Aortic stiffness is sympathetically mediated in fructose‐induced salt‐sensitive hypertension

Abstract

Introduction Hypertension is one of the leading risk factors for major adverse cardiovascular events (MACE). Likewise, suboptimal dietary habits, including high fructose and sodium intake, are major leading causes of mortality. High dietary fructose alone predisposes to salt-sensitivity of blood pressure, which is an independent, significant cardiovascular risk factor. Aortic stiffness is now recognized as the most robust predictor of MACE and renal failure. Sympathoexcitation also imparts increased cardiovascular risk. Emerging data show that sympathetic inputs strongly impact aortic stiffness, and renal sympathetic denervation improves aortic distensibility. Recently published studies from our laboratory showed that with even short-term fructose in combination with high salt intake renal sympathetic nerve activity (RSNA) is significantly elevated prior to any increase in blood pressure and is responsible for activation of the renin-angiotensin-aldosterone system (RAS). Most recently, we also reported increased aortic stiffness in the fructose-induced salt-sensitive hypertension rat model. The present investigation was designed to assess the impact of acute blockade of RAS and/or sympathetic nervous activity on cardiovascular function in a rat model of fructose- induced salt-sensitive hypertension. Methods Sprague-Dawley rats were placed on a diet containing either 20% fructose or 20% glucose in their drinking water while consuming normal sodium. After one week, the fructose group was switched to a 4% sodium chow (FHS) and the rats were maintained on their respective diets for two additional weeks. At the beginning of week three, arterial and venous catheters were implanted and rats allowed to recover for one day. The following day, aortic pulsed wave velocity was measured using Vevo3100 ultrasound at two time points: 1) at baseline and 2) after intravenous injection of either sympatholytic agent clonidine, RAS inhibitor enalapril or diuretic hydrochlorothiazide (HCTZ). Blood pressure and heart rate were monitored throughout the entire experiment. Results Intravenous administration of clonidine, a central sympatholytic agent, reduced MAP and PWV in FHS rats significantly (by 23 ± 3 mmHg and by 212 ± 39 mm/s, respectively). A similar decline in blood pressure occurred in control rats (27 mmHg) but PWV did not change. The dose of enalapril used to inhibit RAS was chosen to provide a similar decline in MAP as clonidine. The reduction in MAP was slightly less profound (17 ± 4 mmHg); nonetheless, only a minimal change was observed in PWV in FHS (10 ± 6 mm/s) and no change in control rats. The diuretic HCTZ given acutely did not change either MAP or PWV. Conclusion Increase in aortic stiffness after two weeks of fructose and high salt diet appears to be sympathetically driven, since the abrogation of the sympathetic activity with clonidine decreased PWV in FHS rats. The effects of the RAS blockade may require a longer period of treatment to permit vascular remodeling and other cellular mechanisms and, thus, may not have been observable in an acute setting. Likewise, the intravascular volume changes due to the diuretic may also require longer exposure.