Indomethacin-sensitive CO2 reactivity of cerebral arterioles is restored by vasodilator prostaglandin

1994 ◽  
Vol 266 (4) ◽  
pp. H1332-H1338 ◽  
Author(s):  
L. C. Wagerle ◽  
P. A. Degiulio
Keyword(s):  
Sodium Nitroprusside ◽  
Intracellular Signaling ◽  
Receptor Activation ◽  
Cyclooxygenase Inhibitors ◽  
Relaxation Response ◽  
Cyclic Monophosphate ◽  
Cranial Window ◽  
Vasodilator Response ◽  
Cerebral Arterioles ◽  
Arteriolar Diameter

To investigate the role of vasodilator prostanoids in the CO2-induced relaxation of cerebral arterioles, the present study examined the effect of exogenous prostaglandin (PG) E2 and nonprostanoid vasodilators, adenosine and sodium nitroprusside, on the indomethacin-impaired pial arteriolar response to CO2 in newborn piglets. Reactivity of pial arterioles (52-131 microns diam) was determined using a closed cranial window with intravital microscopy. Cortical prostanoid synthesis was assessed by analyzing for select prostanoids in cerebrospinal fluid sampled from under the cranial window. Inhalation of 7% CO2 caused an elevation of cortical 6-keto-PGF1 alpha and thromboxane (Tx) B2 and increased pial arteriolar diameter by 34 +/- 5%. Two cyclooxygenase inhibitors, indomethacin (5 mg/kg i.v.) and ibuprofen (30 mg/kg i.v.), abolished the CO2-induced elevation of cortical prostanoids. Indomethacin, but not ibuprofen, blocked the CO2-induced increase in pial arteriolar diameter. The indomethacin-impaired vasodilator response to CO2 was restored when PGE2 (0.1-1 microM) was applied topically to the cortical surface. Adenosine (1-100 microM) and sodium nitroprusside (0.5 microM) only partially restored the vasodilator response to CO2. The data suggest that vasodilator prostanoids facilitate cerebrovascular relaxation to CO2 and may play a permissive role in the relaxation response of vascular smooth muscle. The fact that adenosine (adenosine 3',5'-cyclic monophosphate-mediated dilator) and sodium nitroprusside (guanosine 3',5'-cyclic monophosphate-mediated dilator), were partially effective suggests a role for those intracellular signaling pathways. We speculate that receptor activation of intracellular pathways may alter Ca2+ sensitivity of the contractile apparatus in such a way that the relaxation response to CO2 can occur.(ABSTRACT TRUNCATED AT 250 WORDS)

Dilation of cerebral arterioles by cytochrome P-450 metabolites of arachidonic acid

1990 ◽  
Vol 259 (4) ◽  
pp. H1171-H1177 ◽  
Author(s):  
E. F. Ellis ◽  
R. J. Police ◽  
L. Yancey ◽  
J. S. McKinney ◽  
S. C. Amruthesh
Keyword(s):  
Arachidonic Acid ◽  
Oxygen Radicals ◽  
Cyclooxygenase Inhibitors ◽  
Epoxyeicosatrienoic Acid ◽  
Cranial Window ◽  
Window Technique ◽  
Cerebral Arterioles ◽  
Pg E2 ◽  
Cytochrome P 450

We have recently shown that brain tissue can synthesize cytochrome P-450 monooxygenase metabolites of arachidonic acid (AA), including 5,6-epoxyeicosatrienoic acid (5,6-EET), and 14,15-EET. The purpose of this investigation was to determine the vasoactivity of EETs and AA on the cerebral microcirculation. Pial arteriolar diameter was measured in rabbits and cats using in vivo microscopy and the closed cranial window technique. Prostaglandin (PG) E2 and 6-keto-PGF1 alpha formed by the brain cortex during application of these fatty acids was measured in cerebrospinal fluid by use of radioimmunoassay. A transient dose-dependent dilation was produced by 5,6-EET (1-15 micrograms/ml), with the maximum being 23% of control in both species. Other EETs had little or no activity, and AA-induced dilation was greater in rabbits than in cats. Indomethacin or superoxide dismutase plus catalase prevented dilation by 5,6-EET and AA, indicating that both produce dilation via cyclooxygenase-dependent oxygen radicals. PGE2 and 6-keto-PGF1 alpha levels were increased by AA but not by EETs, implying that EETs do not directly activate AA metabolism. Since 5,6-EET, but not other EETs, is known to be a substrate for cyclooxygenase, our data are consistent with brain cyclooxygenase metabolism of 5,6-EET with concomitant generation of dilator oxygen radicals. An implication of these results is that many previous studies of the cerebral circulation which based conclusions on results with cyclooxygenase inhibitors may need to be additionally interpreted.

Potassium channels modulate cerebral autoregulation during acute hypertension

2000 ◽  
Vol 278 (6) ◽  
pp. H2003-H2007 ◽  
Author(s):  
Roberto Paternò ◽  
Donald D. Heistad ◽  
Frank M. Faraci ◽  
Keyword(s):  
Blood Pressure ◽  
Arterial Pressure ◽  
Cerebral Autoregulation ◽  
Acute Hypertension ◽  
Calcium Dependent ◽  
Control Value ◽  
Cranial Window ◽  
Cerebral Arterioles ◽  
Arteriolar Diameter ◽  
Baseline Diameter

We tested the hypothesis that constriction of cerebral arterioles during acute increases in blood pressure is attenuated by activation of potassium (K+) channels. We tested the effects of inhibitors of calcium-dependent K+ channels [iberiotoxin (50 nM) and tetraethylammonium (TEA, 1 mM)] on changes in arteriolar diameter during acute hypertension. Diameter of cerebral arterioles (baseline diameter = 46 ± 2 μm, mean ± SE) was measured using a cranial window in anesthetized rats. Arterial pressure was increased from a control value of 96 ± 1 mmHg to 130, 150, 170, and 200 mmHg by intravenous infusion of phenylephrine. Increases in arterial pressure from baseline to 130 and 150 mmHg decreased the diameter of cerebral arterioles by 5–10%. Greater increases in arterial pressure produced large increases in arteriolar diameter (i.e., “breakthrough of autoregulation”). Iberiotoxin or TEA inhibited increases in arteriolar diameter when arterial pressure was increased to 170 and 200 mmHg. The change in arteriolar diameter at 200 mmHg was 20 ± 3% and −1 ± 4% in the absence and presence of iberiotoxin, respectively. These findings suggest that calcium-dependent K+ channels attenuate cerebral microvascular constriction during acute increases in arterial pressure, and that increases in arteriolar diameter at high levels of arterial pressure are not simply a passive phenomenon.

Nitric oxide contributes to dilatation of cerebral arterioles during seizures

1993 ◽  
Vol 265 (6) ◽  
pp. H2209-H2212 ◽  
Author(s):  
F. M. Faraci ◽  
K. R. Breese ◽  
D. D. Heistad
Keyword(s):  
Nitric Oxide ◽  
Amino Acids ◽  
Arterial Pressure ◽  
Excitatory Amino Acids ◽  
No Synthase ◽  
Cerebral Microcirculation ◽  
Cranial Window ◽  
Cerebral Arterioles ◽  
Endogenous Release ◽  
Arteriolar Diameter

Endogenous release of excitatory amino acids during seizures produces marked increases in neuronal activity and guanosine 3',5'-cyclic monophosphate levels in brain tissue, which are mediated by nitric oxide (NO). We tested the hypothesis that dilatation of the cerebral microcirculation during seizures is mediated by NO. Diameters of cerebral arterioles were measured using a closed cranial window in anesthetized rabbits. Three, five, nine, and eleven minutes after the onset of pentylenetetrazole-induced seizure (which releases endogenous excitatory amino acids), arteriolar diameter increased by 42 +/- 6, 30 +/- 3, 20 +/- 2, and 16 +/- 2% (means +/- SE), respectively, from a control diameter of 86 +/- 6 microns. Arterial pressure was maintained at control levels during seizures. In the presence of NG-nitro-L-arginine (L-NNA, 300 microM), an inhibitor of NO synthase, vasodilatation during seizures was not affected at 3 min (40 +/- 8%) but was significantly reduced at 5, 9, and 11 min (17 +/- 5, 6 +/- 3, and 1 +/- 3%, respectively, P < 0.05 vs. control). Vasodilatation in response to topical application of acetylcholine (1 microM) was also inhibited by L-NNA (33 +/- 5 vs. 3 +/- 2%, P < 0.05). Dilatation of cerebral arterioles in response to nitroprusside (1 and 10 microM) was not inhibited by L-NNA. Thus sustained, but not initial, dilatation of cerebral arterioles during seizures appears to be mediated in part by NO.

Mechanisms of endotoxin-induced dilatation of cerebral arterioles

1995 ◽  
Vol 269 (3) ◽  
pp. H783-H788 ◽  
Author(s):  
J. E. Brian ◽  
D. D. Heistad ◽  
F. M. Faraci
Keyword(s):  
No Synthase ◽  
Vascular Responses ◽  
Time Points ◽  
Cranial Window ◽  
Inducible No Synthase ◽  
Calcitonin Gene ◽  
Cerebral Arterioles ◽  
Arteriolar Diameter ◽  
Inducible Nitric Oxide

Lipopolysaccharide (LPS; endotoxin) produces dilatation of cerebral arterioles in vivo which may be due, in part, to expression of inducible nitric oxide (NO) synthase. We tested the hypothesis that aminoguanidine, an inhibitor of inducible NO synthase, would reduce endotoxin-induced dilatation of cerebral arterioles. Because mechanisms other than expression of inducible NO synthase may contribute to endotoxin-induced dilatation of cerebral arterioles, we also tested the hypothesis that calcitonin gene-related peptide (CGRP) contributes to vascular responses to endotoxin. Cerebral arteriolar diameter was measured using a closed cranial window in anesthetized rabbits under control conditions [77 +/- 3 (SE) microns] and during topical application of endotoxin (100 micrograms/ml). After 4 h, diameter of cerebral arterioles increased by 41 +/- 5%. Coapplication of aminoguanidine (0.3 mM) with endotoxin reduced vasodilatation at all time points (30 min to 4 h). Relative to control values, endotoxin treatment increased guanosine 3',5'-cyclic monophosphate (cGMP) concentration in cerebrospinal fluid (CSF) by approximately 20 fold at 4 h. Aminoguanidine attenuated the endotoxin-induced increased in CSF cGMP concentration. Aminoguanidine (0.3 mM) did not alter acetylcholine-mediated dilatation of cerebral arterioles. Coapplication of CGRP-(8-37) (0.5 microM), a specific blocker of CGRP receptors, with endotoxin significantly reduced vasodilatation in response to endotoxin at 2, 3, and 4 h. Thus 1) aminoguanidine inhibits endotoxin- but not acetylcholine-mediated dilatation of cerebral arterioles, and 2) activation of CGRP receptors mediates a portion of endotoxin-induced dilation of cerebral arterioles.

Cyclic nucleotides and cerebrovascular tone in newborn pigs

1993 ◽  
Vol 265 (6) ◽  
pp. H1972-H1982 ◽  
Author(s):  
H. Parfenova ◽  
M. Shibata ◽  
S. Zuckerman ◽  
R. Mirro ◽  
C. W. Leffler
Keyword(s):  
Cerebrospinal Fluid ◽  
Cyclic Nucleotides ◽  
Vascular Tone ◽  
Dibutyryl Camp ◽  
Cyclic Monophosphate ◽  
Cranial Window ◽  
Pial Arterioles ◽  
Newborn Pigs ◽  
Camp And Cgmp ◽  
Arteriolar Diameter

Relationships between cyclic nucleotides and cerebrovascular tone were investigated using closed cranial windows in anesthetized newborn pigs. Pial arteriolar diameter was monitored and cerebrospinal fluid (CSF) was collected from beneath the cranial window. Adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) concentrations in CSF were 1,690 +/- 200 and 730 +/- 40 fmol/ml, respectively. Topically applied isozyme-selective and nonselective inhibitors [3-isobutyl-1-methylxanthine (IBMX), theophylline, Ro 201724, dipyridamole, zaprinast, calmidazolium, and W-7] of cyclic nucleotide phosphodiesterases dilated pial arterioles with concomitant increases in cAMP and/or cGMP levels in CSF. Topical application of dibutyryl-cAMP and dibutyryl-cGMP also resulted in pial arteriolar dilation. Ten-minute hypercapnia, which results in pial arteriolar dilation, increased cAMP to 5,240 +/- 900 and cGMP to 1,350 +/- 200 fmol/ml. IBMX and zaprinast potentiated the increases in cAMP and cGMP as well as the cerebrovascular dilation in response to hypercapnia. These data suggest that cyclic nucleotides contribute to regulation of cerebral vascular tone during control conditions. Furthermore, cAMP and/or cGMP appears to be involved in arterial vasodilation in response to hypercapnia in newborn pigs.

Lipoxins A4 and B4 dilate cerebral arterioles of newborn pigs

1989 ◽  
Vol 256 (2) ◽  
pp. H468-H471 ◽  
Author(s):  
D. W. Busija ◽  
W. Armstead ◽  
C. W. Leffler ◽  
R. Mirro
Keyword(s):  
Cerebrospinal Fluid ◽  
Topical Application ◽  
Cerebral Microcirculation ◽  
Lipoxin A4 ◽  
Vascular Responses ◽  
Neonatal Pigs ◽  
Cranial Window ◽  
Cerebral Arterioles ◽  
Newborn Pigs ◽  
Arteriolar Diameter

We determined the effects of lipoxins A4 and B4 on the cerebral microcirculation of neonatal pigs and whether vascular responses were modulated by prostanoids. Pial arteriolar diameters were determined using a closed cranial window and intravital microscopy. Before lipoxin A4 application, arteriolar diameter was 143 +/- 6 microns (means +/- SE). Topical application of lipoxin A4 increased the diameter to 160 +/- 7 microns at 0.1 ng/ml, 167 +/- 7 microns at 1 ng/ml, and 173 +/- 7 microns at 10 ng/ml (n = 9). Before application of lipoxin B4, arteriolar diameter was 146 +/- 7 microns. Topical application of lipoxin B4 increased the diameter to 165 +/- 7, 169 +/- 6, and 175 +/- 6 microns at 0.1, 1, and 10 ng/ml (n = 9), respectively. Intravenous injection of indomethacin (5 mg/kg) or vehicle did not affect these responses. Levels of prostaglandins E2 and F2 alpha in cerebrospinal fluid (measured by radioimmunoassay) did not increase in response to lipoxins. We conclude that lipoxins are dilator stimuli in the cerebral circulation and that prostanoids do not mediate these responses.

Influence of endothelin on piglet cerebral microcirculation

1989 ◽  
Vol 257 (2) ◽  
pp. H707-H710 ◽  
Author(s):  
W. M. Armstead ◽  
R. Mirro ◽  
C. W. Leffler ◽  
D. W. Busija
Keyword(s):  
Endothelial Cells ◽  
Cerebrospinal Fluid ◽  
Cerebral Microcirculation ◽  
Cranial Window ◽  
Pial Arterioles ◽  
Cerebral Arterioles ◽  
Newborn Pigs ◽  
Fluid Levels ◽  
Porcine Endothelial Cells ◽  
Arteriolar Diameter

The purpose of this study was to determine responses of the newborn pig cerebral microcirculation to endothelin. Pial arterioles were observed directly using a closed cranial window in chloralose-anesthetized piglets. Topical application of endothelin derived from porcine endothelial cells produced increases in pial arteriolar diameter at the lowest concentration (0.1 ng/ml) (159 +/- 6 to 180 +/- 8 microns) and concentration-dependent decreases in pial arteriolar diameter at higher concentrations (141 +/- 6, 127 +/- 5, and 110 +/- 4 microns at 1, 10, and 100 ng/ml, respectively). Indomethacin (5 mg/kg iv) and aspirin (50 mg/kg iv) blocked dilator responses to endothelin and attenuated constrictor responses. Endothelin produced concentration-dependent increases in cortical periarachnoid cerebrospinal fluid levels of 6-ketoprostaglandin (6-keto-PG) F1 alpha, PGE2, PGF2 alpha, and thromboxane B2. Thus endothelin can produce either dilation or constriction of cerebral arterioles in newborn pigs, depending on concentration. Furthermore, prostanoids appear to mediate vasodilation induced by the lowest concentration of endothelin and contribute to constriction induced by higher concentrations of endothelin.

scholarly journals Effect of Leukotrienes, 12-HETE, Histamine, Bradykinin, and 5-Hydroxytryptamine on in vivo Rabbit Cerebral Arteriolar Diameter

1985 ◽  
Vol 5 (4) ◽  
pp. 554-559 ◽  
Author(s):  
Toshiharu Kamitani ◽  
Marcia H. Little ◽  
Earl F. Ellis
Keyword(s):  
Pial Arteries ◽  
Peripheral Tissues ◽  
Cranial Window ◽  
Lipoxygenase Products ◽  
Cerebral Arterioles ◽  
Potent Vasoconstrictor ◽  
Arteriolar Vasodilation ◽  
Dose Dependent ◽  
Arteriolar Diameter

To determine the possible role that leukotrienes (LTs) may play in the regulation of cerebral blood flow, the responses of cerebral arterioles to LTs and 12-hydroxyeicosatetraenoic acid (12-HETE) were studied in vivo in rabbits equipped with a cranial window for direct observation of the microcirculation. Topical application of LTC, LTD4, or 12-HETE (1.6 × 10−9–3.1 × 10−6 M) neither constricted nor dilated the pial arteries. LTB4 produced only a 5% vasoconstriction at 3.0 × 10−6 M. However, bradykinin induced dose-dependent arteriolar vasodilation and histamine and 5-hydroxytryptamine induced dose-dependent arteriolar vasoconstriction. Although some LTs have potent vasoconstrictor activity in peripheral tissues and 5-lipoxygenase products have been hypothesized to be mediators of vasospasm after subarachnoid hemorrhage, LTB4, LTC4, LTD4, and 12-HETE apparently are unable to induce significant constriction of the cerebral arterioles in the anesthetized rabbit.

Role of neuronal NO synthase in relationship between NO and opioids in hypoxia-induced pial artery dilation

1997 ◽  
Vol 273 (4) ◽  
pp. H1807-H1815 ◽  
Author(s):  
M. J. Wilderman ◽  
W. M. Armstead
Keyword(s):  
Nitric Oxide ◽  
Sodium Nitroprusside ◽  
Sodium Salt ◽  
No Synthase ◽  
Cyclic Monophosphate ◽  
Cranial Window ◽  
Pial Artery ◽  
Nos Inhibitor ◽  
Neuronal Nos

Nitric oxide (NO) contributes to hypoxia-induced pial artery dilation, at least in part, via the formation of guanosine 3′,5′-cyclic monophosphate (cGMP) and subsequent release of Met-enkephalin and Leu-enkephalin in the newborn pig. In separate studies, these opioids were also observed to elicit NO-dependent pial dilation. The present study was designed to investigate the role of the neuronal isoform of NO synthase (NOS) in hypoxic pial dilation, associated opioid release, and opioid dilation in piglets equipped with a closed cranial window. Tetrodotoxin (10−6 M) attenuated the dilation resulting from hypoxia ([Formula: see text]∼35 mmHg; 25 ± 1 vs. 14 ± 1%). Similarly, 7-nitroindazole, sodium salt (7-NINA, 10−6M), a purported neuronal NOS inhibitor, attenuated hypoxic pial dilation (26 ± 1 vs. 14 ± 2%). Hypoxic dilation was accompanied by elevated cerebrospinal (CSF) cGMP, which was blocked by 7-NINA (433 ± 19 and 983 ± 36 vs. 432 ± 19 and 441 ± 19 fmol/ml for control and hypoxia in absence and presence of 7-NINA, respectively). Additionally, hypoxic dilation was also accompanied by elevated CSF Met-enkephalin, which was attenuated by 7-NINA (1,027 ± 47 and 2,871 ± 134 vs. 779 ± 78 and 1,551 ± 42 pg/ml for control and hypoxia in absence and presence of 7-NINA, respectively). In contrast, Met-enkephalin (10−10, 10−8, and 10−6 M) induced dilation that was unchanged by 7-NINA (7 ± 1, 12 ± 1, and 18 ± 1 vs. 6 ± 1, 10 ± 1, and 17 ± 1%, respectively). N-methyl-d-aspartate (NMDA, 10−8 and 10−6 M), an activator of neuronal NOS, induced pial dilation that was blocked by 7-NINA (10 ± 1 and 20 ± 2 vs. 1 ± 1 and 2 ± 1%, respectively). However, sodium nitroprusside-induced dilation was unchanged by 7-NINA. These data indicate that neuronal NOS contributes to hypoxic pial artery dilation but not to opioid-induced dilation. Furthermore, these data suggest that neuronally derived NO contributes to hypoxic dilation, at least in part, via formation of cGMP and the subsequent release of opioids.

Arginine analogues inhibit responses mediated by ATP-sensitive K+ channels

1996 ◽  
Vol 271 (4) ◽  
pp. H1498-H1506 ◽  
Author(s):  
H. A. Kontos ◽  
E. P. Wei
Keyword(s):  
Sodium Nitroprusside ◽  
Guanylate Cyclase ◽  
No Donors ◽  
K Channels ◽  
Cyclic Monophosphate ◽  
Vasodilator Response ◽  
Subsequent Application ◽  
Vessel Response ◽  
Pial Arterioles ◽  
Ly 83583

Because arginine analogues have been reported to block the vasodilator response to hypercapnia, we investigated the effect of nitro-L-arginine (L-NNA) on the dilation of pial arterioles to arterial hypercapnia induced by inhalation of 3, 5, and 7% CO2 in anesthetized cats equipped with cranial windows. L-NNA at 250 microM, but not at lower concentrations, significantly reduced hypercapnia-induced dilation. This effect could be reversed by L-arginine. However, hypercapnic hyperemia is not the result of increased guanosine 3',5'-cyclic monophosphate via the usual NO-mediated activation of guanylate cyclase, because application of LY-83583, which blocks guanylate cyclase, did not alter the vessel response to CO2. L-NNA at 250 microM also abolished the pial arteriolar dilation in response to cromakalim, minoxidil, and pinacidil, three known openers of ATP-sensitive K+ channels, and this effect could be reversed by L-arginine. Application of glyburide, which blocks ATP-sensitive K+ channels, also reduced the response to CO2. Subsequent application of L-NNA in these experiments had no additional effect. Vasodilation induced by sodium nitroprusside and 3-morpholinosydnonimine, two known NO donors, was unaffected by glyburide. NG-monomethyl-L-arginine had effects similar to those of L-NNA in the cat and rat at concentrations as low as 20 microM. Our findings suggest that arginine analogues inhibit hypercapnic vasodilation by blocking ATP-sensitive K+ channels, independently of activation of guanylate cyclase via increased production of NO. Furthermore, the data suggest that ATP-sensitive K+ channels may have an arginine site that influences their function.

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