Brainstem mechanisms that impair autonomic regulation of blood pressure with obesity

Metabolic syndrome (MetS) is emerging as a global health threat due to its strong association with increased risk for cardiovascular disease and diabetes. Currently, 20-25% of the world's population exhibits some traits of MetS, namely obesity, dyslipidemia, hyperinsulinemia, hypertension, and hyperglycemia. In addition, MetS also promotes the development of impaired short-term regulation of mean arterial pressure (AP) by baroreflexes, which normally act to stabilize AP. The resulting increased AP variability, which is an independent risk factor for poor outcomes, is overlooked as a trait of MetS and goes without evaluation or treatment. People who have controlled hypertension without minimizing elevated AP variability are still at significant risk for detrimental cardiovascular events such as stroke and cognitive decline. Therefore, understanding mechanisms impairing baroreflexes with MetS will help determine appropriate therapeutic management to restore baroreflexes and promote stability of AP. Furthermore, because sex differences in the development of impaired baroreflexes with obesity have been reported, an understanding of how females are protected would provide valuable insights for underlying causes for early onset of impaired baroreflexes in obese males and eventual development of impaired baroreflexes in obese females. In this project, I utilized a rodent model of MetS, obese Zucker rats (OZR), to examine contributions of hypertension and hyperglycemia in the development of impaired baroreflexes in male OZR, and whether hypertensive female OZR have delayed onset of impaired baroreflexes because they have the ability to maintain glycemic control. Male and female OZR have excess weight gain from an early age because the mutation of a leptin receptor renders them insensitive to leptin's actions to regulate appetite and metabolism, promoting excess intake of standard chow and storage of ingested calories. Like obese humans, OZR develop dyslipidemia, hypertension, and insulin resistance that eventually progresses to type 2 diabetes, making them a suitable model for the consequences of MetS. Young adult male OZR (12-15 weeks) develop sympathetically driven hypertension with pronounced attenuation of baroreflex control of heart rate (HR) and sympathetic nerve activity (SNA) compared to juvenile OZR and lean Zucker rats (LZR). In male OZR, the development of impaired baroreflexes coincides with blunted activation of the NTS, the brain stem region that receives baroreceptor afferent inputs to promote baroreflex-mediated changes in HR and SNA, and this deficit likely yields diminished baroreflexes observed in young adult male OZR. In the first project I examined whether improvement of impaired glycemic control in young adult male OZR restores baroreflex-mediated bradycardia and activation of the NTS. Both type 1 and type 2 diabetic rats have impaired vagally-mediated activation of the NTS, in agreement with the reported loss of glucose's ability to enhance glutamatergic neurotransmission within the NTS of hyperglycemic, diabetic rodents. Male OZR develop insulin resistance at an early age, characterized by elevated insulin and triglycerides with impaired glucose tolerance but normal fasting hyperglycemia. We examined glucose homeostasis using chronic measures of blood glucose by telemetry in undisturbed rats because of previous reports of exaggerated stress responses. We observed that although young adult (12-14 weeks old) male OZR have normal fasting blood glucose, they are chronically hyperglycemic with access to food. Treatment of OZR with metformin or pioglitazone restored fed blood glucose levels with access to food and enhanced baroreflex-mediated bradycardia and activation of the NTS, as suggested by phenylehphrine-induced c-Fos expression. In contrast, treatment of LZR did not alter glucose or affect baroreflex-mediated bradycardia and activation of the NTS. Neither treatment reduced elevated AP and insulin in OZR, suggesting the lowering of blood glucose was effective for restoring baroreflexes in young adult male OZR, even in the face of hypertension. In the second project I examined whether the delayed onset of impaired baroreflexes in hypertensive female OZR could be due to their ability to maintain a normal blood glucose and baroreflex-mediated activation of the NTS. Premenopausal obese women protected from diabetes, suggesting they would be protected from deficits produced by hyperglycemia. I observed that intact baroreflex-mediated bradycardia in young adult female OZR extended to preserved sympathetic baroreflexes and baroreflex-mediated activation of the NTS in 12-15-week-old female OZR. Furthermore, although these OZR were hypertensive and hyperinsulinemic, fed glucose levels and glucose tolerance are comparable to LZR. In contrast, by 6 months of age, baroreflex-mediated bradycardia was blunted in female OZR. However, fed glucose was only mildly elevated and baroreflex-mediated activation of the NTS was comparable in OZR and LZR. These data suggest the ability to maintain glucose homeostasis in young adult female OZR coincides with a preservation of baroreflex-mediated bradycardia and activation of the NTS. However, the later development of impaired baroreflex-mediated bradycardia in female OZR occurs through mechanisms distinct from those observed in male OZR. The third project examined whether preventing hypertension in male OZR protected against the development of impaired baroreflexes and activation of the NTS. Treatment with losartan or hydralazine normalized baseline AP in male OZR without affecting hyperinsulinemia, dyslipidemia, or hyperglycemia. Furthermore, these treatments enhanced baroreflex-mediated bradycardia and activation of the NTS in male OZR. However, even when AP was normalized in male OZR, baroreflex-mediated bradycardia was still smaller in treated OZR compared to like-treated LZR, suggesting other mechanisms also contribute to the blunted baroreflexes. Together these studies suggest that the development of hyperglycemia and hypertension in male OZR contribute to impaired baroreflex-mediated bradycardia and activation of the NTS in male OZR. However, the ability of female OZR to maintain glucose homeostasis preserves baroreflexes despite the presence of hypertension and hyperinsulinemia. Furthermore, when female OZR later develop impaired baroreflex-mediated bradycardia, this deficit occurs by mechanisms that differ from male OZR, highlighting the need to examine both sexes for the development of cardiovascular and metabolic disorders.