Anh Thuc Ngo, Mads Riemann, Niels-Henrik Holstein-Rathlou, Christian Torp-Pedersen, Lars Jørn Jensen
{"title":"K(ATP)通道、l型Ca 2 +通道和CYP450-4A酶在小鼠肌小动脉体内氧传感中的意义","authors":"Anh Thuc Ngo, Mads Riemann, Niels-Henrik Holstein-Rathlou, Christian Torp-Pedersen, Lars Jørn Jensen","doi":"10.1186/1472-6793-13-8","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>ATP-sensitive K⁺ channels (KATP channels), NO, prostaglandins, 20-HETE and L-type Ca²⁺ channels have all been suggested to be involved in oxygen sensing in skeletal muscle arterioles, but the role of the individual mechanisms remain controversial. We aimed to establish the importance of these mechanisms for oxygen sensing in arterioles in an in vivo model of metabolically active skeletal muscle. For this purpose we utilized the exteriorized cremaster muscle of anesthetized mice, in which the cremaster muscle was exposed to controlled perturbation of tissue PO₂.</p><p><strong>Results: </strong>Change from \"high\" oxygen tension (PO₂ = 153.4 ± 3.4 mmHg) to \"low\" oxygen tension (PO₂ = 13.8 ± 1.3 mmHg) dilated cremaster muscle arterioles from 11.0 ± 0.4 μm to 32.9 ± 0.9 μm (n = 28, P < 0.05). Glibenclamide (KATP channel blocker) caused maximal vasoconstriction, and abolished the dilation to low oxygen, whereas the KATP channel opener cromakalim caused maximal dilation and prevented the constriction to high oxygen. When adding cromakalim on top of glibenclamide or vice versa, the reactivity to oxygen was gradually restored. Inhibition of L-type Ca²⁺ channels using 3 μM nifedipine did not fully block basal tone in the arterioles, but rendered them unresponsive to changes in PO₂. Inhibition of the CYP450-4A enzyme using DDMS blocked vasoconstriction to an increase in PO₂, but had no effect on dilation to low PO₂.</p><p><strong>Conclusions: </strong>We conclude that: 1) L-type Ca²⁺ channels are central to oxygen sensing, 2) KATP channels are permissive for the arteriolar response to oxygen, but are not directly involved in the oxygen sensing mechanism and 3) CYP450-4A mediated 20-HETE production is involved in vasoconstriction to high PO₂.</p>","PeriodicalId":35905,"journal":{"name":"BMC Physiology","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2013-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1472-6793-13-8","citationCount":"18","resultStr":"{\"title\":\"Significance of K(ATP) channels, L-type Ca²⁺ channels and CYP450-4A enzymes in oxygen sensing in mouse cremaster muscle arterioles in vivo.\",\"authors\":\"Anh Thuc Ngo, Mads Riemann, Niels-Henrik Holstein-Rathlou, Christian Torp-Pedersen, Lars Jørn Jensen\",\"doi\":\"10.1186/1472-6793-13-8\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>ATP-sensitive K⁺ channels (KATP channels), NO, prostaglandins, 20-HETE and L-type Ca²⁺ channels have all been suggested to be involved in oxygen sensing in skeletal muscle arterioles, but the role of the individual mechanisms remain controversial. We aimed to establish the importance of these mechanisms for oxygen sensing in arterioles in an in vivo model of metabolically active skeletal muscle. For this purpose we utilized the exteriorized cremaster muscle of anesthetized mice, in which the cremaster muscle was exposed to controlled perturbation of tissue PO₂.</p><p><strong>Results: </strong>Change from \\\"high\\\" oxygen tension (PO₂ = 153.4 ± 3.4 mmHg) to \\\"low\\\" oxygen tension (PO₂ = 13.8 ± 1.3 mmHg) dilated cremaster muscle arterioles from 11.0 ± 0.4 μm to 32.9 ± 0.9 μm (n = 28, P < 0.05). Glibenclamide (KATP channel blocker) caused maximal vasoconstriction, and abolished the dilation to low oxygen, whereas the KATP channel opener cromakalim caused maximal dilation and prevented the constriction to high oxygen. When adding cromakalim on top of glibenclamide or vice versa, the reactivity to oxygen was gradually restored. Inhibition of L-type Ca²⁺ channels using 3 μM nifedipine did not fully block basal tone in the arterioles, but rendered them unresponsive to changes in PO₂. Inhibition of the CYP450-4A enzyme using DDMS blocked vasoconstriction to an increase in PO₂, but had no effect on dilation to low PO₂.</p><p><strong>Conclusions: </strong>We conclude that: 1) L-type Ca²⁺ channels are central to oxygen sensing, 2) KATP channels are permissive for the arteriolar response to oxygen, but are not directly involved in the oxygen sensing mechanism and 3) CYP450-4A mediated 20-HETE production is involved in vasoconstriction to high PO₂.</p>\",\"PeriodicalId\":35905,\"journal\":{\"name\":\"BMC Physiology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2013-05-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1186/1472-6793-13-8\",\"citationCount\":\"18\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"BMC Physiology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1186/1472-6793-13-8\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"Biochemistry, Genetics and Molecular Biology\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"BMC Physiology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1186/1472-6793-13-8","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Biochemistry, Genetics and Molecular Biology","Score":null,"Total":0}
Significance of K(ATP) channels, L-type Ca²⁺ channels and CYP450-4A enzymes in oxygen sensing in mouse cremaster muscle arterioles in vivo.
Background: ATP-sensitive K⁺ channels (KATP channels), NO, prostaglandins, 20-HETE and L-type Ca²⁺ channels have all been suggested to be involved in oxygen sensing in skeletal muscle arterioles, but the role of the individual mechanisms remain controversial. We aimed to establish the importance of these mechanisms for oxygen sensing in arterioles in an in vivo model of metabolically active skeletal muscle. For this purpose we utilized the exteriorized cremaster muscle of anesthetized mice, in which the cremaster muscle was exposed to controlled perturbation of tissue PO₂.
Results: Change from "high" oxygen tension (PO₂ = 153.4 ± 3.4 mmHg) to "low" oxygen tension (PO₂ = 13.8 ± 1.3 mmHg) dilated cremaster muscle arterioles from 11.0 ± 0.4 μm to 32.9 ± 0.9 μm (n = 28, P < 0.05). Glibenclamide (KATP channel blocker) caused maximal vasoconstriction, and abolished the dilation to low oxygen, whereas the KATP channel opener cromakalim caused maximal dilation and prevented the constriction to high oxygen. When adding cromakalim on top of glibenclamide or vice versa, the reactivity to oxygen was gradually restored. Inhibition of L-type Ca²⁺ channels using 3 μM nifedipine did not fully block basal tone in the arterioles, but rendered them unresponsive to changes in PO₂. Inhibition of the CYP450-4A enzyme using DDMS blocked vasoconstriction to an increase in PO₂, but had no effect on dilation to low PO₂.
Conclusions: We conclude that: 1) L-type Ca²⁺ channels are central to oxygen sensing, 2) KATP channels are permissive for the arteriolar response to oxygen, but are not directly involved in the oxygen sensing mechanism and 3) CYP450-4A mediated 20-HETE production is involved in vasoconstriction to high PO₂.
BMC PhysiologyBiochemistry, Genetics and Molecular Biology-Physiology
CiteScore
9.60
自引率
0.00%
发文量
0
期刊介绍:
BMC Physiology is an open access journal publishing original peer-reviewed research articles in cellular, tissue-level, organismal, functional, and developmental aspects of physiological processes. BMC Physiology (ISSN 1472-6793) is indexed/tracked/covered by PubMed, MEDLINE, BIOSIS, CAS, EMBASE, Scopus, Zoological Record and Google Scholar.