Characterization of pituitary adenylate cyclase activating polypeptide (PACAP) induced pial arteriolar dilation in piglets

F. Bari, Laura Lenti, David Kis, F. Domoki, G. Tóth, David W. Busija

Research output: Article

Abstract

PACAP has been found neuroprotective in numerous models of cerebral ischemia. PACAP-induced neuroprotection in vivo is partially based on its vasorelaxant effect. Cerebral ischemia occurring during the perinatal period often result in neurological sequelae. One possible contributor to the neurological damage is the cerebrovascular dysfunction, e.g. hypercapnia-induced arteriolar vasodilation is severely attenuated after ischemia reperfusion (I/R). The mechanism of PACAP induced cerebrovascular changes in newborns is unexplored. We sought to characterize the vascular reactivity to PACAP-27 and -38 (naturally existing forms), as well as to shorter PACAP sequences in a piglet model that correlates well with the vascular physiology of newborn babies. Using the non selective cyclooxygenase (COX) inhibitor indomethacin (5 mg/kg, iv), the selective COX-1 inhibitor SC 560 (1 mg/kg, iv) and the selective COX-2 inhibitor NS 398 (1 mg/kg, iv), we investigated if COX-derived metabolites play a role in the cerebrovascular effects of PACAP. We also determined the effect of the nitric oxide synthase (NOS) inhibition by N-nitro-l-arginine methyl ester (L NAME, 15 mg/kg, iv). We examined the influence of short PACAP fragments (10-5 M topically) on PACAP-27 and-38 induced vasodilation. Further, we tested whether application of PACAP preserves hypercapnia-induced cerebrovascular dilator responses after I/R. Anesthetized (Na thiopenthal 40 mg/kg, ip, followed by ? chloralose 40 mg/kg, iv), ventilated piglets (1 day old, 1 2 kg, n=104) were equipped with closed cranial windows. Pial arteriolar diameters were determined via intravital microscopy. Topical PACAP-27 and -38 elicited similar, repeatable, dose dependent pial arteriolar dilations. Percent changes in diameters to 10-8, 10-7, and 10-6 M PACAP-38 and-27 were 6±1, 16±2, and 40±4, and 9±2, 19±3, 36±4 (mean±SEM), respectively. In contrast, the shorter segments of the peptides (6-27, 6-38, 6-15, 20-31, and 1-15) did not display any vasoactivity. Arteriolar dilations to PACAP-38 were abolished 20 min after indomethacin and SC-560 (to 10-6 M 35±4% vs. - 1±1%*, and 36±6% vs. 1±1*, *p

Original languageEnglish
JournalJournal of Cerebral Blood Flow and Metabolism
Volume27
Issue numberSUPPL. 1
Publication statusPublished - nov. 13 2007

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Pituitary Adenylate Cyclase-Activating Polypeptide
Dilatation
Cyclooxygenase Inhibitors
Hypercapnia
Brain Ischemia
Vasodilation
Indomethacin
Blood Vessels
Cyclooxygenase 1
Chloralose
Cyclooxygenase 2 Inhibitors
NG-Nitroarginine Methyl Ester

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Endocrinology, Diabetes and Metabolism

Cite this

@article{da491b6c02054a808e96e1f88c4fe3ec,
title = "Characterization of pituitary adenylate cyclase activating polypeptide (PACAP) induced pial arteriolar dilation in piglets",
abstract = "PACAP has been found neuroprotective in numerous models of cerebral ischemia. PACAP-induced neuroprotection in vivo is partially based on its vasorelaxant effect. Cerebral ischemia occurring during the perinatal period often result in neurological sequelae. One possible contributor to the neurological damage is the cerebrovascular dysfunction, e.g. hypercapnia-induced arteriolar vasodilation is severely attenuated after ischemia reperfusion (I/R). The mechanism of PACAP induced cerebrovascular changes in newborns is unexplored. We sought to characterize the vascular reactivity to PACAP-27 and -38 (naturally existing forms), as well as to shorter PACAP sequences in a piglet model that correlates well with the vascular physiology of newborn babies. Using the non selective cyclooxygenase (COX) inhibitor indomethacin (5 mg/kg, iv), the selective COX-1 inhibitor SC 560 (1 mg/kg, iv) and the selective COX-2 inhibitor NS 398 (1 mg/kg, iv), we investigated if COX-derived metabolites play a role in the cerebrovascular effects of PACAP. We also determined the effect of the nitric oxide synthase (NOS) inhibition by N-nitro-l-arginine methyl ester (L NAME, 15 mg/kg, iv). We examined the influence of short PACAP fragments (10-5 M topically) on PACAP-27 and-38 induced vasodilation. Further, we tested whether application of PACAP preserves hypercapnia-induced cerebrovascular dilator responses after I/R. Anesthetized (Na thiopenthal 40 mg/kg, ip, followed by ? chloralose 40 mg/kg, iv), ventilated piglets (1 day old, 1 2 kg, n=104) were equipped with closed cranial windows. Pial arteriolar diameters were determined via intravital microscopy. Topical PACAP-27 and -38 elicited similar, repeatable, dose dependent pial arteriolar dilations. Percent changes in diameters to 10-8, 10-7, and 10-6 M PACAP-38 and-27 were 6±1, 16±2, and 40±4, and 9±2, 19±3, 36±4 (mean±SEM), respectively. In contrast, the shorter segments of the peptides (6-27, 6-38, 6-15, 20-31, and 1-15) did not display any vasoactivity. Arteriolar dilations to PACAP-38 were abolished 20 min after indomethacin and SC-560 (to 10-6 M 35±4{\%} vs. - 1±1{\%}*, and 36±6{\%} vs. 1±1*, *p",
author = "F. Bari and Laura Lenti and David Kis and F. Domoki and G. T{\'o}th and Busija, {David W.}",
year = "2007",
month = "11",
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TY - JOUR

T1 - Characterization of pituitary adenylate cyclase activating polypeptide (PACAP) induced pial arteriolar dilation in piglets

AU - Bari, F.

AU - Lenti, Laura

AU - Kis, David

AU - Domoki, F.

AU - Tóth, G.

AU - Busija, David W.

PY - 2007/11/13

Y1 - 2007/11/13

N2 - PACAP has been found neuroprotective in numerous models of cerebral ischemia. PACAP-induced neuroprotection in vivo is partially based on its vasorelaxant effect. Cerebral ischemia occurring during the perinatal period often result in neurological sequelae. One possible contributor to the neurological damage is the cerebrovascular dysfunction, e.g. hypercapnia-induced arteriolar vasodilation is severely attenuated after ischemia reperfusion (I/R). The mechanism of PACAP induced cerebrovascular changes in newborns is unexplored. We sought to characterize the vascular reactivity to PACAP-27 and -38 (naturally existing forms), as well as to shorter PACAP sequences in a piglet model that correlates well with the vascular physiology of newborn babies. Using the non selective cyclooxygenase (COX) inhibitor indomethacin (5 mg/kg, iv), the selective COX-1 inhibitor SC 560 (1 mg/kg, iv) and the selective COX-2 inhibitor NS 398 (1 mg/kg, iv), we investigated if COX-derived metabolites play a role in the cerebrovascular effects of PACAP. We also determined the effect of the nitric oxide synthase (NOS) inhibition by N-nitro-l-arginine methyl ester (L NAME, 15 mg/kg, iv). We examined the influence of short PACAP fragments (10-5 M topically) on PACAP-27 and-38 induced vasodilation. Further, we tested whether application of PACAP preserves hypercapnia-induced cerebrovascular dilator responses after I/R. Anesthetized (Na thiopenthal 40 mg/kg, ip, followed by ? chloralose 40 mg/kg, iv), ventilated piglets (1 day old, 1 2 kg, n=104) were equipped with closed cranial windows. Pial arteriolar diameters were determined via intravital microscopy. Topical PACAP-27 and -38 elicited similar, repeatable, dose dependent pial arteriolar dilations. Percent changes in diameters to 10-8, 10-7, and 10-6 M PACAP-38 and-27 were 6±1, 16±2, and 40±4, and 9±2, 19±3, 36±4 (mean±SEM), respectively. In contrast, the shorter segments of the peptides (6-27, 6-38, 6-15, 20-31, and 1-15) did not display any vasoactivity. Arteriolar dilations to PACAP-38 were abolished 20 min after indomethacin and SC-560 (to 10-6 M 35±4% vs. - 1±1%*, and 36±6% vs. 1±1*, *p

AB - PACAP has been found neuroprotective in numerous models of cerebral ischemia. PACAP-induced neuroprotection in vivo is partially based on its vasorelaxant effect. Cerebral ischemia occurring during the perinatal period often result in neurological sequelae. One possible contributor to the neurological damage is the cerebrovascular dysfunction, e.g. hypercapnia-induced arteriolar vasodilation is severely attenuated after ischemia reperfusion (I/R). The mechanism of PACAP induced cerebrovascular changes in newborns is unexplored. We sought to characterize the vascular reactivity to PACAP-27 and -38 (naturally existing forms), as well as to shorter PACAP sequences in a piglet model that correlates well with the vascular physiology of newborn babies. Using the non selective cyclooxygenase (COX) inhibitor indomethacin (5 mg/kg, iv), the selective COX-1 inhibitor SC 560 (1 mg/kg, iv) and the selective COX-2 inhibitor NS 398 (1 mg/kg, iv), we investigated if COX-derived metabolites play a role in the cerebrovascular effects of PACAP. We also determined the effect of the nitric oxide synthase (NOS) inhibition by N-nitro-l-arginine methyl ester (L NAME, 15 mg/kg, iv). We examined the influence of short PACAP fragments (10-5 M topically) on PACAP-27 and-38 induced vasodilation. Further, we tested whether application of PACAP preserves hypercapnia-induced cerebrovascular dilator responses after I/R. Anesthetized (Na thiopenthal 40 mg/kg, ip, followed by ? chloralose 40 mg/kg, iv), ventilated piglets (1 day old, 1 2 kg, n=104) were equipped with closed cranial windows. Pial arteriolar diameters were determined via intravital microscopy. Topical PACAP-27 and -38 elicited similar, repeatable, dose dependent pial arteriolar dilations. Percent changes in diameters to 10-8, 10-7, and 10-6 M PACAP-38 and-27 were 6±1, 16±2, and 40±4, and 9±2, 19±3, 36±4 (mean±SEM), respectively. In contrast, the shorter segments of the peptides (6-27, 6-38, 6-15, 20-31, and 1-15) did not display any vasoactivity. Arteriolar dilations to PACAP-38 were abolished 20 min after indomethacin and SC-560 (to 10-6 M 35±4% vs. - 1±1%*, and 36±6% vs. 1±1*, *p

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