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.

CO2 and cerebral circulation in newborn pigs: cyclic nucleotides and prostanoids in vascular regulation

1994 ◽  
Vol 266 (4) ◽  
pp. H1494-H1501 ◽  
Author(s):  
H. Parfenova ◽  
M. Shibata ◽  
S. Zuckerman ◽  
C. W. Leffler
Keyword(s):  
Cyclic Nucleotides ◽  
Cerebrovascular Reactivity ◽  
Cyclic Monophosphate ◽  
Cranial Window ◽  
Vascular Regulation ◽  
Newborn Pigs ◽  
Cerebral Vasodilation ◽  
Ly 83583 ◽  
Camp And Cgmp

The role of cyclic nucleotides and prostanoids in cerebrovascular reactivity to increased carbon dioxide was investigated in anesthetized and artificially ventilated newborn pigs equipped with closed cranial windows. Pial arteriolar diameter was measured, and cortical periarachnoid cerebrospinal fluid (CSF) was collected from beneath the cranial window for determination of adenosine 3',5'-cyclic monophosphate (cAMP), guanosine 3',5'-cyclic monophosphate (cGMP), and prostanoids. Progressively increasing arterial PCO2 (PaCO2) from normocapnia (33 +/- 1 mmHg) to hypercapnia (final PaCO2, 83 +/- 2 mmHg) resulted in dose-dependent pial arteriolar dilation and concomitant increases in cAMP, cGMP, and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) in cortical CSF. N omega-methyl-L-arginine, N omega-nitro-L-arginine, N omega-nitro-L-arginine methyl ester, methylene blue, and LY 83583 did not inhibit cerebral vasodilation or the increases in cortical cAMP/cGMP induced by hypercapnia. Indomethacin abolished the vasodilatory response to hypercapnia and attenuated the hypercapnia-induced increases in cAMP and cGMP. Prostacyclin analogues increased both cAMP and cGMP levels in cortical CSF and induced pial arteriolar dilation (iloprost > carbaprostacyclin). The present data suggest that in newborn pigs cyclic nucleotides are involved in cerebral vasodilation in response to hypercapnia via a prostanoid-dependent mechanism.

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.

Recombinant human interleukin 1 alpha dilates pial arterioles and increases cerebrospinal fluid prostanoids in piglets

1990 ◽  
Vol 259 (5) ◽  
pp. H1486-H1491 ◽  
Author(s):  
M. Shibata ◽  
C. W. Leffler ◽  
D. W. Busija
Keyword(s):  
Cerebrospinal Fluid ◽  
Prostaglandin E2 ◽  
Interleukin 1 ◽  
Vasomotor Tone ◽  
Initial Size ◽  
Cranial Window ◽  
Window Method ◽  
Pial Arterioles ◽  
Csf Levels ◽  
Arteriolar Diameter

Effects of recombinant human interleukin 1 alpha (IL-1 alpha) on vasomotor tone of pial arterioles and cerebrospinal fluid (CSF) prostanoid levels were examined in anesthetized piglets by employing the closed cranial window method. IL-1 alpha in a dose of 10.8 micrograms infused under the window increased pial arteriolar diameter [initial size, 160 +/- 9 (SE) micrograms] significantly at 15 min postinfusion through 30 min (30-min study), exhibiting a maximum dilation of 13 +/- 1% (n = 8) over the control levels. Significant increases in levels of prostaglandin E2 (PGE2, 75%), 6-keto-PGF1 alpha (84%), and PGF2 alpha (35%) but not for thromboxane B2 (TxB2, 2%) were observed when CSF was sampled from under the window 30 min after 10.8 micrograms IL-1 alpha. A lower dose of IL-1 alpha (1.0 micrograms, n = 4) significantly increased the diameter of pial arterioles with a tendency for longer onset (25-30 min) and smaller magnitude (9-10%) than the higher dose. In IL-1 alpha time-response studies, CSF sampled 10 min after 10.8 micrograms IL-1 alpha infusion (10-min study, n = 6) under the window exhibited the same levels of PGE2, 6-keto-PGF1 alpha, PGF2 alpha, and TxB2 as those of the controls. There was no vasodilation in the 10-min study. However, when sampled 20 min after 10.8 micrograms IL-1 alpha (20-min study, n = 6), CSF levels of all prostanoids except for TxB2 significantly increased over the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral ischemia alters cerebral microvascular reactivity in newborn pigs

1989 ◽  
Vol 257 (1) ◽  
pp. H266-H271 ◽  
Author(s):  
C. W. Leffler ◽  
D. G. Beasley ◽  
D. W. Busija
Keyword(s):  
Cerebrospinal Fluid ◽  
Cerebral Ischemia ◽  
Sham Control ◽  
Microvascular Reactivity ◽  
Pial Arterioles ◽  
Newborn Pigs ◽  
Pg E2 ◽  
Cerebral Vasodilator ◽  
Arteriolar Diameter ◽  
Prostanoid Synthesis

The effects of cerebral ischemia on cerebral microvascular reactivity and prostanoid synthesis were examined in chloralose-anesthetized newborn pigs. Microvascular responses and periarachnoid cerebrospinal fluid (CSF) prostanoid concentrations were determined between 10 and 140 min after a 20-min period of total cerebral ischemia, as well as in sham-control piglets without cerebral ischemia. After cerebral ischemia, the decrease in pial arteriolar diameter in response to topical norepinephrine (10(-4) M) was similar in sham (-27 +/- 6%) and postischemic (-25 +/- 5%) piglets. However, the increase in pial arteriolar diameter in response to hypercapnia (10% CO2 ventilation) that was observed in sham piglets (+21 +/- 5%) was absent after ischemia (-2 +/- 3%). In contrast, dilations of pial arterioles in response to topical prostaglandin (PG)E2 (at 100 ng PGE2/ml: sham, +13 +/- 3%; postischemia, +21 +/- 4%) and topical isoproterenol (10(-6) M) (sham, +29 +/- 4%; postischemia, +23 +/- 3%) were not decreased by prior cerebral ischemia. In sham piglets, norepinephrine and hypercapnia produced increases in cortical periarachnoid prostanoid concentrations, whereas after cerebral ischemia, neither stimulus increased cortical periarachnoid prostanoid concentrations. The results are consistent with the hypothesis that failure of hypercapnia to dilate pial arterioles after cerebral ischemia results from the inability of this stimulus to increase cerebral vasodilator prostanoid synthesis.

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.

Cerebral arteriolar dilation to hypoxia: role of prostanoids

1997 ◽  
Vol 272 (1) ◽  
pp. H418-H424 ◽  
Author(s):  
C. W. Leffler ◽  
H. Parfenova
Keyword(s):  
Cerebrospinal Fluid ◽  
Rapid Decrease ◽  
Primary Mechanism ◽  
Pial Arterioles ◽  
Newborn Pigs ◽  
Cerebral Vasodilation ◽  
Arteriolar Diameter ◽  
Indomethacin Treatment

Experiments addressed the hypothesis that dilator prostanoids contribute to maintenance of low cerebral microvascular tone during hypoxia in the newborn. Anesthetized newborn pigs equipped with closed cranial windows were used to measure responses of pial arterioles (approximately 60 microns) to treatments. Hypoxia (Pao2 approximately equal to 25 mmHg) caused dilation of pial arterioles (approximately 50% increase in diameter). Hypoxia (5 min) caused an increase in cortical cerebrospinal fluid 6-ketoprostaglandin F1 alpha concentration from 907 +/- 171 (normoxia) to 1,408 +/- 213 pg/ml (hypoxia). Pretreatment with indomethacin (5 mg/kg) did not affect pial arteriolar dilation to hypoxia. Conversely, indomethacin treatment during hypoxia caused a rapid decrease in arteriolar diameter to nearly the normoxia diameter within 3 min, returning to the original hypoxia diameter by 10 min. Ibuprofen treatment (30 mg/kg) had no effect on pial arteriolar diameter during normoxia or hypoxia, and pretreatment did not alter dilation to hypoxia. However, pretreatment with ibuprofen abolished the constrictor effect of indomethacin given during hypoxia. These data suggest that the primary mechanism by which hypoxia produces cerebral vasodilation does not involve prostanoids, but prostanoids can contribute to cerebral vasodilation in response to hypoxia.

Altered cerebrovascular responsiveness to N-methyl-D-aspartate after asphyxia in piglets

1993 ◽  
Vol 265 (1) ◽  
pp. H389-H394 ◽  
Author(s):  
D. W. Busija ◽  
M. Wei
Keyword(s):  
Topical Application ◽  
Intravital Microscopy ◽  
Cranial Window ◽  
Time Control ◽  
Pial Arterioles ◽  
Newborn Pigs ◽  
Arteriolar Diameter ◽  
Baseline Diameter ◽  
H 30

We examined effects of prior asphyxia and reventilation on pial arteriolar responses to arterial hypercapnia, topical application of forskolin, and topical application of N-methyl-D-aspartate (NMDA) in newborn pigs. Piglets were anesthetized and ventilated with a respirator. Pial arteriolar diameter was determined using a closed cranial window and intravital microscopy. After baseline diameter was determined, the respirator was turned off for 10 min. Then the respirator was turned on, and the piglet was ventilated for 4 h. At 1, 2, and 4 h after asphyxia, arteriolar diameter was determined during control conditions and during arterial hypercapnia (inspiration of 10% CO2 in air; n = 4), topical application of 2.4 x 10(-8) M forskolin (n = 6), and topical application of 10(-5) M NMDA (n = 6). At 1 h after asphyxia, arterial hypercapnia dilated pial arterioles by 39 +/- 3%, topical forskolin dilated pial arterioles by 24 +/- 3%, and NMDA dilated pial arterioles by 10 +/- 1%. For arterial hypercapnia and forskolin application, arteriolar responses were not different from 1 h at 2 and 4 h postasphyxia. In contrast, for NMDA, arteriolar responses were greater at 2 h (23 +/- 6%) and 4 h (30 +/- 5%) than at 1 h. In time-control animals, NMDA dilated arterioles by 20 +/- 5% at 1 h, by 24 +/- 8% at 2 h, and by 21 +/- 4% at 4 h (n = 5). Indomethacin administration (5 mg/kg iv) before asphyxia resulted in a 23 +/- 3% arteriolar dilation in response to NMDA at 1 h (n = 7).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Effects of indomethacin on newborn pig pial arteriolar responses to PCO2

1993 ◽  
Vol 75 (3) ◽  
pp. 1300-1305 ◽  
Author(s):  
R. Mirro ◽  
L. J. Pharris ◽  
W. M. Armstead ◽  
M. Shibata ◽  
C. W. Leffler
Keyword(s):  
Cerebrospinal Fluid ◽  
Absolute Level ◽  
Arterial Pco2 ◽  
Cerebral Vasoconstriction ◽  
Pial Arterioles ◽  
Newborn Pigs ◽  
The Absolute ◽  
The Relationship ◽  
Arteriolar Diameter ◽  
Cerebral Vascular

The present experiments were designed to determine whether hypocapnic cerebral vasoconstriction, like hypercapnic dilation, involves prostanoids and, if not, whether alternative mechanisms are related to the absolute arterial PCO2 (PaCO2) or the direction of change. We determined effects of indomethacin (5 mg/kg iv) on pial arteriolar responses to 1) increased PCO2 from normal, 2) decreased PCO2 from normal, and 3) increased PCO2 from hypocapnia to normocapnia in anesthetized newborn pigs. Pial arterioles constricted in response to hypocapnia (PaCO2 = 15–24 Torr) similarly before (-13 +/- 3%) and after (-16 +/- 2%) indomethacin. Cortical periarachnoid cerebrospinal fluid prostanoids were not increased by hypocapnia. As previously reported, cerebral vascular responses to hypercapnia (which increases cerebrospinal fluid prostanoids) were lost after indomethacin. To determine whether the failure of indomethacin to affect the responses to hypocapnia was due to the direction of change (decreasing) or the absolute level of PCO2, piglets were hyperventilated to approximately 15 Torr PaCO2. Increasing PaCO2 in these piglets to approximately 44 Torr caused pial arteriolar dilation (46 +/- 7%) that was not blocked by indomethacin (33 +/- 5%). Cortical periarachnoid prostanoids were not altered when PaCO2 was raised from hypocapnia to normocapnia. Therefore the relationship between CO2 and piglet cerebral vascular tone appears to involve multiple mechanisms. Specifically, dilation in response to CO2 above the normal range appears to involve prostanoids but changes in pial arteriolar diameter at low PaCO2 do not.

Interleukin-1 beta peptides induce cerebral pial arteriolar dilation in anesthetized newborn pigs

1996 ◽  
Vol 270 (5) ◽  
pp. R1044-R1050 ◽  
Author(s):  
M. Shibata ◽  
H. Parfenova ◽  
S. L. Zuckerman ◽  
J. M. Seyer ◽  
J. M. Krueger ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cyclic Nucleotides ◽  
Interleukin 1 ◽  
Amino Acid Sequences ◽  
Cyclic Monophosphate ◽  
Pial Arterioles ◽  
Csf Levels ◽  
Newborn Pigs ◽  
Beta Dose ◽  
Relationship Of

Inflammatory cytokines may affect cerebral circulation under pathological conditions. Responses of cerebral pial arterioles to one such cytokine, interleukin (IL)-1 beta and its inhibitor [soluble IL-1 receptor (sIL-1R)] were examined in anesthetized newborn pigs using closed cranial windows. Levels of prostanoids and cyclic nucleotides in periarachnoid cerebral spinal fluid (CSF) were measured. To examine the structure-activity relationship of the parent IL-1 beta molecule, two IL-1 beta fragments with amino acid sequences of 187-204 [IL-1 beta-(187-204)] and 208-240 [IL-1 beta-(208-240)] were tested for their effects on pial arterioles. Diameter changes of pial arterioles were sequentially recorded every 5 min for 30 min after topical application of IL-1 peptides. CSF was sampled at the end of the 30 min. IL-1 beta dose dependently induced arteriolar dilation and increased prostaglandin E2 (PGE2), 6-keto-PGF1 alpha adenosine 3',5'-cyclic monophosphate (cAMP), and guanosine 3',5'-cyclic monophosphate (cGMP). Intravenous indomethacin blocked the IL-1 beta-induced vasodilation, the increased prostanoids, and the increased cAMP, but not the increased cGMP. Neither heat-inactivated IL-1 beta nor IL-1 beta vehicle affected arteriolar diameter or CSF levels of prostanoids. The sIL-1R blocked the IL-1 beta-induced vasodilation and the increased CSF prostanoids. IL-1 beta-(208-240) also induced pial arteriolar dilation; however, its vasodilatory potency was 1,000 times less than that of the whole IL-1 beta molecule. IL-1 beta-(187-204) did not induce pial arteriolar dilation even when its dose was increased to the level of IL-1 beta-(208-240). These results suggest that IL-1 beta, through the activation of membrane-bound IL-1 beta receptors, induces pial arteriolar dilation via mechanisms that involve prostanoids and cyclic nucleotides. The results also indicate that the 208-240 amino acid sequence of IL-1 beta has a sequence-specific physiological function.

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