Elevated Sympathetic Activity Contributes to Hypertension and Salt Sensitivity in Diabetic Obese Zucker Rats

Abstract

Abstract-Zucker rats are a useful model in which to define the mechanisms that link obesity to diabetes and associated cardiovascular disease. The present study tests the hypothesis that diabetic obese (compared with nondiabetic lean) Zucker rats are hypertensive and display a further increase in arterial pressure when fed a high salt diet. Male, nondiabetic lean and diabetic obese Zucker rats were chronically instrumented with telemetry probes and fed a basal salt diet for 3 weeks followed by exposure to a high salt diet for 11 days. On the basal diet, obese (vs lean) rats had significantly higher arterial pressures (Ϸ13 mm Hg), and the high salt diet significantly elevated mean arterial pressure (MAP) in obese (but not lean) Zucker rats (Ϸ12 mm Hg). Blockade of the sympathetic nervous system with hexamethonium caused a significantly larger decrease in MAP in obese (vs lean) Zucker rats fed the basal diet (51 vs 33 mm Hg), but the high salt diet did not increase the hexamethonium-induced reduction in arterial pressure in obese rats. Acute blockade of angiotensin receptors with losartan resulted in similar decreases in MAP in both groups on either diet. Acetylcholine-induced vasodilatory capacity of the carotid artery was significantly less in the obese (vs lean) Zucker rats. Together these data indicate that increased sympathetic nervous system activity and decreased vascular reactivity may contribute to elevated arterial pressure in type 2 diabetic, obese Zucker rats, but the sympathetic nervous system does not appear to contribute to the dietary salt-sensitive hypertension in this model. which results in numerous pathological changes, including nephropathy, retinopathy, neuropathy, and cardiovascular disease. Of these factors, cardiovascular disease is the single largest cause of death in diabetes mellitus, accounting for an estimated 80% of deaths in diabetic individuals. 2 The risk of cardiovascular disease in diabetic individuals is increased by concomitant hypertension, which occurs in an estimated 70% of type 2 diabetic patients. 3 Results from the Framingham 4 and MRFIT 5 trials indicate that the coexistence of the 2 diseases triples the risk of cardiovascular disease. Moreover, the presence of hypertension probably accelerates diabetic nephropathy, which in turn exacerbates the hypertension, creating a vicious feedforward cycle that contributes to the extremely high occurrence of end-stage kidney failure in type 2 diabetic patients. 6

Altered regulation of the rostral ventrolateral medulla in hypertensive obese Zucker rats

“…Baseline MAP of the OZR was significantly higher than the LZR under urethane anesthesia (Table 1), as previously reported for conscious adult Zucker rats (5,29). Rectified SNA voltage was also significantly higher in the OZR compared with the LZR (Table 1), in agreement with previous observations of elevated renal and splanchnic SNA in the OZR (16,27).…”

Increased peripheral vascular disease risk progressively constrains perfusion adaptability in the skeletal muscle microcirculation

“…While there are multiple reports that alterations to adrenergic signaling are a major contributor to phenylephrineinduced (constrictor) responses (6,10,41,52), there is also considerable evidence in the existing literature that the impairments to endothelial function result in the loss of a "buffering" of adrenergic responses, such that these are enhanced independent from any changes to adrenergic signaling per se (29,42,43). Myogenic activation tended to be mildly increased with conditions of elevated PVD risk that included hypertension, potentially for a protective effect on the downstream microcirculation (14,59).…”

“…While certainly some of these effects are the result of the changes to endothelial function impacting the constrictor responses (29,42,43), there is previous evidence to support increases in adrenergic activity (6), receptor sensitivity (52), or downstream signaling gain (41) as potential contributors to increased constrictor responses in many of these models. While this would potentially reduce attractor variability further and would represent an additional, and possibly extremely robust, depressor of arteriolar function and flexibility in the control of tissue perfusion, it is unclear that a simple "increase in adrenergic constrictor reactivity" accurately represents the prevailing condition in conditions of elevated PVD risk that are associated with obesity and hypertension (28,30,37).…”

Downregulation of Basal iNOS at the Rostral Ventrolateral Medulla Is Innate in SHR

“…[1][2][3][4][5] At the same time, a key determinant of the prevailing sympathetic vasomotor drive is the balance between the physiologically active nNOS and iNOS at the RVLM, which are responsible, respectively, for the excitatory and inhibitory actions of endogenous NO on the premotor sympathetic neurons. 11 It follows that additional shifts in balance toward nNOS by a significant reduction in both synthesis and activity of iNOS at the RVLM underlie the augmented sympathetic vasomotor tone during hypertension.…”

“…hereas the notion that hypertension in human patients 1,2 and animal models [3][4][5] is attributable to an augmented central sympathetic outflow to the heart or peripheral vasculature is well accepted, the mechanism that underlies sympathetic overactivity during hypertension requires further delineation. Recent studies 6 -8 implicate an abnormality of the nitric oxide (NO) system in the brain in hypertension.…”