Rapid functional upregulation of vasocontractile endothelin ET_B receptors in rat coronary arteries

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• 作者：Gry Freja Skovsted ; Anne Fog Pedersen ; Rikke Larsen ; Majid Sheykhzade ; Lars Edvinsson
• 关键词：Endothelin b receptor ; Endothelin-1 ; Coronary ; Smooth muscle ; Vasoconstriction ; Extracellular signal-regulated kinase ; Sarafotoxin 6c
• 刊名：Life Sciences
• 出版年：2012
• 出版时间：15 October, 2012
• 年：2012
• 卷：91
• 期：13-14
• 页码：593-599
• 全文大小：951 K

文摘

Aims

Endothelin ET_B receptors mediate under normal physiological conditions vasorelaxation in coronary arteries. However, vasocontractile ET_B receptors appear in coronary arteries of ischemic heart disease patients. Interestingly, organ culture of isolated coronary arteries also induces upregulation of vasocontractile ET_B receptors. This study examines the early time course and mechanism behind upregulation of contractile ET_B receptors in isolated rat coronary arteries during short-term organ culture.

Main methods

Coronary artery segments were mounted in wire-myographs and incubated in physiological saline solution. Contractions were measured after exposure to the specific ET_B receptor agonist Sarafotoxin 6c (S6c) and the endogenous agonists endothelin-1 and endothelin-3. Protein localization and levels of ET_B and phosphorylated-extracellular-signal-regulated-kinase-1/2 (ERK1/2) were examined by immunohistochemistry.

Key findings

Fresh arteries showed negligible vasoconstriction to S6c. However, incubation for only 4 and 7 h increased S6c contractions two- and seven-fold, respectively. Furthermore, 7 h incubation enhanced vasocontractile responses to endothelin-3 and increased ET_B receptor density in vascular smooth muscle cells. ERK1/2 was activated rapidly after start of incubation. Moreover, incubation with either the transcriptional inhibitor actinomycin D or the mitogen-activated-protein kinase kinase 1/2 (MEK1/2) inhibitor U0126 attenuated contractile ET_B receptor upregulation. U0126 attenuated ET_B receptor protein levels after 24 h of incubation.

Significance

Coronary arteries rapidly upregulate vasocontractile ET_B receptors during organ culture via transcriptional mechanisms and MEK-ERK1/2 signalling. This model may mimic the mechanisms seen in ischemic conditions. Furthermore, these findings have important experimental implications in tissue bath experiments lasting for more than 4 h.