**1. Introduction**

The prevalence of hypertension has been increasing in recent decades in the United States both independently and concurrently with diabetes [1]. Elevated fructose consumption has been implicated in metabolic disorders and subsequent cardiovascular morbidity [2–4]. In pre-clinical models, high levels of fructose consumption—often exceeding 60% of daily caloric intake—elicit hypertension and cardiovascular dysfunction, and implicate insulin signaling as the pathogenic mechanism [4,5]. Ingestion of 20% fructose in drinking water together with high-salt chow, which is more representative of the diet ingested by the upper quintile in humans in the United States, results in sodium and fluid retention in rats, enhanced sympathetic activation, and inadequate suppression of plasma renin activity, leading to a hypertensive state prior to development of frank metabolic syndrome or diabetes mellitus [6,7].

Adolescence is marked by the continuous development and growth of physiologic systems. In early stages of life, various systems undergo substantial ontogenetic changes, some of which are susceptible to modulation by external stimuli. Several studies have demonstrated the effect of excess fructose consumption on cardiovascular systems in

**Citation:** Levanovich, P.E.; Chung, C.S.; Komnenov, D.; Rossi, N.F. Fructose plus High-Salt Diet in Early Life Results in Salt-Sensitive Cardiovascular Changes in Mature Male Sprague Dawley Rats. *Nutrients* **2021**, *13*, 3129. https://doi.org/10.3390/nu13093129

Academic Editor: Hayato Tada

Received: 30 July 2021 Accepted: 3 September 2021 Published: 8 September 2021

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adults [8–10]. However, little is understood regarding the impact of fructose-rich diets during adolescence on cardiovascular parameters later in life [11–15]. The major consumers of fructose are adolescents and young adults, with sugar-sweetened beverages representing the main source. Fructose intake in adolescents accounts for nearly 20% of daily energy consumption [16,17].

Western diets use high-fructose corn syrup extensively as a sweetener but are also high in sodium content [3]. Since pre-clinical studies indicate that a diet high in both fructose and salt results in hypertension [5,6,10,11], aortic stiffness, and early diastolic dysfunction [12], the question arises whether ingestion of high fructose and salt during a critical period early in life predisposes to salt-sensitive hypertension and cardiovascular dysfunction in later life. This window of plasticity during adolescence has been well recognized in behavioral science [18,19]. Likewise, with cardiovascular development, rat models have shown that interventions during critical time periods of ontogeny may modulate susceptibility to hypertension later in life. Insights into post-gestational influences on arterial pressure have been garnered predominantly from studies using genetically hypertensive-strain rats such as Dahl salt-sensitive and spontaneously hypertensive rats to investigate the impact on disease progression [20]. For example, four-week treatment of young spontaneously hypertensive rats with angiotensin-converting enzyme inhibition attenuated development of elevated blood pressure in later life [21]. The converse has not been given much attention, namely, whether factors such as diet or environment during this critical developmental period may adversely alter cardiovascular parameters in maturity, even in a rat strain that is not genetically prone to hypertension.

One in five adolescents in the United States are now considered pre-diabetic [22]. This increasing incidence of pre-diabetes raises the potential of cardiovascular dysfunction later in life that can be further impacted by poor dietary habits at this stage. Thus, the purpose of the present study was to investigate whether exposure to high fructose with or without high salt during the critical adolescent period will lead to hypertension and cardiovascular dysfunction in response to high-salt diet later in life. We hypothesized that rats consuming 20% fructose plus with 4% sodium diet during five to eight weeks of age (comparable to human pre- and early adolescence) [19,23] will develop elevated salt-sensitive blood pressure, reduced arterial compliance, and left ventricular diastolic dysfunction in adulthood when challenged with high dietary sodium in the absence of fructose.
