Hypertension is the most common chronic disease in developed countries [1
]. Numerous studies have shown that the prevalence of hypertension in the United State has increased from approximately 5% to 10% of the adult population to approximately 31% since the early 20th century [2
]. There has been a significant ∼10% to 20% increase in mean total fructose intake in children, and a marked ∼20% to 60% increase in teenagers and adults between 1978 and 2004 [3
]. Obesity, type 2 diabetes, and cardiovascular diseases were shown to be linked to fructose consumption in large amounts [5
]. High fructose consumption has shown greater adverse effects on metabolism and vascular health than glucose consumption in several animal studies, and it causes detrimental health effects, such as fatty liver diseases [7
]. In addition, a high-fructose diet (60%) and intake of 10% fructose water over an eight-week period induced hypertension, hypertriglyceridemia, and hyperuricemia in rats [8
]. Fructose, a sweeter alternative to glucose, is usually used in smaller amounts than glucose. Because fructose cannot be used directly as a source of energy, the metabolisms of fructose and glucose are very different [9
]. The actual mechanism of how fructose affects the central nervous system (CNS) and subsequently influences BP regulation is still unknown.
Many studies indicated that the mechanism of BP elevation due to excessive fructose consumption falls into three broad categories: chronic stimulation of the sympathetic nervous system (SNS), dysfunction of the endothelium, and upregulation of salt absorption [10
]. There is evidence suggesting that the chronic sympathetic nerve is overactivated in fructose-induced hypertension. Fructose-fed rats have significantly higher serum norepinephrine and triglycerides levels than the control rats, and these parameters are involved in increases in BP [11
]. Previous studies revealed that chemical sympathectomy restored increased BP in fructose-fed rats, suggesting that the development of hypertension is linked to the function of the SNS [12
]. Information in the sympathetic and parasympathetic nerves is transmitted by renal afferent fibers. The information converges at the nucleus tractus solitarii (NTS), which is the primary site of BP and sympathetic nerve activity (SNA) modulation [13
]. Experimental lesions in the NTS cause a loss of baroreflex control of BP and sympathetic activation, and evoke severe hypertension in animals [15
]. In this study, we focused on the mechanisms underlying BP elevation after excessive fructose intake for one week. In a previous study, compared with those in glucose-fed rats, serum triglyceride levels increased to a greater degree in fructose-fed rats [17
]. Our previous studies revealed that serum triglyceride concentrations increased much more significantly in the group fed 10% fructose water than in the control group [18
]. Therefore, we speculate that increased serum triglyceride levels caused by increased fructose intake may be a possible trigger for elevated BP. Moreover, we examined whether excessive consumption of fructose for one week is associated with sympathetic nerve overactivation and impairment of baroreflex sensitivity.
Epidemiologic studies all pointed to the fact that fructose may be involved in hypertension; however, there is no direct evidence to support such a claim. A previous study showed that fructose acts as a stimulus for triglyceride synthesis, triggering sympathetic nerve overactivation in the NTS following fructose intake for four weeks [18
]. In this study, we hypothesized that increased fructose intake decreased nitric oxide (NO) level in the NTS, diminished baroreflex sensitivity, increased serum triglycerides, and further overactivated SNS, thereby increasing BP. This study aimed to investigate whether increased fructose intake induces BP elevation and to determine the mechanisms in rats fed fructose for one week. Here, we show that a one-week consumption of 10% fructose water upregulated BP, leading to hyperactivation of the SNS and impairment of baroreflex sensitivity.
Here, we describe a link between fructose and NO levels in the NTS, as well as its association with baroreflex sensitivity and activation of the CNS. Our findings showed that excessive fructose consumption increased BP and renal SNA, decreased NO bioavailability, and impaired baroreflex response. Excessive fructose intake increased serum triglycerides levels and induced BP elevation by stimulating SNA; however, alleviation of hypertriglyceridemia did not attenuate sympathetic activation and only slightly lowered BP. It was suggested that, mechanistically, SNA played a role in modulating changes in BP due to increased fructose consumption through another unknown pathway.
Epidemiological studies have hinted at a link between fructose consumption and elevated blood pressure. Jalal et al. [25
] reported that excess dietary fructose (≥74 g/day) in the form of added sugar was associated with higher BP values in adults in the United States who did not have a history of hypertension. Similarly, a study of 4867 adolescents found that SBP rose by 2 mmHg following the intake of sugar-sweetened beverages from the lowest to the highest category [26
]. In a prospective study involving adults in the United States, Chen et al. [27
] found that intake of one less sugar-sweetened beverage per day was associated with a 1.8 mmHg reduction in SBP and a 1.1 mmHg reduction in DBP over 18 months. Some animal studies showed that a high-fructose diet was associated with hypertriglyceridemia, hyperinsulinemia, impaired glucose tolerance, insulin resistance, and increased BP and body weight [28
]. However, these adverse effects were not indicated with equivalent calories of glucose. In this study, increased fructose intake for 0 to 2 days evoked increases in BP levels, and the high BP levels were maintained until day 7 (Figure 2
The great increase in fructose consumption in the last decades leads to the rapid accumulation of triglyceride in the Occidental population [29
]. Tran et al. reported [11
] that serum norepinephrine and triglyceride levels are significantly increased in fructose-fed hypertensive rats, as reflected by high SNA. According to Tran et al., hypertension can develop in rats owing to excessive fructose consumption, and the developed hypertension can be treated using a sympatholytic agent called prazosin, which blocks the α1-adrenoreceptors [30
]. Hypertension inhibition by prazosin did not reduce the level of triglyceride in serum. Consistent with this previous result, our data showed that the use of a DGAT1 inhibitor for inhibiting serum triglyceride level led to a slight decrease in BP but did not affect SNA (Figure 3
The baroreflex system is an important mechanism in the regulation of heart rate, sympathetic tone, and consequently BP. Impairment of baroreflex sensitivity is involved in the sympathoexcitatory and sympathoinhibitory effects of metabolic syndromes [31
]. A previous study showed that hypertriglyceridemia may be the main contributory factor associated with impaired baroreflex sensitivity during a metabolic syndrome [32
]. Soncrant et al. reported that elevated BP was increased by sympathoexcitation in 20% fructose-induced, salt-sensitive, hypertensive rats [33
]. It has been shown that the ingestion of fructose altered the secretion of hormones that regulate energy balance associated with increased SNA [34
]. However, in the current study, although a DGAT1 inhibitor was administered orally to block triglycerides production, sympathoexcitation was not inhibited in fructose-fed rats. Dos Santos et al indicated that fructose consumption similarly reduced both baroreflex sensitivity and activity [35
]. Our research further indicated that fructose intake may reduce NO levels in the NTS and cause baroreflex dysfunction, which further stimulates SNA and induces the development of high BP (Figure 4
and Figure 5
Generally, anesthetics affect the basal levels of sympathetic nerve activity to regulate blood pressure, which plays an important role in controlling cardiovascular function [36
]. Sun et al. indicated that anesthesia attenuated the excitatory response of RSNA and HR to anaphylactic hypotension, while these excitatory responses were attenuated by anesthetics in the order ketamine-xylazine > urethane = pentobarbital [38
]. Bencze et al. found that pentobarbital anesthesia had a modest influence on the BP level and its maintenance by the above vasoactive systems [37
]. In addition, anesthetics may inhibit the primary area in the baroreceptor reflex pathway of the central nervous system, resulting in attenuation of the baroreceptor reflex [39
]. Therefore, sympathetic nerve activity and cardiovascular function may be affected by the anesthetic. However, there were some limitations to our study. First, we measured BP during consciousness, whereas RSNA and baroreflex sensitivity measurements were performed under the anesthetic. Second, our sample size was relatively small and the study used nonparametric methods for analysis. Third, the fructose group was used as the control group only on day 0.
With regards to the relationship between baroreflex sensitivity and NO level in the NTS, our previous studies indicated that central endogenous NO is involved in the medullary regulation of BP and that a NO synthase inhibitor attenuates baroreflex activation [40
]. In addition, unilateral microinjection of the nitric oxide synthase (NOS) inhibitor L-NMMA into the NTS generates dose-dependent bradycardic effects, but these effects were inhibited after intravenous injection of atropine, indicating that the bradycardic effect of L-NMMA is mediated by baroreflex responses [41
]. In terms of the mechanisms by which fructose in the CSF induces suppression of NO levels in the NTS and further damages baroreflex sensitivity, our previous studies indicated that superoxide production increases in the NTS of rats fed fructose for one week [42
]. Fructose-induced neurogenic hypertension might be mediated by the activation of p38, followed by phosphorylation of the insulin receptor substrate 1 ser307, which might occur via superoxide overexpression in the NTS [43
]. In this study, we showed that fructose intake may reduce NO levels in the NTS and cause baroreflex dysfunction, which further stimulated SNA and induced the development of high BP.