2 purinoceptors on the endothelium of isolated middle cerebral arteries (MCAs), third-order branches of the MCA (bMCAs), and penetrating arterioles (PAs) of the rat were studied. After pressurization and development of spontaneous tone (25% contraction), resting diameters for MCAs, bMCAs, and PAs were 203 ± 5 ( n = 50), 99 ± 2 ( n = 42), and 87 ± 2 μm ( n = 53), respectively. Luminal application of the P2Y1-selective agonist 2-methylthioadenosine 5′-triphosphate elicited dose-dependent dilations (or loss of intrinsic tone) in MCAs but not in bMCAs or PAs. The dilation in MCAs was completely blocked by removal of the endothelium or by nitro-l-arginine methyl ester (10−5 M), an inhibitor of NO synthase. Luminal application of the P2Y2-selective agonist ATP elicited dilations in MCAs, bMCAs, and PAs. Removal of the endothelium abolished the dilations in all vessel groups. Dilations in MCAs have been shown to involve both NO and endothelium-derived hyperpolarizing factor (EDHF). The dilations in bMCAs and PAs had a minor NO component and prominent EDHF component; that is, 1) the dilations to ATP were not diminished by the combined inhibition of NO synthase and cyclooxygenase, 2) the dilations were accompanied by significant hyperpolarizations of the vascular smooth muscle (∼15 mV), and 3) the dilations were completely abolished by the calcium-activated potassium channel blocker charybdotoxin. We concluded that the role of NO in purinoceptor-induced dilations diminishes along the cerebrovascular tree in the rat, whereas the role of EDHF becomes more prominent.

Impaired pressure-induced constriction in mouse middle cerebral arteries of ASIC2 knockout mice

2008 ◽  
Vol 294 (4) ◽  
pp. H1793-H1803 ◽  
Author(s):  
Kimberly P. Gannon ◽  
Lauren G. VanLandingham ◽  
Nikki L. Jernigan ◽  
Samira C. Grifoni ◽  
Gina Hamilton ◽  
...  
Keyword(s):  
Ion Channel ◽  
Sensory Neurons ◽  
Knockout Mice ◽  
Cerebral Arteries ◽  
Normal Pressure ◽  
Intraluminal Pressure ◽  
Myogenic Tone ◽  
Wild Type ◽  
Middle Cerebral Arteries

Recent studies from our laboratory demonstrated the importance of mechanosensitive epithelial Na+ channel (ENaC) proteins in pressure-induced constriction in renal and cerebral arteries. ENaC proteins are closely related to acid-sensing ion channel 2 (ASIC2), a protein known to be required for normal mechanotransduction in certain sensory neurons. However, the role of the ASIC2 protein in pressure-induced constriction has never been addressed. The goal of the current study was to investigate the role of ASIC2 proteins in pressure-induced, or myogenic, constriction in the mouse middle cerebral arteries (MCAs) from ASIC2 wild-type (+/+), heterozygous (+/−), and null (−/−) mice. Constrictor responses to KCl (20–80 mM) and phenylephrine (10−7–10−4 M) were not different among groups. However, vasoconstrictor responses to increases in intraluminal pressure (15–90 mmHg) were impaired in MCAs from ASIC2−/− and +/− mice. At 60 and 90 mmHg, MCAs from ASIC2+/+ mice generated 13.7 ± 2.1% and 15.8 ± 2.0% tone and ASIC2−/− mice generated 7.4 ± 2.8% and 12.5 ± 2.4% tone, respectively. Surprisingly, MCAs from ASIC2+/− mice generated 1.2 ± 2.2% and 3.9 ± 1.8% tone at 60 and 90 mmHg. The reason underlying the total loss of myogenic tone in the ASIC2+/− is not clear, although the loss of mechanosensitive β- and γ-ENaC proteins may be a contributing factor. These results demonstrate that normal ASIC2 expression is required for normal pressure-induced constriction in the MCA. Furthermore, ASIC2 may be involved in establishing the basal level of myogenic tone.

Experimental determination of rupture pressure and stress of adventitia of human middle cerebral arteries

2017 ◽  
Vol 12 (6) ◽  
pp. 636-640 ◽  
Author(s):  
Adam Piechna ◽  
Leszek Lombarski ◽  
Bogdan Ciszek ◽  
Krzysztof Cieslicki
Keyword(s):  
Balloon Angioplasty ◽  
Cerebral Arteries ◽  
Biomechanical Properties ◽  
Leading Role ◽  
Middle Cerebral Arteries ◽  
Rupture Pressure ◽  
The Difference ◽  
Age Range

Background Intracranial arterial dissections might be attributed to the particular biomechanical properties of their specific layers. Also, knowledge of adventitia properties would be crucial in the context of intracranial balloon angioplasty. Aims The purpose of this work was to determine the rupture pressure of separated adventitia and compare it to intact cerebral arterial segments. Methods Brain specimens were harvested from 14 autopsy subjects (age range from 23 to 86 years). Pressure-inflation tests were conducted on proximal segments of middle cerebral arteries and separated adventitia layers from contralateral arteries to assess the rupture pressure values. Results The averaged rupture pressure of adventitia layers was 1.41 SD 0.25 atm (1072 SD 190 mmHg), whereas for intact arterial segments it was 2.32 SD 0.70 atm (1763 SD 532 mmHg) and diminished with age according to nonlinear regression trends. The difference beetween the aformentioned rupture pressures was positively correlated with rupture pressure of intact arterial segments ( R2 = 0.88; p < 0.001). Conclusions The obtained experimental results indicate a leading role of adventitia in building arterial strength under supraphysiological pressure conditions. The greater the rupture pressure of complete cerebral arteries, the smaller the contribution of adventitia in overall wall resistance.

Mechanical Properties of Active and Passive Rat Middle Cerebral Arteries

2002 ◽  
Author(s):  
Rebecca J. Coulson ◽  
Marilyn J. Cipolla ◽  
Lisa Vitullo ◽  
Naomi C. Chesler
Keyword(s):  
Mechanical Properties ◽  
Blood Flow ◽  
Smooth Muscle ◽  
Cell Activation ◽  
Cerebral Arteries ◽  
Disease States ◽  
Middle Cerebral Arteries ◽  
Extracellular Matrix Components ◽  
Brain Tissue Damage

Cerebral arteries play an important role in the regulation of cerebral blood flow through autoregulation, a well established phenomenon which is caused by a combination of myogenic, neuronal and metabolic mechanisms [1]. Myogenic reactivity is the ability of the vascular smooth muscle cells (SMC) to contract in response to stretch or to an increase in transmural pressure (TMP), and to dilate in response to a decrease in TMP [2]. It is this active constriction of arteries within the autoregulatory range that prompts studies of not just passive mechanical properties, but also active mechanical properties. Passive properties provide an understanding of the behavior of the extracellular matrix components of arteries (i.e. collagen and elastin); but, in order to understand how the artery behaves in vivo, it is necessary to understand the mechanical properties with smooth muscle cell activation. Mechanical properties might also be altered if the vessel is diseased or damaged. Ischemia has been shown to reduce vascular tone, which might lead to brain tissue damage during stroke [3]. Therefore studying the mechanical properties of vessels in disease states to determine if they are able to adequately take part in controlling local blood flow is also important.

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