title: Role of brainstem thyrotropin-releasing hormone-triggered sympathetic overactivation in cardiovascular mortality in type 2 diabetic Goto-Kakizaki rats.
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 β-hydroxylase (DβH), and greater plasma catecholamine and adrenal DβH 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.
authors: Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. hoyang@ucla.edu
authors: Hong
authors: H
authors: Yang
authors: Michael D
authors: MD
authors: Nyby
authors: Yan
authors: Y
authors: Ao
authors: Ai
authors: A
authors: Chen
authors: David W
authors: DW
authors: Adelson
authors: Victoria
authors: V
authors: Smutko
authors: Janake
authors: J
authors: Wijesuriya
authors: Vay Liang W
authors: VL
authors: Go
authors: Michael L
authors: ML
authors: Tuck
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism / Q000502:physiology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000818:Animals; D001713:Biphenyl Compounds / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D001933:Brain Stem / Q000502:physiology*; D002318:Cardiovascular Diseases / Q000235:genetics / Q000401:mortality* / Q000503:physiopathology*; D002946:Cisterna Magna; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D006339:Heart Rate / Q000502:physiology; D007249:Inflammation / Q000473:pathology; D007267:Injections; D000077405:Irbesartan; D008297:Male; D009206:Myocardium / Q000378:metabolism; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000502:physiology; D013777:Tetrazoles / Q000627:therapeutic use; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D001786:Blood Glucose; D012333:RNA, Messenger; D013777:Tetrazoles; D019010:Vascular Cell Adhesion Molecule-1; D013973:Thyrotropin-Releasing Hormone; C027979:L-pyroglutamyl-L-histidyl-3,3-dimethylprolinamide; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D000077405:Irbesartan; D011761:Pyrrolidonecarboxylic Acid