Contributions of KATP and KCa channels to cerebral arteriolar dilation to hypercapnia in neonatal brain

Chukwuma C. Nnorom, Corinne Davis, Alexander L. Fedinec, Khadesia Howell, Jonathan Jaggar, Elena Parfenova, Massroor Pourcyrous, Charles Leffler

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Mechanisms by which PCO2 controls cerebral vascular tone remain uncertain. We hypothesize that potassium channel activation contributes to the neonatal cerebrovascular dilation in response to increases in PaCO2. To test this hypothesis, experiments were performed on newborn pigs with surgically implanted, closed cranial windows. Hypercapnia was induced by ventilation with elevated PCO2 gas in the absence and presence of the KATP channel inhibitor, glibenclamide and/or the KCa channel inhibitor, paxillin. Dilations to pinacidil, a selective KATP channel activator, without and with glibenclamide, were used to evaluate the efficacy of KATP channel inhibition. Dilations to NS1619, a selective KCa channel activator, without and with paxillin, were used to evaluate the efficacy of KCa channel inhibition. Cerebrovascular responses to the KATP and KCa channel activators, pinacidil and NS1619, respectively, cAMP-dependent dilator, isoproterenol, and cGMP-dependent dilator, sodium nitroprusside (SNP), were used to evaluate the selectivity of glibenclamide and paxillin. Glibenclamide blocked dilation to pinacidil, but did not inhibit dilations to NS1619, isoproterenol, or SNP. Glibenclamide prior to hypercapnia decreased mean pial arteriole dilation ~60%. Glibenclamide treatment during hypercapnia constricted arterioles ~35%. The level of hypercapnia, PaCO2 between 50 and 75 mmHg, did not appear to be involved in efficacy of glibenclamide in blocking dilation to PaCO2. Similarly to glibenclamide and KATP channel inhibition, paxillin blocked dilation to the KCa channel agonist, NS1619, and attenuated, but did not block, arteriolar dilation to hypercapnia. Treatment with both glibenclamide and paxillin abolished dilation to hypercapnia. Therefore, either glibenclamide or paxillin that block dilation to their channel agonists, pinacidil or NS1619, respectively, only partially inhibit dilation to hypercapnia. Block of both KATP and KCa channels completely prevent dilation hypercapnia. These data suggest hypercapnia activates both KATP and KCa channels leading to cerebral arteriolar dilation in newborn pigs.

Original languageEnglish (US)
Article numbere12127
JournalPhysiological Reports
Volume2
Issue number8
DOIs
StatePublished - Jan 1 2014

Fingerprint

KATP Channels
Hypercapnia
Dilatation
Glyburide
Paxillin
Brain
Pinacidil
Arterioles
Nitroprusside
Isoproterenol
Swine
Potassium Channels
Blood Vessels
Ventilation

All Science Journal Classification (ASJC) codes

  • Physiology (medical)
  • Physiology

Cite this

Contributions of KATP and KCa channels to cerebral arteriolar dilation to hypercapnia in neonatal brain. / Nnorom, Chukwuma C.; Davis, Corinne; Fedinec, Alexander L.; Howell, Khadesia; Jaggar, Jonathan; Parfenova, Elena; Pourcyrous, Massroor; Leffler, Charles.

In: Physiological Reports, Vol. 2, No. 8, e12127, 01.01.2014.

Research output: Contribution to journalArticle

@article{8905dc62050c468db9d489b86b8e4ddd,
title = "Contributions of KATP and KCa channels to cerebral arteriolar dilation to hypercapnia in neonatal brain",
abstract = "Mechanisms by which PCO2 controls cerebral vascular tone remain uncertain. We hypothesize that potassium channel activation contributes to the neonatal cerebrovascular dilation in response to increases in PaCO2. To test this hypothesis, experiments were performed on newborn pigs with surgically implanted, closed cranial windows. Hypercapnia was induced by ventilation with elevated PCO2 gas in the absence and presence of the KATP channel inhibitor, glibenclamide and/or the KCa channel inhibitor, paxillin. Dilations to pinacidil, a selective KATP channel activator, without and with glibenclamide, were used to evaluate the efficacy of KATP channel inhibition. Dilations to NS1619, a selective KCa channel activator, without and with paxillin, were used to evaluate the efficacy of KCa channel inhibition. Cerebrovascular responses to the KATP and KCa channel activators, pinacidil and NS1619, respectively, cAMP-dependent dilator, isoproterenol, and cGMP-dependent dilator, sodium nitroprusside (SNP), were used to evaluate the selectivity of glibenclamide and paxillin. Glibenclamide blocked dilation to pinacidil, but did not inhibit dilations to NS1619, isoproterenol, or SNP. Glibenclamide prior to hypercapnia decreased mean pial arteriole dilation ~60{\%}. Glibenclamide treatment during hypercapnia constricted arterioles ~35{\%}. The level of hypercapnia, PaCO2 between 50 and 75 mmHg, did not appear to be involved in efficacy of glibenclamide in blocking dilation to PaCO2. Similarly to glibenclamide and KATP channel inhibition, paxillin blocked dilation to the KCa channel agonist, NS1619, and attenuated, but did not block, arteriolar dilation to hypercapnia. Treatment with both glibenclamide and paxillin abolished dilation to hypercapnia. Therefore, either glibenclamide or paxillin that block dilation to their channel agonists, pinacidil or NS1619, respectively, only partially inhibit dilation to hypercapnia. Block of both KATP and KCa channels completely prevent dilation hypercapnia. These data suggest hypercapnia activates both KATP and KCa channels leading to cerebral arteriolar dilation in newborn pigs.",
author = "Nnorom, {Chukwuma C.} and Corinne Davis and Fedinec, {Alexander L.} and Khadesia Howell and Jonathan Jaggar and Elena Parfenova and Massroor Pourcyrous and Charles Leffler",
year = "2014",
month = "1",
day = "1",
doi = "10.14814/phy2.12127",
language = "English (US)",
volume = "2",
journal = "Physiological Reports",
issn = "2051-817X",
publisher = "John Wiley and Sons Inc.",
number = "8",

}

TY - JOUR

T1 - Contributions of KATP and KCa channels to cerebral arteriolar dilation to hypercapnia in neonatal brain

AU - Nnorom, Chukwuma C.

AU - Davis, Corinne

AU - Fedinec, Alexander L.

AU - Howell, Khadesia

AU - Jaggar, Jonathan

AU - Parfenova, Elena

AU - Pourcyrous, Massroor

AU - Leffler, Charles

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Mechanisms by which PCO2 controls cerebral vascular tone remain uncertain. We hypothesize that potassium channel activation contributes to the neonatal cerebrovascular dilation in response to increases in PaCO2. To test this hypothesis, experiments were performed on newborn pigs with surgically implanted, closed cranial windows. Hypercapnia was induced by ventilation with elevated PCO2 gas in the absence and presence of the KATP channel inhibitor, glibenclamide and/or the KCa channel inhibitor, paxillin. Dilations to pinacidil, a selective KATP channel activator, without and with glibenclamide, were used to evaluate the efficacy of KATP channel inhibition. Dilations to NS1619, a selective KCa channel activator, without and with paxillin, were used to evaluate the efficacy of KCa channel inhibition. Cerebrovascular responses to the KATP and KCa channel activators, pinacidil and NS1619, respectively, cAMP-dependent dilator, isoproterenol, and cGMP-dependent dilator, sodium nitroprusside (SNP), were used to evaluate the selectivity of glibenclamide and paxillin. Glibenclamide blocked dilation to pinacidil, but did not inhibit dilations to NS1619, isoproterenol, or SNP. Glibenclamide prior to hypercapnia decreased mean pial arteriole dilation ~60%. Glibenclamide treatment during hypercapnia constricted arterioles ~35%. The level of hypercapnia, PaCO2 between 50 and 75 mmHg, did not appear to be involved in efficacy of glibenclamide in blocking dilation to PaCO2. Similarly to glibenclamide and KATP channel inhibition, paxillin blocked dilation to the KCa channel agonist, NS1619, and attenuated, but did not block, arteriolar dilation to hypercapnia. Treatment with both glibenclamide and paxillin abolished dilation to hypercapnia. Therefore, either glibenclamide or paxillin that block dilation to their channel agonists, pinacidil or NS1619, respectively, only partially inhibit dilation to hypercapnia. Block of both KATP and KCa channels completely prevent dilation hypercapnia. These data suggest hypercapnia activates both KATP and KCa channels leading to cerebral arteriolar dilation in newborn pigs.

AB - Mechanisms by which PCO2 controls cerebral vascular tone remain uncertain. We hypothesize that potassium channel activation contributes to the neonatal cerebrovascular dilation in response to increases in PaCO2. To test this hypothesis, experiments were performed on newborn pigs with surgically implanted, closed cranial windows. Hypercapnia was induced by ventilation with elevated PCO2 gas in the absence and presence of the KATP channel inhibitor, glibenclamide and/or the KCa channel inhibitor, paxillin. Dilations to pinacidil, a selective KATP channel activator, without and with glibenclamide, were used to evaluate the efficacy of KATP channel inhibition. Dilations to NS1619, a selective KCa channel activator, without and with paxillin, were used to evaluate the efficacy of KCa channel inhibition. Cerebrovascular responses to the KATP and KCa channel activators, pinacidil and NS1619, respectively, cAMP-dependent dilator, isoproterenol, and cGMP-dependent dilator, sodium nitroprusside (SNP), were used to evaluate the selectivity of glibenclamide and paxillin. Glibenclamide blocked dilation to pinacidil, but did not inhibit dilations to NS1619, isoproterenol, or SNP. Glibenclamide prior to hypercapnia decreased mean pial arteriole dilation ~60%. Glibenclamide treatment during hypercapnia constricted arterioles ~35%. The level of hypercapnia, PaCO2 between 50 and 75 mmHg, did not appear to be involved in efficacy of glibenclamide in blocking dilation to PaCO2. Similarly to glibenclamide and KATP channel inhibition, paxillin blocked dilation to the KCa channel agonist, NS1619, and attenuated, but did not block, arteriolar dilation to hypercapnia. Treatment with both glibenclamide and paxillin abolished dilation to hypercapnia. Therefore, either glibenclamide or paxillin that block dilation to their channel agonists, pinacidil or NS1619, respectively, only partially inhibit dilation to hypercapnia. Block of both KATP and KCa channels completely prevent dilation hypercapnia. These data suggest hypercapnia activates both KATP and KCa channels leading to cerebral arteriolar dilation in newborn pigs.

UR - http://www.scopus.com/inward/record.url?scp=85002975247&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85002975247&partnerID=8YFLogxK

U2 - 10.14814/phy2.12127

DO - 10.14814/phy2.12127

M3 - Article

VL - 2

JO - Physiological Reports

JF - Physiological Reports

SN - 2051-817X

IS - 8

M1 - e12127

ER -