Mitochondrial potassium channel opener diazoxide preserves neuronal- vascular function after cerebral ischemia in newborn pigs

F. Domoki, James V. Perciaccante, Roland Veltkamp, F. Bari, David W. Busija

Research output: Contribution to journalArticle

99 Citations (Scopus)

Abstract

Background and Purpose - N-Methyl-D-aspartate (NMDA) elicits neuronally mediated cerebral arteriolar vasodilation that is reduced by ischemia/reperfusion (I/R). This sequence has been preserved by pretreatment with the ATP-sensitive potassium (K(ATP)) channel opener aprikalim, although the mechanism was unclear. In the heart, mitochondrial K(ATP) channels (mitoK(ATP)) are involved in the ischemic preconditioning-like effect of K+ channel openers. We determined whether the selective mitoK(ATP) channel opener diazoxide preserves the vascular dilation to NMDA after I/R. Methods - Pial arteriolar diameters were determined with the use of closed cranial window/intravital microscopy in anesthetized piglets. Vascular responses to NMDA were assessed before and 1 hour after 10 minutes of global cerebral ischemia induced by raising intracranial pressure. Subgroups received 1 of the following pretreatments before I/R: vehicle; 1 to 10 μmol/L diazoxide; and coapplication of 100 μmol/L 5-hydroxydecanoic acid (5-HD), a K(ATP) antagonist with diazoxide. Results - NMDA-induced dose-dependent pial arteriolar dilation was not affected by diazoxide treatment only but was severely attenuated by I/R. In contrast, diazoxide dose-dependently preserved the NMDA vascular response after I/R; at 10 μmol/L, diazoxide arteriolar responses were unaltered by I/R. The effect of diazoxide was antagonized by coapplication of 5-HD with diazoxide. Percent preservation of 100 μmol/L NMDA-induced vasodilation after I/R was 53±19% (mean±SEM, n=8) in vehicle- treated controls versus 55±10%, 85±5%, and 99±15% in animals pretreated with 1, 5, and 10 μmol/L diazoxide (n=8, n=8, and n=12, respectively) and 60±15% in the group treated with 5-HD+diazoxide (n=5). Conclusions - The mitoK(ATP) channel opener diazoxide in vivo preserves neuronal function after I/R, shown by pial arteriolar responses to NMDA, in a dose-dependent manner. Thus, activation of mitoK(ATP) channels may play a role in mediating the protective effect of other K+ channel openers.

Original languageEnglish
Pages (from-to)2713-2719
Number of pages7
JournalStroke
Volume30
Issue number12
Publication statusPublished - Dec 1999

Fingerprint

Diazoxide
Potassium Channels
Brain Ischemia
Blood Vessels
Swine
N-Methylaspartate
Reperfusion
Ischemia
Vasodilation
Dilatation
Adenosine Triphosphate
KATP Channels
Ischemic Preconditioning
Intracranial Pressure

Keywords

  • Cerebral ischemia, global
  • N-methyl-D-aspartate
  • Pigs
  • Potassium channels
  • Reperfusion injury

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Neuroscience(all)

Cite this

Mitochondrial potassium channel opener diazoxide preserves neuronal- vascular function after cerebral ischemia in newborn pigs. / Domoki, F.; Perciaccante, James V.; Veltkamp, Roland; Bari, F.; Busija, David W.

In: Stroke, Vol. 30, No. 12, 12.1999, p. 2713-2719.

Research output: Contribution to journalArticle

Domoki, F. ; Perciaccante, James V. ; Veltkamp, Roland ; Bari, F. ; Busija, David W. / Mitochondrial potassium channel opener diazoxide preserves neuronal- vascular function after cerebral ischemia in newborn pigs. In: Stroke. 1999 ; Vol. 30, No. 12. pp. 2713-2719.
@article{838605fd733649e494c12d2e68763b95,
title = "Mitochondrial potassium channel opener diazoxide preserves neuronal- vascular function after cerebral ischemia in newborn pigs",
abstract = "Background and Purpose - N-Methyl-D-aspartate (NMDA) elicits neuronally mediated cerebral arteriolar vasodilation that is reduced by ischemia/reperfusion (I/R). This sequence has been preserved by pretreatment with the ATP-sensitive potassium (K(ATP)) channel opener aprikalim, although the mechanism was unclear. In the heart, mitochondrial K(ATP) channels (mitoK(ATP)) are involved in the ischemic preconditioning-like effect of K+ channel openers. We determined whether the selective mitoK(ATP) channel opener diazoxide preserves the vascular dilation to NMDA after I/R. Methods - Pial arteriolar diameters were determined with the use of closed cranial window/intravital microscopy in anesthetized piglets. Vascular responses to NMDA were assessed before and 1 hour after 10 minutes of global cerebral ischemia induced by raising intracranial pressure. Subgroups received 1 of the following pretreatments before I/R: vehicle; 1 to 10 μmol/L diazoxide; and coapplication of 100 μmol/L 5-hydroxydecanoic acid (5-HD), a K(ATP) antagonist with diazoxide. Results - NMDA-induced dose-dependent pial arteriolar dilation was not affected by diazoxide treatment only but was severely attenuated by I/R. In contrast, diazoxide dose-dependently preserved the NMDA vascular response after I/R; at 10 μmol/L, diazoxide arteriolar responses were unaltered by I/R. The effect of diazoxide was antagonized by coapplication of 5-HD with diazoxide. Percent preservation of 100 μmol/L NMDA-induced vasodilation after I/R was 53±19{\%} (mean±SEM, n=8) in vehicle- treated controls versus 55±10{\%}, 85±5{\%}, and 99±15{\%} in animals pretreated with 1, 5, and 10 μmol/L diazoxide (n=8, n=8, and n=12, respectively) and 60±15{\%} in the group treated with 5-HD+diazoxide (n=5). Conclusions - The mitoK(ATP) channel opener diazoxide in vivo preserves neuronal function after I/R, shown by pial arteriolar responses to NMDA, in a dose-dependent manner. Thus, activation of mitoK(ATP) channels may play a role in mediating the protective effect of other K+ channel openers.",
keywords = "Cerebral ischemia, global, N-methyl-D-aspartate, Pigs, Potassium channels, Reperfusion injury",
author = "F. Domoki and Perciaccante, {James V.} and Roland Veltkamp and F. Bari and Busija, {David W.}",
year = "1999",
month = "12",
language = "English",
volume = "30",
pages = "2713--2719",
journal = "Stroke",
issn = "0039-2499",
publisher = "Lippincott Williams and Wilkins",
number = "12",

}

TY - JOUR

T1 - Mitochondrial potassium channel opener diazoxide preserves neuronal- vascular function after cerebral ischemia in newborn pigs

AU - Domoki, F.

AU - Perciaccante, James V.

AU - Veltkamp, Roland

AU - Bari, F.

AU - Busija, David W.

PY - 1999/12

Y1 - 1999/12

N2 - Background and Purpose - N-Methyl-D-aspartate (NMDA) elicits neuronally mediated cerebral arteriolar vasodilation that is reduced by ischemia/reperfusion (I/R). This sequence has been preserved by pretreatment with the ATP-sensitive potassium (K(ATP)) channel opener aprikalim, although the mechanism was unclear. In the heart, mitochondrial K(ATP) channels (mitoK(ATP)) are involved in the ischemic preconditioning-like effect of K+ channel openers. We determined whether the selective mitoK(ATP) channel opener diazoxide preserves the vascular dilation to NMDA after I/R. Methods - Pial arteriolar diameters were determined with the use of closed cranial window/intravital microscopy in anesthetized piglets. Vascular responses to NMDA were assessed before and 1 hour after 10 minutes of global cerebral ischemia induced by raising intracranial pressure. Subgroups received 1 of the following pretreatments before I/R: vehicle; 1 to 10 μmol/L diazoxide; and coapplication of 100 μmol/L 5-hydroxydecanoic acid (5-HD), a K(ATP) antagonist with diazoxide. Results - NMDA-induced dose-dependent pial arteriolar dilation was not affected by diazoxide treatment only but was severely attenuated by I/R. In contrast, diazoxide dose-dependently preserved the NMDA vascular response after I/R; at 10 μmol/L, diazoxide arteriolar responses were unaltered by I/R. The effect of diazoxide was antagonized by coapplication of 5-HD with diazoxide. Percent preservation of 100 μmol/L NMDA-induced vasodilation after I/R was 53±19% (mean±SEM, n=8) in vehicle- treated controls versus 55±10%, 85±5%, and 99±15% in animals pretreated with 1, 5, and 10 μmol/L diazoxide (n=8, n=8, and n=12, respectively) and 60±15% in the group treated with 5-HD+diazoxide (n=5). Conclusions - The mitoK(ATP) channel opener diazoxide in vivo preserves neuronal function after I/R, shown by pial arteriolar responses to NMDA, in a dose-dependent manner. Thus, activation of mitoK(ATP) channels may play a role in mediating the protective effect of other K+ channel openers.

AB - Background and Purpose - N-Methyl-D-aspartate (NMDA) elicits neuronally mediated cerebral arteriolar vasodilation that is reduced by ischemia/reperfusion (I/R). This sequence has been preserved by pretreatment with the ATP-sensitive potassium (K(ATP)) channel opener aprikalim, although the mechanism was unclear. In the heart, mitochondrial K(ATP) channels (mitoK(ATP)) are involved in the ischemic preconditioning-like effect of K+ channel openers. We determined whether the selective mitoK(ATP) channel opener diazoxide preserves the vascular dilation to NMDA after I/R. Methods - Pial arteriolar diameters were determined with the use of closed cranial window/intravital microscopy in anesthetized piglets. Vascular responses to NMDA were assessed before and 1 hour after 10 minutes of global cerebral ischemia induced by raising intracranial pressure. Subgroups received 1 of the following pretreatments before I/R: vehicle; 1 to 10 μmol/L diazoxide; and coapplication of 100 μmol/L 5-hydroxydecanoic acid (5-HD), a K(ATP) antagonist with diazoxide. Results - NMDA-induced dose-dependent pial arteriolar dilation was not affected by diazoxide treatment only but was severely attenuated by I/R. In contrast, diazoxide dose-dependently preserved the NMDA vascular response after I/R; at 10 μmol/L, diazoxide arteriolar responses were unaltered by I/R. The effect of diazoxide was antagonized by coapplication of 5-HD with diazoxide. Percent preservation of 100 μmol/L NMDA-induced vasodilation after I/R was 53±19% (mean±SEM, n=8) in vehicle- treated controls versus 55±10%, 85±5%, and 99±15% in animals pretreated with 1, 5, and 10 μmol/L diazoxide (n=8, n=8, and n=12, respectively) and 60±15% in the group treated with 5-HD+diazoxide (n=5). Conclusions - The mitoK(ATP) channel opener diazoxide in vivo preserves neuronal function after I/R, shown by pial arteriolar responses to NMDA, in a dose-dependent manner. Thus, activation of mitoK(ATP) channels may play a role in mediating the protective effect of other K+ channel openers.

KW - Cerebral ischemia, global

KW - N-methyl-D-aspartate

KW - Pigs

KW - Potassium channels

KW - Reperfusion injury

UR - http://www.scopus.com/inward/record.url?scp=0032727351&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032727351&partnerID=8YFLogxK

M3 - Article

C2 - 10583002

AN - SCOPUS:0032727351

VL - 30

SP - 2713

EP - 2719

JO - Stroke

JF - Stroke

SN - 0039-2499

IS - 12

ER -