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). Thyrotropinreleasing 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 (426 mmol l À1 ), 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 b-hydroxylase (DbH), and greater plasma catecholamine and adrenal DbH 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.

Food-intake dysregulation in type 2 diabetic Goto-Kakizaki rats: Hypothesized role of dysfunctional brainstem thyrotropin-releasing hormone and impaired vagal output

“…We found impaired vagal regulation of visceral organs in GK rats, a consequence of reduced vagal efferent outflow activation by brainstem TRH (Ao et al, 2010; Ao et al, 2005a; Yang et al, 2012). TRH analog intracisternal injection (ic), at doses that did not influence blood glucose levels and heart rate in non-diabetic Wistar rats, induced persistent sympathetic activation-mediated increases in glucose levels, blood pressure and heart rate in GK rats, concomitant with remarkably damaged vagal-counterregulation on insulin stimulation and cardiac inhibition (Ao et al, 2010; Ao et al, 2005a; Yang et al, 2012). The extreme and prolonged hyperglycemia and acute heart failure-induced cardiovascular mortality in GK rats indicate severely damaged TRH action on DMV vagal motor neurons (Ao et al, 2010; Ao et al, 2005a; Yang et al, 2012).…”

“…TRH microinjected into the DMV, or endogenously released into the DMV after chemical stimulation of neurons in the raphe nuclei, induces potent vagal-mediated visceral responses (Ishikawa et al, 1988; Yang et al, 1993; Yang et al, 2002). Substantial evidence shows that TRH is the only brain peptide fulfilling all of the criteria as a neurotransmitter and/or neuromodulator activating vagal motor neurons in the DMV, where it assists vagal regulation of food digestion and nutrition metabolism by increasing gastric/intestinal secretory/motility and stimulating gut/pancreatic hormone release (Ao et al, 2006; Ao et al, 2010; Ao et al, 2005a; Taché and Yang, 1994; Yang et al, 2012). Activation of brainstem TRH receptors increases food intake by stimulating vagal-cholinergic pathway-mediated gastric ghrelin release (Ao et al, 2006).…”

“…The GK rat is a “non-obese” T2D model generated by selective breeding from non-diabetic Wistar rats with poor glucose tolerance, and shows basal hyperglycemia, hypertension, and insulin resistance (Goto et al, 1988; Yang et al, 2012). We found impaired vagal regulation of visceral organs in GK rats, a consequence of reduced vagal efferent outflow activation by brainstem TRH (Ao et al, 2010; Ao et al, 2005a; Yang et al, 2012).…”

“…The GK rat is a “non-obese” T2D model generated by selective breeding from non-diabetic Wistar rats with poor glucose tolerance, and shows basal hyperglycemia, hypertension, and insulin resistance (Goto et al, 1988; Yang et al, 2012). We found impaired vagal regulation of visceral organs in GK rats, a consequence of reduced vagal efferent outflow activation by brainstem TRH (Ao et al, 2010; Ao et al, 2005a; Yang et al, 2012). TRH analog intracisternal injection (ic), at doses that did not influence blood glucose levels and heart rate in non-diabetic Wistar rats, induced persistent sympathetic activation-mediated increases in glucose levels, blood pressure and heart rate in GK rats, concomitant with remarkably damaged vagal-counterregulation on insulin stimulation and cardiac inhibition (Ao et al, 2010; Ao et al, 2005a; Yang et al, 2012).…”

“…TRH analog intracisternal injection (ic), at doses that did not influence blood glucose levels and heart rate in non-diabetic Wistar rats, induced persistent sympathetic activation-mediated increases in glucose levels, blood pressure and heart rate in GK rats, concomitant with remarkably damaged vagal-counterregulation on insulin stimulation and cardiac inhibition (Ao et al, 2010; Ao et al, 2005a; Yang et al, 2012). The extreme and prolonged hyperglycemia and acute heart failure-induced cardiovascular mortality in GK rats indicate severely damaged TRH action on DMV vagal motor neurons (Ao et al, 2010; Ao et al, 2005a; Yang et al, 2012). In this study, we first established body adipose tissue content in the GK and Wistar rats and then evaluated the inappropriately management of central and peripheral signaling in response to fasting and refeeding in T2D GK rats, with focus on brainstem TRH dysfunction-associated impairment of vagal regulation.…”