The cold receptor TRPM8 activation leads to attenuation of endothelium-dependent cerebral vascular functions during head cooling

2021 ◽  
pp. 0271678X2110180
Author(s):  
Alex L Fedinec ◽  
Jianxiong Liu ◽  
Rong Zhang ◽  
Mimily Harsono ◽  
Massroor Pourcyrous ◽  
...  
Keyword(s):  
Mild Hypothermia ◽  
Brain Parenchyma ◽  
Trpm8 Channel ◽  
Cranial Window ◽  
Head Cooling ◽  
Window Technique ◽  
Pial Arterioles ◽  
Cold Sensitive ◽  
The Brain ◽  
Cerebral Vascular

Using the cranial window technique, we investigated acute effects of head cooling on cerebral vascular functions in newborn pigs. Head cooling lowered the rectal and extradural brain temperatures to 34.3 ± 0.6°C and 26.1 ± 0.6°C, respectively. During the 3-h hypothermia period, responses of pial arterioles to endothelium-dependent dilators bradykinin and glutamate were reduced, whereas the responses to hypercapnia and an endothelium-independent dilator sodium nitroprusside (SNP) remained intact. All vasodilator responses were restored after rewarming, suggesting that head cooling did not produce endothelial injury. We tested the hypothesis that the cold-sensitive TRPM8 channel is involved in attenuation of cerebrovascular functions. TRPM8 is immunodetected in cerebral vessels and in the brain parenchyma. During normothermia, the TRPM8 agonist icilin produced constriction of pial arterioles that was antagonized by the channel blocker AMTB. Icilin reduced dilation of pial arterioles to bradykinin and glutamate but not to hypercapnia and SNP, thus mimicking the effects of head cooling on vascular functions. AMTB counteracted the impairment of endothelium-dependent vasodilation caused by hypothermia or icilin. Overall, mild hypothermia produced by head cooling leads to acute reversible reduction of selected endothelium-dependent cerebral vasodilator functions via TRPM8 activation, whereas cerebral arteriolar smooth muscle functions are largely preserved.

Endothelial and nonendothelial cyclooxygenase mediate rabbit pial arteriole dilation by bradykinin

1995 ◽  
Vol 268 (1) ◽  
pp. H458-H466 ◽  
Author(s):  
J. R. Copeland ◽  
K. A. Willoughby ◽  
T. M. Tynan ◽  
S. F. Moore ◽  
E. F. Ellis
Keyword(s):  
Selective Inhibition ◽  
Gas Mixture ◽  
Cerebral Microvessels ◽  
Co2 Gas ◽  
Cranial Window ◽  
Cyclooxygenase Activity ◽  
Window Technique ◽  
Pial Arterioles ◽  
Cerebral Arterioles ◽  
The Brain

Aspirin (acetylsalicylic acid, ASA) was administered to rabbits in an attempt to inhibit selectively endothelial cyclooxygenase activity and therefore to determine its role in bradykinin-induced radical-mediated dilation of cerebral arterioles. With the use of the cranial window technique in anesthetized rabbits, pial arteriolar diameters were recorded in response to topically applied bradykinin, acetylcholine, and ventilation with 10% O2-9% CO2 gas mixture. Prostaglandins were measured in isolated cerebral microvessels and cerebrospinal fluid (CSF) using radioimmunoassay. Microvessel prostaglandin production was reduced significantly by 90 mg/kg i.v. ASA, whereas acetylcholine-stimulated increases of CSF prostaglandins were not similarly affected. This treatment reduced bradykinin-induced dilation of pial arterioles by 47%. After concurrent 90 mg/kg i.v. ASA plus 300 microM ASA topically applied to the brain, stimulated increases of CSF prostaglandins were reduced by 79%, while bradykinin-induced dilation was reduced by 78%. ASA did not reduce the dilator activity of either acetylcholine or ventilation with 10% O2-9% CO2. Acetylcholine- but not bradykinin-induced dilation was reduced by NG-nitro-L-arginine methyl ester. These results indicate intravenous ASA produced a relatively selective inhibition of cerebral microvascular cyclooxygenase and partial inhibition of bradykinin-induced dilation. Further inhibition of dilation occurred following ASA administered both systemically and topically to the brain. This indicates two sources of cyclooxygenase, endothelial and nonendothelial, mediate the bradykinin-induced dilation of rabbit pial arterioles. Furthermore, systemic doses of ASA do not eliminate brain prostaglandin formation.

Segmental Vascular Resistance after Mild Controlled Cortical Impact Injury in the Rat

2003 ◽  
Vol 23 (2) ◽  
pp. 210-218 ◽  
Author(s):  
Elke M. Golding ◽  
Claudia S. Robertson ◽  
Jane C. K. Fitch ◽  
J. Clay Goodman ◽  
Robert M. Bryan
Keyword(s):  
Vascular Resistance ◽  
Controlled Cortical Impact ◽  
Small Vessels ◽  
Cranial Window ◽  
Window Technique ◽  
Pial Arterioles ◽  
Controlled Cortical Impact Injury ◽  
Cortical Impact ◽  
Impact Injury ◽  
The Brain

In an effort to localize the site at which increased resistance occurs after brain trauma, pial arteriole diameter and pressure were assessed after mild controlled cortical impact (CCI) injury in rats using an open cranial window technique. The authors tested the hypothesis that an increase in resistance accompanied by vasoconstriction occurs at the level of the pial arterioles within the injured cortex of the brain. At 1 hour after mild CCI injury, ipsilateral cerebral blood flow was significantly reduced by 42% compared with sham injury (n = 4; P < 0.05). Pial arteriole diameter and pressure remained unchanged. Resistance in the larger arteries (proximal resistance), however, was significantly greater after CCI injury (1.87 ± 0.26 mm Hg/[mL · 100 g · min]) compared with sham injury (0.91 ± 0.21 mm Hg/[mL · 100 g ·min]; P < 0.0001). Resistance in small vessels, arterioles, and venules (distal resistance) was also significantly greater after CCI injury (1.13 ± 0.05 mm Hg/[mL · 100 g · min]) compared with sham injury (0.74 ± 0.13 mm Hg/[mL · 100 g · min]; P = 0.0001). The authors conclude that, at 1 hour after mild CCI injury, changes in vascular resistance comprise a 53% increase in the resistance distal to the area of injury and, surprisingly, a 105% increase in resistance in the arteries proximal to the injury site.

scholarly journals New optical method for analyzing cortical blood flow heterogeneity in small animals: validation of the method

2000 ◽  
Vol 279 (3) ◽  
pp. H1291-H1298 ◽  
Author(s):  
Istvan Schiszler ◽  
Minoru Tomita ◽  
Yasuo Fukuuchi ◽  
Norio Tanahashi ◽  
Koji Inoue
Keyword(s):  
Blood Flow ◽  
Mean Transit Time ◽  
Region Of Interest ◽  
Brain Parenchyma ◽  
Sprague Dawley ◽  
Doppler Flowmetry ◽  
Cranial Window ◽  
Brain Surface ◽  
Fine Glass ◽  
The Brain

In pentobarbital-anesthetized male Sprague-Dawley rats, a small cranial window was trephined, and the cortex was transilluminated with a fine glass fiber inserted into the brain parenchyma. The light intensity at the surface area of 2 × 2 mm was recorded during intracarotid injection of 25 μl of carbon black (CB) solution. The region of interest (ROI) was divided into a 50 × 50 matrix, and the mean transit time of CB transport was calculated in each matrix element. We found rapid transits of CB along the microvasculature, with considerable heterogeneity in the avascular area, and heterogeneous efficiency in autoregulatory capacity in the ROI during hypotension. The method was validated by comparison with laser-Doppler flowmetry. The average mean difference was 0.03 ± 0.05%. Five percent CO2 inhalation increased the flow by 85%, but heterogeneously. We concluded that the technique is exclusively sensitive to indicator transits in a very small area on the brain surface with potential usefulness in detecting regional heterogeneity in blood flow.

Hypoglycemia selectively abolishes hypoxic reactivity of pial arterioles in piglets: role of adenosine

1995 ◽  
Vol 268 (2) ◽  
pp. H871-H878 ◽  
Author(s):  
T. S. Park ◽  
E. R. Gonzales ◽  
A. R. Shah ◽  
J. M. Gidday
Keyword(s):  
Arterial Pco2 ◽  
Adenosine Receptor Antagonist ◽  
Cranial Window ◽  
Newborn Piglets ◽  
Window Technique ◽  
Pial Arterioles ◽  
Cerebrovascular Regulation ◽  
Arterial Po2 ◽  
Arteriolar Diameter

Episodes of hypoxia often occur in hypoglycemic newborns, but it is not known whether dysfunctions in cerebrovascular regulation contribute to brain injury incurred by these affected neonates. We tested the hypotheses that 1) perinatal hypoglycemia impairs cerebrovascular responses to hypoxia and 2) a reduced vascular smooth muscle sensitivity to adenosine accounts for this impairment. Responses of 25- to 50-mu m-diam pial arterioles were determined using the cranial window technique in isoflurane-anesthetized newborn piglets < 5 days of age. Hypoxia (arterial PO2 = 28 +/- 1 mmHg) caused a 47 +/- 5% increase (P = 0.0008) in arteriolar diameter, 89% of which could be blocked by prior superfusion of the window space with the preferential A2-adenosine receptor antagonist 3,7-dimethyl-1-propargylxanthine (DMPX; 50 microM). Insulin-induced hypoglycemia (blood glucose = 18 +/- 1 mg/dl without isoelectric electroencephalogram) caused a 31 +/- 5% increase (P = 0.002) in arteriolar diameter; however, no additional dilatative response to hypoxia (arterial PO2 = 28 +/- 1 mmHg) could be elicited in these animals. Arteriolar dilation of 41 +/- 6% (P = 0.002) induced by superfusion of 20 microM adenosine under normoglycemic conditions was also completely abolished after the animals were rendered hypoglycemic. Unlike the response to hypoxia and adenosine, hypoglycemia only attenuated prostanoid-dependent dilations to hypercapnia (arterial PCO2 = 68 +/- 3 mmHg) by 55 +/- 9%. These results indicate that, in the newborn, hypoglycemia selectively abolishes hypoxic reactivity through an impairment in adenosine-mediated cerebrovascular dilation.

Inhibitory effect of indomethacin on prostacyclin receptor-mediated cerebral vascular responses

1995 ◽  
Vol 268 (5) ◽  
pp. H1884-H1890 ◽  
Author(s):  
H. Parfenova ◽  
S. Zuckerman ◽  
C. W. Leffler
Keyword(s):  
Inhibitory Effect ◽  
Prostaglandin H Synthase ◽  
Vascular Responses ◽  
Cranial Window ◽  
Prostacyclin Receptor ◽  
Window Technique ◽  
Effective Inhibition ◽  
Prostaglandin H ◽  
Cerebral Vasodilation ◽  
Cerebral Vascular

The present study addresses the hypothesis that indomethacin, in addition to blocking prostaglandin synthesis, directly inhibits prostacyclin receptor-mediated cerebral vascular responses. To test this hypothesis, the effects of indomethacin on pial arteriolar dilation in response to the prostacyclin receptor agonist iloprost were investigated using a cranial window technique in newborn pigs. Topically applied iloprost resulted in dose-dependent pial arteriolar dilation and concomitant increases in cortical adenosine 3',5'-cyclic monophosphate (cAMP). Indomethacin (5 mg/kg iv + 10(-4) M topically) greatly reduced both the vasodilation and the increase in cortical cAMP in response to iloprost. In contrast, indomethacin did not attenuate beta-adrenoreceptor-mediated vasodilation and the increase in cortical cAMP in response to isoproterenol. Aspirin (50 mg/kg iv + 10(-3) M topically) did not affect pial arteriolar dilation or the increase in cortical cAMP in response to iloprost. Unlike indomethacin, aspirin was not effective in inhibiting prostanoid-associated cerebral vasodilation and increase in cortical cAMP in response to hypercapnia. The present data suggest that indomethacin selectively inhibits prostacyclin receptor-mediated responses in the newborn pig cerebral circulation. The combination of highly effective inhibition of prostaglandin H synthase and prostacyclin receptor-mediated vasodilation may contribute to the increased efficacy of indomethacin compared with other prostaglandin H synthase inhibitors in blocking certain vasodilator responses associated with prostanoids.

Dilator effects of amino acid neurotransmitters on piglet pial arterioles

1989 ◽  
Vol 257 (4) ◽  
pp. H1200-H1203 ◽  
Author(s):  
D. W. Busija ◽  
C. W. Leffler
Keyword(s):  
Amino Acids ◽  
Cranial Window ◽  
Window Technique ◽  
Prolonged Contact ◽  
Vascular Responsiveness ◽  
Pial Arterioles ◽  
Csf Levels ◽  
Newborn Pigs ◽  
Arteriolar Tone ◽  
Arteriolar Diameter

We examined the effects of topically applied amino acids (glutamate, aspartate, glycine, and taurine) and a synthetic glutamate analogue [N-methyl-D-aspartate (NMDA)] on pial arteriolar tone and cortical surface cerebrospinal fluid (CSF) dilator prostanoid concentrations in anesthetized newborn pigs. We also determined whether prolonged contact of pial arterioles with glutamate (10(-3) M) and aspartate (10(-3) M) would alter arteriolar responses to exogenous isoproterenol or norepinephrine. Vascular responses were determined using the closed cranial window technique and intravital microscopy. Concentrations of prostaglandin E2 and 6-ketoprostaglandin F1 alpha in CSF under the cranial window were determined using radioimmunoassay. At the highest dose tested (10(-3) M), NMDA dilated arterioles by 30 +/- 4% (n = 8), glutamate by 21 +/- 5% (n = 6), aspartate by 28 +/- 10% (n = 5), and taurine by 21 +/- 2% (n = 7). Glycine application did not change pial arteriolar diameter significantly (n = 8). The amino acids tested (NMDA and glutamate) did not increase CSF levels of dilator prostagnoids, and intravenous indomethacin trihydrate did not change vascular responsiveness to NMDA. Furthermore, dilator responsiveness to isoproterenol and constrictor responsiveness to norepinephrine were not affected significantly after 30 min of topical application of glutamate and aspartate to the pial surface (n = 4). We conclude that these amino acids are potent dilators of the neonatal cerebral circulation. The mechanism of dilation in the cases of NMDA and glutamate does not appear to involve dilator prostanoids. Furthermore, prolonged contact with excitatory amino acids under these conditions does not alter subsequent cerebrovascular responsiveness.

scholarly journals Selective head cooling and whole body cooling as neuroprotective agents in severe perinatal asphyxia

2019 ◽  
Vol 65 (8) ◽  
pp. 1116-1121 ◽  
Author(s):  
Mahara Nonato ◽  
Larissa Gheler ◽  
João Vitor Balestrieri ◽  
Marise Audi ◽  
Mirto Prandini
Keyword(s):  
Perinatal Asphyxia ◽  
Brain Structures ◽  
Brain Parenchyma ◽  
Cerebral Injury ◽  
Whole Body ◽  
Cortical Region ◽  
Head Cooling ◽  
Body Cooling ◽  
The Brain ◽  
Full Body

SUMMARY INTRODUCTION The possibility that hypothermia has a therapeutic role during or after resuscitation from severe perinatal asphyxia has been a longstanding focus of research. Studies designed around this fact have shown that moderate cerebral hypothermia, initiated as early as possible, has been associated with potent, long-lasting neuroprotection in perinatal patients. OBJECTIVES To review the benefits of hypothermia in improving cellular function, based on the cellular characteristics of hypoxic-ischemic cerebral injury and compare the results of two different methods of cooling the brain parenchyma. METHODS Medline, Lilacs, Scielo, and PubMed were searched for articles registered between 1990 and 2019 in Portuguese and English, focused on trials comparing the safety and effectiveness of total body cooling with selective head cooling with HIE. RESULTS We found that full-body cooling provides homogenous cooling to all brain structures, including the peripheral and central regions of the brain. Selective head cooling provides a more extensive cooling to the cortical region of the brain than to the central structures. CONCLUSIONS Both methods demonstrated to have neuroprotective properties, although full-body cooling provides a broader area of protection. Recently, head cooling combined with some body cooling has been applied, which is the most promising approach. The challenge for the future is to find ways of improving the effectiveness of the treatment.

scholarly journals Reactivity of Rat Pial Arterioles and Venules to Adenosine and Carbon Dioxide: With Detailed Description of the Closed Cranial Window Technique in Rats

1986 ◽  
Vol 6 (1) ◽  
pp. 34-41 ◽  
Author(s):  
Seiji Morii ◽  
Al C. Ngai ◽  
H. Richard Winn
Keyword(s):  
Carbon Dioxide ◽  
Video Camera ◽  
Vessel Diameter ◽  
Resolving Power ◽  
Camera System ◽  
Cranial Window ◽  
Window Technique ◽  
Adenosine Concentration ◽  
Pial Arterioles

This study describes a closed cranial window technique that allows the observation and measurement of rat pial arterioles and venules in situ. The resolving power of this system is 1–2 μm. Using this sensitive technique, we characterized the responses to 7% carbon dioxide inhalation and adenosine in arterioles (10–70 μm) and venules (15–100 μm). During carbon dioxide inhalation, larger arterioles (>40μm) dilated more than smaller arterioles (<20 μm). There was limited vasoreac-tivity of pial venules during CO2 inhalation. Dilation of arterioles was initially observed with an adenosine concentration of 10−8 M. Almost a twofold increase in diameter was noted at 10−3 M. In contrast to the effect of CO2 inhalation, the degree of dilation with topical application of adenosine was not size dependent. Pial venules did not respond to adenosine. The technique for observation of pial vessels using the closed cranial window and for measurement of vessel diameter by video camera system microscopy is a powerful tool for studying in vivo the cerebral circulation in the rat.

Neuronal NOS-cGMP-dependent ACh-induced relaxation in pial arterioles of endothelial NOS knockout mice

1998 ◽  
Vol 274 (2) ◽  
pp. H411-H415 ◽  
Author(s):  
Wei Meng ◽  
Cenk Ayata ◽  
Christian Waeber ◽  
Paul L. Huang ◽  
Michael A. Moskowitz
Keyword(s):  
Soluble Guanylyl Cyclase ◽  
Enos Gene ◽  
Wild Type ◽  
Compensatory Mechanisms ◽  
Cranial Window ◽  
Pial Arterioles ◽  
Oxide Synthase ◽  
The Brain ◽  
Type Strains

We evaluated the effects of superfusing 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), eNOS null ( B)an inhibitor of soluble guanylyl cyclase, and 7-nitroindazole sodium (7-NI), a selective neuronal nitric oxide synthase (nNOS) inhibitor, on the acetylcholine (ACh) response in endothelial NOS (eNOS) null mice. Pial arteriolar diameter was measured by intravital microscopy through a closed cranial window under α-chloralose anesthesia. NOS activity was measured by [3H]arginine-to-[3H]citrulline conversion in subjacent cortex in vitro. The density and distribution of muscarinic receptors in the brain were determined by quantitative [3H]quinuclidinyl benzilate autoradiography and did not differ between the eNOS mutants and wild-type mice. ACh superfusion (1 and 10 μM) dose dependently dilated pial arterioles in eNOS null and wild-type mice. ODQ (10 μM) attenuated ACh-induced dilation in both eNOS mutants (41% decrease at 10 μM ACh, P < 0.01, n = 6) and wild-type strains ( n = 5 per group). By contrast, topical superfusion of 7-NI (100 μM) attenuated the ACh response in eNOS mutants only (66%, P < 0.05, and 25% decrease, P < 0.05, at 1 and 10 μM ACh, respectively). Our findings suggest that nNOS-guanosine 3′,5′-cyclic monophosphate (cGMP)-dependent pathways dilate pial arterioles by compensatory mechanisms after eNOS gene disruption.

scholarly journals Effects of Dopamine on Pial Arteriolar Diameter and CSF Prostanoid Levels in Piglets

1989 ◽  
Vol 9 (3) ◽  
pp. 264-267 ◽  
Author(s):  
David W. Busija ◽  
Charles W. Leffler
Keyword(s):  
Topical Application ◽  
Intravital Microscopy ◽  
Prostaglandin E ◽  
Vascular Responses ◽  
Cranial Window ◽  
Window Technique ◽  
Pial Arterioles ◽  
Newborn Pigs ◽  
High Doses ◽  
Arteriolar Diameter

We examined effects of topically applied dopamine on pial arteriolar diameter and CSF prostanoid levels in newborn pigs. Vascular responses were determined using the closed cranial window technique and intravital microscopy, and prostanoids were determined by radioimmunoassay. Topical application of dopamine did not change arteriolar diameter at 10−7–10−5 M, but constricted arterioles at 10−4 (16%) and 10−3 M (30%). Intravenous administration of indomethacin (5 mg/kg) did not alter this constriction. In addition, CSF prostanoid levels did not increase in response to application of dopamine except for a modest increase of prostaglandin E2 at 10−3 M. We conclude that dopamine is a constrictor at high doses of piglet pial arterioles and that this response is not modified by endogenous prostanoids.

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