scholarly journals Enteral Supplements of a Carbon Monoxide Donor CORM-A1 Protect against Cerebrovascular Dysfunction Caused by Neonatal Seizures

2014 ◽  
Vol 35 (2) ◽  
pp. 193-199 ◽  
Author(s):  
Jianxiong Liu ◽  
Alexander L Fedinec ◽  
Charles W Leffler ◽  
Helena Parfenova
Keyword(s):  
Carbon Monoxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Therapeutic Option ◽  
Neurovascular Unit ◽  
Neonatal Seizures ◽  
Quisqualic Acid ◽  
Effective Therapeutic Option ◽  
Pial Arterioles ◽  
Cerebral Vascular

Cerebral blood flow dysregulation caused by oxidative stress contributes to adverse neurologic outcome of seizures. A carbon monoxide (CO) donor CORM-A1 has antioxidant and cytoprotective properties. We investigated whether enteral supplements of CORM-A1 can improve cerebrovascular outcome of bicuculline-induced seizures in newborn piglets. CORM-A1 (2 mg/kg) was given to piglets via an oral gastric tube 10 minutes before or 20 minutes after seizure onset. Enteral CORM-A1 elevated CO in periarachnoid cerebrospinal fluid and produced a dilation of pial arterioles. Postictal cerebral vascular responses to endothelium-, astrocyte-, and vascular smooth muscle-dependent vasodilators were tested 48 hours after seizures by intravital microscopy. The postictal responses of pial arterioles to bradykinin, glutamate, the AMPA receptor agonist quisqualic acid, ADP, and heme were greatly reduced, suggesting that seizures cause injury to endothelial and astrocyte components of the neurovascular unit. In contrast, in the two groups of piglets receiving enteral CORM-A1, the postictal cerebral vascular responsiveness to these dilators was improved. Overall, enteral supplements of CORM-A1 before or during seizures offer a novel effective therapeutic option to deliver cytoprotective mediator CO to the brain, reduce injury to endothelial and astrocyte components of cerebral blood flow regulation and to improve the cerebrovascular outcome of neonatal seizures.

scholarly journals H2S mediates the vasodilator effect of endothelin-1 in the cerebral circulation

2018 ◽  
Vol 315 (6) ◽  
pp. H1759-H1764 ◽  
Author(s):  
Shalinkumar Patel ◽  
Alexander L. Fedinec ◽  
Jiangxiong Liu ◽  
Max A. Weiss ◽  
Massroor Pourcyrous ◽  
...  
Keyword(s):  
Blood Flow ◽  
Smooth Muscle ◽  
Cerebral Blood Flow ◽  
Vascular Endothelium ◽  
Cerebral Circulation ◽  
Bk Channels ◽  
Endothelin 1 ◽  
Pial Arterioles ◽  
Cerebral Vascular

H2S is an endogenous gasotransmitter that increases cerebral blood flow. In the cerebral vascular endothelium, H2S is produced by cystathionine δ-lyase (CSE). Endothelin-1 (ET-1) has constrictor and dilator influences on the cerebral circulation. The mechanism of the vasodilation caused by ET-1 may involve endothelium-derived factors. We hypothesize that ET-1-elicited dilation of pial arterioles requires an elevation of H2S production in the cerebral vascular endothelium. We investigated the effects of ET-1 on CSE-catalyzed brain H2S production and pial arteriolar diameter using cranial windows in newborn pigs in vivo. H2S was measured in periarachnoid cerebrospinal fluid. ET-1 (10−12–10−8 M) caused an elevation of H2S that was reduced by the CSE inhibitors propargylglycine (PPG) and β-cyano-l-alanine (BCA). Low doses of ET-1 (10−12–10−11 M) produced vasodilation of pial arterioles that was blocked PPG and BCA, suggesting the importance of H2S influences. The vasodilator effects of H2S may require activation of smooth muscle cell membrane ATP-sensitive K+ (KATP) channels and large-conductance Ca2+-activated K+ (BK) channels. The KATP inhibitor glibenclamide and the BK inhibitor paxilline blocked CSE/H2S-dependent dilation of pial arterioles to ET-1. In contrast, the vasoconstrictor response of pial arterioles to 10−8 M ET-1 was not modulated by PPG, BCA, glibenclamide, or paxilline and, therefore, was independent of CSE/H2S influences. Pial arteriolar constriction response to higher levels of ET-1 was independent of CSE/H2S and KATP/BKCa channel activation. These data suggest that H2S is an endothelium-derived factor that mediates the vasodilator effects of ET-1 in the cerebral circulation via a mechanism that involves activation of KATP and BK channels in vascular smooth muscle. NEW & NOTEWORTHY Disorders of the cerebral circulation in newborn infants may lead to lifelong neurological disabilities. We report that vasoactive peptide endothelin-1 exhibits vasodilator properties in the neonatal cerebral circulation by stimulating production of H2S, an endothelium-derived messenger with vasodilator properties. The ability of endothelin-1 to stimulate brain production of H2S may counteract the reduction in cerebral blood flow and prevent the cerebral vascular dysfunction caused by stroke, asphyxia, cerebral hypoxia, ischemia, and vasospasm.

scholarly journals Astrocyte-produced carbon monoxide and the carbon monoxide donor CORM-A1 protect against cerebrovascular dysfunction caused by prolonged neonatal asphyxia

2018 ◽  
Vol 315 (4) ◽  
pp. H978-H988 ◽  
Author(s):  
Helena Parfenova ◽  
Massroor Pourcyrous ◽  
Alex L. Fedinec ◽  
Jianxiong Liu ◽  
Shyamali Basuroy ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Carbon Monoxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Glutamate Excitotoxicity ◽  
Neonatal Asphyxia ◽  
Cerebrovascular Dysfunction ◽  
Tin Protoporphyrin ◽  
Newborn Pigs ◽  
Cerebral Vascular

Neonatal asphyxia leads to cerebrovascular disease and neurological complications via a mechanism that may involve oxidative stress. Carbon monoxide (CO) is an antioxidant messenger produced via a heme oxygenase (HO)-catalyzed reaction. Cortical astrocytes are the major cells in the brain that express constitutive HO-2 isoform. We tested the hypothesis that CO, produced by astrocytes, has cerebroprotective properties during neonatal asphyxia. We developed a survival model of prolonged asphyxia in newborn pigs that combines insults of severe hypoxia, hypercapnia, and acidosis while avoiding extreme hypotension and cerebral blood flow reduction. During the 60-min asphyxia, CO production by brain and astrocytes was continuously elevated. Excessive formation of reactive oxygen species during asphyxia/reventilation was potentiated by the HO inhibitor tin protoporphyrin, suggesting that endogenous CO has antioxidant effects. Cerebral vascular outcomes tested 24 and 48 h after asphyxia demonstrated the sustained impairment of cerebral vascular responses to astrocyte- and endothelium-specific vasodilators. Postasphyxia cerebral vascular dysfunction was aggravated in newborn pigs pretreated with tin protoporphyrin to inhibit brain HO/CO. The CO donor CO-releasing molecule-A1 (CORM-A1) reduced brain oxidative stress during asphyxia/reventilation and prevented postasphyxia cerebrovascular dysfunction. The antioxidant and antiapoptotic effects of HO/CO and CORM-A1 were confirmed in primary cultures of astrocytes from the neonatal pig brain exposed to glutamate excitotoxicity. Overall, prolonged neonatal asphyxia leads to neurovascular injury via an oxidative stress-mediated mechanism that is counteracted by an astrocyte-based constitutive antioxidant HO/CO system. We propose that gaseous CO or CO donors can be used as novel approaches for prevention of neonatal brain injury caused by prolonged asphyxia. NEW & NOTEWORTHY Asphyxia in newborn infants may lead to lifelong neurological disabilities. Using the model of prolonged asphyxia in newborn piglets, we propose novel antioxidant therapy based on systemic administration of low doses of a carbon monoxide donor that prevent loss of cerebral blood flow regulation and may improve the neurological outcome of asphyxia.

Telmisartan prevents high-fat diet-induced neurovascular impairments and reduces anxiety-like behavior

2021 ◽  
pp. 0271678X2110034
Author(s):  
Gianna Huber ◽  
Mikolaj Ogrodnik ◽  
Jan Wenzel ◽  
Ines Stölting ◽  
Lukas Huber ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
High Fat Diet ◽  
Neurovascular Unit ◽  
Laser Speckle ◽  
Angiotensin Ii Receptor ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Whisker Pad ◽  
Receptor Blockers

Angiotensin II receptor blockers (telmisartan) prevent rodents from diet-induced obesity and improve their metabolic status. Hyperglycemia and obesity are associated with reduced cerebral blood flow and neurovascular uncoupling which may lead to behavioral deficits. We wanted to know whether a treatment with telmisartan prevents these changes in obesity. We put young mice on high-fat diet and simultaneously treated them with telmisartan. At the end of treatment, we performed laser speckle imaging and magnetic resonance imaging to assess the effect on neurovascular coupling and cerebral blood flow. Different behavioral tests were used to investigate cognitive function. Mice developed diet-induced obesity and after 16, not 8 weeks of high-fat diet, however, the response to whisker pad stimulation was about 30% lower in obese compared to lean mice. Simultaneous telmisartan treatment increased the response again by 10% compared to obese mice. Moreover, telmisartan treatment normalized high-fat diet-induced reduction of cerebral blood flow and prevented a diet-induced anxiety-like behavior. In addition to that, telmisartan affects cellular senescence and string vessel formation in obesity. We conclude, that telmisartan protects against neurovascular unit impairments in a diet-induced obesity setting and may play a role in preventing obesity related cognitive deficits in Alzheimer’s disease.

scholarly journals Comparison of Cerebrovascular Response to Hypoxic and Carbon Monoxide Hypoxia in Newborn and Adult Sheep

1984 ◽  
Vol 4 (1) ◽  
pp. 115-122 ◽  
Author(s):  
Raymond C. Koehler ◽  
Richard J. Traystman ◽  
Scott Zeger ◽  
Mark C. Rogers ◽  
M. Douglas Jones
Keyword(s):  
Carbon Monoxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Age Groups ◽  
Hypoxic Hypoxia ◽  
Dissociation Curve ◽  
Oxyhemoglobin Dissociation Curve ◽  
Adult Sheep ◽  
Control Value ◽  
Oxyhemoglobin Dissociation

Cerebral blood flow (CBF) responses to two types of isocapnic hypoxia, hypoxic hypoxia (HH) and carbon monoxide hypoxia (COH), were examined in seven unanesthetized adult sheep by the radiolabeled microsphere technique. Comparisons were made with newborn lambs (5–12 days old) previously studied under similar conditions. The arterial O2 content (Cao2) was reduced in a graded manner to 50–60% of the control value. During HH, CBF increased to maintain cerebral O2 delivery (Cao2 x CBF) in both adults and newborns; however, cerebral O2 uptake (CMRO2) did not change. Although CMRO2 was higher in newborns, the responses of CBF/CMRO2 to HH did not differ significantly in newborns and adults. In newborns, regional CBF showed that brainstem areas were particularly responsive to HH. In both age groups, CBF increased to a greater extent with COH than with HH for similar reductions in Cao2. This resulted in an increase in cerebral O2 delivery with COH. The degree to which COH differed from HH correlated with the magnitude of the leftward shift of the oxyhemoglobin dissociation curve that accompanies COH. In adults, CMRO2 fell by 16% with COH but was maintained in newborns. We conclude that maintenance of cerebral O2 delivery during acute, isocapnic HH is a property of CBF regulation common to both newborn and adult sheep. During COH, the position of the oxyhemoglobin dissociation curve is an additional factor that sets the level of O2 delivery. The fetal conditions of low Cao2 and a left-shifted oxyhemoglobin dissociation curve may have provided the newborn with a microcirculation better suited for maintaining CMRO2 during COH.

Abstract P531: Cerebral Blood Flow Analysis Using Flow Wire Measurements and CFD Analysis

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Aichi Chien ◽  
Huy Dinh ◽  
Viktor Szeder ◽  
Fernando Vinuela
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Flow Velocity ◽  
Cfd Simulation ◽  
Cfd Analysis ◽  
Flow Data ◽  
Velocity Data ◽  
Mean Flow ◽  
Good Agreement ◽  
Cerebral Vascular

Introduction: Clinical reports show that cerebral blood flow conditions are indicative of cerebral vascular disease. While methods for characterizing cerebral vascular flow have been extensively reported in the past, comparative analyses between direct flow measurements (DM) and computational flow dynamic (CFD) analysis remain limited. We hypothesize that flow data can be reliably measured both directly and through CFD in normal vessels. Methods: A left heart replicator was used as a realistic cardiac pump which maintained systolic pressure at 120 mmHg and diastolic pressure at 80 mmHg. A stenotic model with 50% stenosis for the ICA was connected to the replicator. A ComboWire was used for DM and recorded flow pressure and velocity. CFD was used to study flow. Results: In areas at the proximal end of the stenosis, the pressure and flow velocity derived from DM and CFD were in good agreement. At the end of systole and diastole, DM pressure were 145.42 mmHg and 73.53 mmHg, respectively. CFD simulation for the same system obtained the pressure at the end of systole and diastole of 147.16 mmHg and 74.64 mmHg, respectively. The velocity data collected from DM was at 15.40 cm/s and 7.74 cm/s for systolic flow and mean flow velocity. CFD measured flow was 17.85 cm/s and 11.37 cm/s, respectively. In areas at the distal end of the stenosis, pressure data showed good agreement between DM and CFD analysis. The DM were 138 and 70.81 mmHg at the end of systole and diastole, respectively; CFD simulation yielded 145.95 and 74.51 mmHg, respectively. Variations in the velocity data were observed at this location (Fig, pink arrows). Conclusion: DM of pressure showed good agreement with CFD simulation in all areas of the vessel. DM of velocity using the flow wire were highly affected by location of the measurement. CFD analysis can provide more consistent flow data for flow information collection along the vasculature.

Vascular response to infusions of a nonextravasating hemoglobin polymer

2002 ◽  
Vol 93 (4) ◽  
pp. 1479-1486 ◽  
Author(s):  
Barbara Matheson ◽  
Herman E. Kwansa ◽  
Enrico Bucci ◽  
Annette Rebel ◽  
Raymond C. Koehler
Keyword(s):  
Molecular Weight ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Arterial Pressure ◽  
Exchange Transfusion ◽  
Pressor Response ◽  
Low Molecular Weight ◽  
Bovine Hemoglobin ◽  
Pial Arterioles ◽  
Awake Cats

The clinical utility of cross-linked tetrameric hemoglobin solutions is limited by peripheral vasoconstriction thought to be due to scavenging of nitric oxide. In addition, transfusion of crude preparations of hemoglobin polymers can cause arterial hypertension. We tested the hypothesis that eliminating low-molecular-weight components from the polymer solution would prevent extravasation and its associated pressor response. A zero-link polymer of bovine hemoglobin was developed without chemical linkers left between the tetramers. Transfusion of unprocessed preparations of these polymers in rats resulted in appearance of the polymer in the renal hilar lymph. However, eliminating the low-molecular-weight components with a 300-kDa diafiltration resulted in an average hydrodynamic radius of 250 Å and in undetectable levels of polymer in hilar lymph. Exchange transfusion in anesthetized rats and cats and in awake cats produced no increase in arterial pressure. In anesthetized cats, exchange transfusion with an albumin solution reduced hematocrit from 30 to 18%, increased cerebral blood flow, and dilated pial arterioles. In contrast, reducing hematocrit by transfusing the diafiltered polymer did not increase cerebral blood flow as pial arterioles constricted. These results are consistent with the hypothesis that the increase in arterial pressure associated with cell-free hemoglobin transfusion depends on hemoglobin extravasation. Constriction observed in the cerebrovascular bed with a nonextravasating hemoglobin polymer at low hematocrit is presumably a regulatory response to prevent overoxygenation at low blood viscosity.

Effects of estrogen on cerebral blood flow and pial microvasculature in rabbits

2000 ◽  
Vol 279 (3) ◽  
pp. H1208-H1214 ◽  
Author(s):  
M. T. Littleton-Kearney ◽  
D. M. Agnew ◽  
R. J. Traystman ◽  
P. D. Hurn
Keyword(s):  
Blood Flow ◽  
Estrogen Receptor ◽  
Cerebral Blood Flow ◽  
Receptor Activation ◽  
Receptor Subtypes ◽  
Dependent Manner ◽  
Pial Arteries ◽  
Concentration Dependent Manner ◽  
Cranial Window ◽  
Pial Arterioles

We tested the hypothesis that intracarotid estrogen infusion increases cerebral blood flow (CBF) in a concentration-dependent manner and direct application of estrogen on pial arterioles yields estrogen receptor-mediated vasodilation. Rabbits of both genders were infused with estrogen via a branch of the carotid artery. Estrogen doses of 20 or 0.05 μg · ml−1 · min−1 were used to achieve supraphysiological or physiological plasma estrogen levels, respectively. CBF and cerebral vascular resistance were determined at baseline, during the infusion, and 60-min postinfusion, and effects on pial diameter were assessed via a cranial window. Pial arteriolar response to estrogen alone and to estrogen after administration of tamoxifen (10−7), an antiestrogen drug that binds to both known estrogen receptor subtypes, was tested. No gender differences were observed; therefore, data were combined for both males and females. Systemic estrogen infusion did not increase regional CBF. Estradiol dilated pial arteries only at concentrations ranging from 10−4–10−7 M ( P ≤ 0.05). Pretreatment with tamoxifen alone had no effect on arteriolar diameter but inhibited estrogen-induced vasodilation ( P < 0.001). Our data suggest that estrogen does not increase CBF under steady-state conditions in rabbits. In the pial circulation, topically applied estradiol at micromolar concentrations dilates vessels. The onset is rapid and dependent on estrogen receptor activation.

Vasopressin and prostanoid mechanisms in control of cerebral blood flow in hypotensive newborn pigs

1990 ◽  
Vol 258 (2) ◽  
pp. H408-H413 ◽  
Author(s):  
W. M. Armstead ◽  
C. W. Leffler ◽  
D. W. Busija ◽  
R. Mirro
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Metabolic Rate ◽  
Vascular Resistance ◽  
Brain Regions ◽  
Cerebral Metabolic Rate ◽  
Cerebral Vasoconstriction ◽  
Newborn Pigs ◽  
Cerebral Vascular Resistance ◽  
Cerebral Vascular

The interaction between vasopressinergic and prostanoid mechanisms in the control of cerebral hemodynamics in the conscious hypotensive newborn pig was investigated. Indomethacin treatment (5 mg/kg) of hypotensive piglets caused a significant decrease in blood flow to all brain regions within 20 min. This decrease in cerebral blood flow resulted from increased cerebral vascular resistances of 52 and 198% 20 and 40 min after treatment, respectively. Cerebral oxygen consumption was reduced from 2.58 +/- 0.32 ml.100 g-1.min-1 to 1.01 +/- 0.12 and 0.29 +/- 0.08 ml.100 g-1.min-1 20 and 40 min after indomethacin, respectively, in hemorrhaged piglets. Treatment with the putative vascular (V1) receptor antagonist [1-(beta-mercapto-beta, beta-cyclopentamethylene propionic acid-2-(O-methyl)tyrosine]arginine vasopressin (MEAVP) had no effect on regional cerebral blood flow, calculated cerebral vascular resistance, or cerebral metabolic rate either before or during hemorrhagic hypotension. However, decreases in cerebral blood flow and metabolic rate and increases in vascular resistance on treatment with indomethacin were blunted markedly in animals treated with MEAVP. These data are consistent with the hypothesis that the prostanoid system contributes to the maintenance of cerebral blood flow and cerebral metabolic rate during hypotension in the newborn pig, as reported previously, and implicate removal of vasopressinergic modulation by prostanoids as a potential mechanism for indomethacin-induced cerebral vasoconstriction in hypotensive newborn piglets.

Sign in / Sign up

Export Citation Format

Share Document