Mechanisms of hypertension in hyperinsulinemic and insulin resistant fructose hypertensive rats
Creators: name: Verma, Subodh
Publisher: name: University of British Columbia
Year: 2009

description: The fructose-induced hypertensive (FH) rat is a diet-induced model of mild hhypertension. In this model, feeding normal Sprague Dawley rats a fructose-enriched diet (66% fructose) results in hyperinsulinemia, insulin resistance and hypertension (independent of obesity). Several lines of evidence suggest that insulin resistance and hyperinsulinemia may play a pathogenic role in the development of high blood pressure in this model. This view is supported by observations which indicate that drugs that specifically counter insulin resistance (and attenuate hyperinsulinemia) exhibit antihypertensive effects. Despite the increasing use of this model, very little information is available regarding the mechanism(s)that link hyperinsulinemia/insulin resistance to high blood pressure in FH rats. A growing body of recent evidence suggests, that insulin, in addition to its well known effects on carbohydrate, protein and lipid metabolism, exerts important hemodynamic effects by modulating both vascular tone and sympathetic activity. This has led to the hypothesis that in states of insulin resistance/hyperinsulinemia, alterations in the hemodynamic actions of insulin may be important in the development and/or reinforcement of hypertension. The experiments outlined in this thesis were designed to examine this proposition in insulin resistant and hyperinsulinemic FH rats. In the first series of experiments, we studied the direct effects of insulin on the reactivity of aortae and perfused mesenteric arteries (MVB) from control (C) and FH rats to norepinephrine and angiotensin JJ. The key observation from this study was that the vascular effects of insulin were vessel-specific and dose-dependent. In the C rat aortae, pharmacological insulin concentrations (100 mU/ml) attenuated the contractile responses, while in the MVB, physiological concentrations (100 μU/ml) potentiated the pressor responses to NE. In contrast to the effects noted in C rats, the vascular effects of insulin were altered in arteries from FH rats. In aortae from FH rats, insulin-induced attenuation of contractile responses was blunted. Conversely, in the MVB, insulin-induced potentiation was further enhanced. To determine if these changes preceded the development of hypertension, we examined the effects of insulin (100 μU/ml) on MVB reactivity in pre-hypertensive FH rats (7 days post-fructose feeding). Strikingly, insulin-induced exaggeration of MVB contractile responses was present even at this time-point. These data indicate that in states of insulin resistance/hyperinsulinemia, the vascular effects of insulin are altered in a fashion consistent with increases in peripheral vascular resistance. The observation that the effects of insulin in the MVB occurred at physiological insulin concentrations (vs. the aortae) suggests that changes in vascular responsiveness of this bed may be of greater relevance to overall hemodynamics in FH rats. Evidence suggesting that insulin, at physiological concentrations, can increase the synthesis, release and gene expression of endothelin-1, led us to hypothesize that hyperinsulinemia in FH rats may serve as a continual stimulus for endothelin-1 release. To examine the contribution of endothelin-1 in FH rats we examined (a) the effects of in-vitro blockade of endothelin receptors (with bosentan, the specific ETa and ETb receptor antagonist) on insulin-induced MVB hyper-reactivity, (b) the effects of chronic bosentan treatment on plasma insulin levels and blood pressure in FH rats, and (c) reactivity of mesenteric arteries from C and FH rats to endothelin-1. Analysis of endothelin-1 levels revealed that the FH rats exhibited a two-fold higher endothelin-1 content in the MVB when compared to C, normotensive rats. Furthermore, in-vitro endothelin receptor blockad prevented the component of insulin-induced hyper-reactivity in the MVB. More importantly, chronic bosentan treatment prevented the development of hypertension in FH rats. These data suggest that hyperinsulinemia in FH rats may serve to increase blood pressure through alterations in ET-1 production. To determine if vasodilation per se is a determinant of insulin sensitivity in FH rats, we studied the effects of mibefradil (a calcium channel blocker) in this model. Chronic mibefradil treatment both prevented and reversed the development of fructose-induced hyperinsulinemia and hypertension and improved insulin sensitivity (estimated by 5 hour insulin/glucose ratio). Lastly, we studied the role of the sympathetic nervous system in FH rats. This was accomplished by studying the effects of chemical sympathectomy (adrenal medullectomy, followed by weekly 6-hydroxydopamine injections) on plasma insulin levels, blood pressure and the MVB effects of insulin. Sympathectomy abrogated the development of both hyperinsulinemia and hypertension, suggesting that a functional sympathetic nervous system is required for the expression of both hyperinsulinemia/insulin resistance and hypertension in FH rats. Sympathectomy also obliterated the vascular effects of insulin in FH rats without affecting these responses in controls. Based on our observations, we propose that a close interplay between the vascular actions of insulin and the sympathetic nervous system is important in the development and maintenance of hyperinsulinemia, insulin resistance and hypertension in rats fed a high fructose diet.