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Hypertens Res ; 35(2): 157-65, 2012 Feb.
Article in English | MEDLINE | ID: mdl-21900943

ABSTRACT

Sympathetic hyperactivity has an important role in cardiovascular mortality in patients with type 2 diabetes (T2D). Thyrotropin-releasing hormone (TRH)-containing fibers innervate autonomic motor and premotor nuclei of the brainstem and spinal cord that regulate cardiovascular functions. We compared cardiovascular responses to application of TRH-analog in the brainstem of Wistar and T2D Goto-Kakizaki (GK) rats. GK rats exhibited basal systolic hypertension (152±2 mm Hg) and had a significantly potentiated, dose-related hypertensive response to intracisternal (i.c.) injection of the TRH-analog RX77368 (10-60 ng). In GK rats only, i.c. RX77368 (30-60 ng) markedly increased heart rate (HR; +88 b.p.m.) and induced acute cardiac mortality (100%), concurrent with extreme hyperglycemia (>26 mmol l(-1)), increased plasma H(2)O(2) and 8-isoprostane, and enhanced heart expression of NADPH oxidase 4 and vascular cell adhesion molecule-1 mRNAs. GK rats also had elevated basal plasma epinephrine, higher adrenal gene expression of tyrosine hydroxylase and dopamine ß-hydroxylase (DßH), and greater plasma catecholamine and adrenal DßH responses to i.c. TRH-analog, compared with Wistar rats. In GK rats, hexamethonium blocked i.c. RX77368-induced hypertensive and tachycardic responses, and reduced mortality by 86%, whereas phentolamine abolished the hypertensive response but enhanced tachycardia (+160 b.p.m.), and reduced mortality by 50%. The angiotensin II type 1 receptor antagonist irbesartan prevented i.c. RX77368-induced increases in blood pressure, HR and mortality. In conclusion, sympathetic overactivation triggered by brainstem TRH contributes to the mechanism of cardiovascular morbidity and mortality in T2D, which involves heightened cardiac inflammation and peripheral oxidative stress responses to sympathetic drive, and a mediating role of the renin-angiotensin system.


Subject(s)
Brain Stem/physiology , Cardiovascular Diseases/mortality , Cardiovascular Diseases/physiopathology , Diabetes Mellitus, Type 2/physiopathology , Sympathetic Nervous System/drug effects , Thyrotropin-Releasing Hormone/pharmacology , Adrenal Glands/metabolism , Adrenal Glands/physiology , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Animals , Biphenyl Compounds/therapeutic use , Blood Glucose/metabolism , Blood Pressure/physiology , Cardiovascular Diseases/genetics , Cisterna Magna , Heart Rate/physiology , Inflammation/pathology , Injections , Irbesartan , Male , Myocardium/metabolism , NADPH Oxidase 4 , NADPH Oxidases/biosynthesis , Oxidative Stress/drug effects , Oxidative Stress/physiology , Pyrrolidonecarboxylic Acid/analogs & derivatives , Pyrrolidonecarboxylic Acid/pharmacology , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Rats , Rats, Wistar , Sympathetic Nervous System/physiology , Tetrazoles/therapeutic use , Thyrotropin-Releasing Hormone/analogs & derivatives , Vascular Cell Adhesion Molecule-1/biosynthesis
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