Nitroglycerin Fails to Lower Blood Pressure in Redox-Dead Cys42Ser PKG1 alpha Knock-In Mouse

Article

关键词: MITOCHONDRIAL ALDEHYDE DEHYDROGENASE;    PROTEIN-KINASE G;    NITRATE TOLERANCE;    THIOL OXIDATION;    NITRIC-OXIDE;    BIOACTIVATION;    DIMERIZATION;    RELAXATION;    ACTIVATION;    SUBUNIT;   

DOI  :  10.1161/CIRCULATIONAHA.112.101287

来源: SCIE

【 摘 要 】

Background-Although nitroglycerin has remained in clinical use since 1879, the mechanism by which it relaxes blood vessels to lower blood pressure remains incompletely understood. Nitroglycerin undergoes metabolism that generates several reaction products, including oxidants, and this bioactivation process is essential for vasodilation. Protein kinase G (PKG) mediates classic nitric oxide-dependent vasorelaxation, but the 1 alpha isoform is also independently activated by oxidation that involves interprotein disulfide formation within this homodimeric protein complex. We hypothesized that nitroglycerin-induced vasodilation is mediated by disulfide activation of PKG1 alpha. Methods and Results-Treating smooth muscle cells or isolated blood vessels with nitroglycerin caused PKG1 alpha disulfide dimerization. PKG1 alpha disulfide formation was increased in wild-type mouse aortas by in vivo nitroglycerin treatment, but this oxidation was lost as tolerance developed. To establish whether kinase oxidation underlies nitroglycerin-induced vasodilation in vivo, we used a Cys42Ser PKG1 alpha knock-in mouse that cannot transduce oxidant signals because it does not contain the vital redox-sensing thiol. This redox-dead knock-in mouse was substantively deficient in hypotensive response to nitroglycerin compared with wild-type littermates as measured in vivo by radiotelemetry. Resistance blood vessels from knock-ins were markedly less sensitive to nitroglycerin-induced vasodilation (EC50 = 39.2 +/- 10.7 mu mol/L) than wild-types (EC50 = 12.1 +/- 2.9 mu mol/ L). Furthermore, after approximate to 24 hours of treatment, wild-type controls stopped vasodilating to nitroglycerin, and the vascular sensitivity to nitroglycerin was decreased, whereas this tolerance phenomenon, which routinely hampers the management of hypertensive patients, was absent in knock-ins. Conclusions-PKG1 alpha disulfide formation is a significant mediator of nitroglycerin-induced vasodilation, and tolerance to nitroglycerin is associated with loss of kinase oxidation. (Circulation. 2012; 126: 287-295.)

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