Tags

Type your tag names separated by a space and hit enter

Mitochondrial K(ATP) channel as an end effector of cardioprotection during late preconditioning: triggering role of nitric oxide.
J Mol Cell Cardiol. 2001 Nov; 33(11):2037-46.JM

Abstract

Nitric oxide (NO) has been implicated in the "second-window" of ischemic preconditioning (PC). However, the identity of the end effector after initiation of preconditioning by NO is not known. It is likely that NO is involved in opening of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels. We hypothesized that NO is an important trigger for the opening of mitoK(ATP) channels in the late phase of preconditioning and inducible nitric oxide synthase (iNOS) up-regulation via NF kappa B plays a critical role in diazoxide-induced cardioprotection. To examine this, diazoxide (7 mg/kg) was administered to wild-type (WT) mice and mice lacking the gene 24 hours before 40 minutes of global ischemia. Hearts were perfused in a Langendorff mode and effects of activation of mitoK(ATP) channel and other interventions on functional, biochemical and pathological changes in ischemic hearts were assessed. In hearts from WT mice treated diazoxide, left-ventricular-developed pressure, end-diastolic pressure and coronary flow were significantly improved after ischemia/reperfusion (I/R); lactate dehydrogenase (LDH) release was also significantly decreased, while ATP contents were significantly higher. Administration of 5-HD, a specific blocker of mitoK(ATP) channel or l -NAME, an inhibitor of iNOS before I/R, during diazoxide-pretreatment completely blocked the late cardioprotection against ischemia. Late cardioprotection was also blocked by inhibition of either PKC- delta by rottlerin or NF kappa B by DDTC before diazoxide pretreatment. Diazoxide pretreatment significantly increased nuclear translocation of p65 which was blocked by protein kinase C (PKC) or nitric oxide synthase (NOS) inhibition. Diazoxide was totally inefffective in iNOS knockout mice. These results suggest that diazoxide activates NF kappa B via PKC signaling pathway and that leads to iNOS up-regulation after 24 hours. NO which is generated upon ischemic stress triggers the opening of mitoK(ATP)channel as an end effector of cardioprotection during late PC.

Authors+Show Affiliations

Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267-0529, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11708847

Citation

Wang, Y, et al. "Mitochondrial K(ATP) Channel as an End Effector of Cardioprotection During Late Preconditioning: Triggering Role of Nitric Oxide." Journal of Molecular and Cellular Cardiology, vol. 33, no. 11, 2001, pp. 2037-46.
Wang Y, Kudo M, Xu M, et al. Mitochondrial K(ATP) channel as an end effector of cardioprotection during late preconditioning: triggering role of nitric oxide. J Mol Cell Cardiol. 2001;33(11):2037-46.
Wang, Y., Kudo, M., Xu, M., Ayub, A., & Ashraf, M. (2001). Mitochondrial K(ATP) channel as an end effector of cardioprotection during late preconditioning: triggering role of nitric oxide. Journal of Molecular and Cellular Cardiology, 33(11), 2037-46.
Wang Y, et al. Mitochondrial K(ATP) Channel as an End Effector of Cardioprotection During Late Preconditioning: Triggering Role of Nitric Oxide. J Mol Cell Cardiol. 2001;33(11):2037-46. PubMed PMID: 11708847.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitochondrial K(ATP) channel as an end effector of cardioprotection during late preconditioning: triggering role of nitric oxide. AU - Wang,Y, AU - Kudo,M, AU - Xu,M, AU - Ayub,A, AU - Ashraf,M, PY - 2001/11/16/pubmed PY - 2002/2/15/medline PY - 2001/11/16/entrez SP - 2037 EP - 46 JF - Journal of molecular and cellular cardiology JO - J Mol Cell Cardiol VL - 33 IS - 11 N2 - Nitric oxide (NO) has been implicated in the "second-window" of ischemic preconditioning (PC). However, the identity of the end effector after initiation of preconditioning by NO is not known. It is likely that NO is involved in opening of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels. We hypothesized that NO is an important trigger for the opening of mitoK(ATP) channels in the late phase of preconditioning and inducible nitric oxide synthase (iNOS) up-regulation via NF kappa B plays a critical role in diazoxide-induced cardioprotection. To examine this, diazoxide (7 mg/kg) was administered to wild-type (WT) mice and mice lacking the gene 24 hours before 40 minutes of global ischemia. Hearts were perfused in a Langendorff mode and effects of activation of mitoK(ATP) channel and other interventions on functional, biochemical and pathological changes in ischemic hearts were assessed. In hearts from WT mice treated diazoxide, left-ventricular-developed pressure, end-diastolic pressure and coronary flow were significantly improved after ischemia/reperfusion (I/R); lactate dehydrogenase (LDH) release was also significantly decreased, while ATP contents were significantly higher. Administration of 5-HD, a specific blocker of mitoK(ATP) channel or l -NAME, an inhibitor of iNOS before I/R, during diazoxide-pretreatment completely blocked the late cardioprotection against ischemia. Late cardioprotection was also blocked by inhibition of either PKC- delta by rottlerin or NF kappa B by DDTC before diazoxide pretreatment. Diazoxide pretreatment significantly increased nuclear translocation of p65 which was blocked by protein kinase C (PKC) or nitric oxide synthase (NOS) inhibition. Diazoxide was totally inefffective in iNOS knockout mice. These results suggest that diazoxide activates NF kappa B via PKC signaling pathway and that leads to iNOS up-regulation after 24 hours. NO which is generated upon ischemic stress triggers the opening of mitoK(ATP)channel as an end effector of cardioprotection during late PC. SN - 0022-2828 UR - https://www.unboundmedicine.com/medline/citation/11708847/Mitochondrial_K_ATP__channel_as_an_end_effector_of_cardioprotection_during_late_preconditioning:_triggering_role_of_nitric_oxide_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-2828(01)91468-3 DB - PRIME DP - Unbound Medicine ER -