Hypertension, an important preventable major risk factor for cardiovascular diseases and strokes that becomes more prevalent with aging, commonly occurs after age 30 years 22
. Many believe that dietary macronutrients, especially refined CHO like sugars, play a significant role in age-related BP elevation 1,2,4
. Although Wotecke et al 23
estimate that total CHO consumption has fallen from 56% to 46% of energy intake over the first 75 years of the 21st
century, this has been wholly at the expense of complex CHO, because the consumption of refined CHO, especially sucrose and fructose, rose steadily to exceed 20% of the energy intake. With the popularity of soft drink consumption, intake of sucrose and fructose has even become greater over the last few years 24
. Could this dietary change be related to the prevalence of hypertension 25
Sprague-Dawley rats (SD) are considered a normotensive strain of rats. Prior to beginning the present study, however, we fortuitously found that female SD consuming a regular diet containing added sucrose showed a gradual rise in the systolic blood pressure (SBP) from normotensive levels to hypertensive levels over a long term (>150 mm Hg). Use of the female gender is important because of lesser information on females who have a particularly difficult time with age-related hypertension 2,22
. Sucrose was added in the present investigation to assure that the regular feed of the SD contained a virtually similar portion of refined CHO calories as the normal American Diet 24
and may have been responsible for the hypertensive range of SBP in the SD 4-6
. Suffice it to say, this BP pattern in SD simulates in many ways the age-related hypertension often noted in humans 22
The pathological mechanism(s) behind the gradually rising, chronic BP elevation associated with refined CHO ingestion and/or aging is uncertain, because the elevated SBP may relate to a number of perturbed underlying regulating mechanisms that include augmented catecholamine levels 26
, disturbed vasodilatory function via disturbances in NO signaling in blood vessels 27
, alterations in fluid and electrolyte balance 28
, and disturbances in the renin-angiotensin system (RAS) manifested by elevated circulating levels of angiotensin-2 29
. The association between the RAS and sugar-induced hypertension is especially intriguing, because, in addition to the elevated BP, recent findings show a direct, deleterious effect of circulating angiotensin-2 on the cardiovascular system 30
. This may explain, at least in part, a previous finding that high consumption of sugars, shown to increase circulating levels of angiotensin 2 29
, can be associated with vascular lesions 31
. The ability of captopril to lower the elevated BP produced by sugar ingestion also corroborates the important role of the RAS in sugar-induced hypertension. Niacin-bound chromium (NBC) has also been shown to lower the activity of the renin-angiotensin system and was, along with captopril, added as a positive control in these experiments 17
. In the present study, both NBC and captopril decreased blood pressure and lessened the activity of the RAS.
In previous investigations, whole maitake mushroom and crude fractions of the mushroom were shown to favorably affect hypertension and glucose-insulin metabolism in rodents 9-13
. The crude fractions included a water extract and an ether extract, and the two rat species examined were genetically hypertensive rats (spontaneously hypertensive rats [SHR]) and genetically insulin-resistant rats (Zucker Fatty Rats [ZFR]). Different results were found in each species. At 35 days, only consumption of the diet containing the ether fraction significantly decreased systolic blood pressure (SBP) in SHR (average 197 vs. 176 mm Hg, p <. 001), while in ZFR only the groups consuming the whole maitake and water extract showed significantly decreased SBP (138 vs. 120-125 mm Hg, p <. 001). Even though the RAS could have played a role in the BP effects of the mushroom and its extracts on the SHR, a losartan challenge test in ZFR suggested that angiotensin 2 did not play a major role in SBP regulation under the conditions examined.
In the present investigation, female SD rats showed gradually, but steadily, increasing SBP as they aged. Similar to the groups consuming captopril or niacin-bound chromium, SBP decreased significantly early on indicating that both SX and D could halt and even reverse to some extent the sugar-induced/age-related elevations of SBP (Figs. ,). By the end of the four months after introduction of the maitake fractions into the diet, the diastolic and mean BP were also significantly reduced compared to control. In the face of no significant differences in body weight and food and fluid intake suggesting that the test rats were receiving the tested substances in the proportions desired, the SBP changed markedly under all test conditions, with the captopril addition bringing the SBP virtually to the same SBP as months earlier - reversing all the age-related elevations. With a single exception, i.e., the rise in creatinine with the maitake fractions, blood chemistries revealed no significant toxic changes to go along with other evidence, i.e., no changes in appetite or body weight. We attribute the rise in creatinine levels in those SD consuming fractions SX and D to changes in muscle mass secondary to the status of insulin sensitivity and not to any problems with renal function, since the BUN levels were similar among groups. An insulin-sensitizing agent like niacin-bound chromium has previously been associated with enhanced muscle build up 32
. Examining a panel of cytokines, all the test groups showed significantly lower levels of circulating Tumor Necrosis Factor-alpha (TNF-α) suggesting some anti-inflammatory capabilities (Table ).
Two tests to assess the activity of the RAS suggest that decreased activity occurred when Fraction SX and all test groups were compared to control. The greater decrease in SBP after losartan challenge in the control group suggests that the RAS was more active in the control group compared to the SX group (Fig.) 19,33
. When estimating the ACE activity in the serum of the SD 34
, the latter was found to be lower in the captopril, fraction D and Fraction SX group compared to control. The NBC group showed a trend toward decreased activity relative to control. Previous in vitro
work pointed out the ACE inhibitory effects of mushrooms 35
Kopilas et al 27] examined sugar-induced BP elevations in SHR and concluded that the NO system was significantly involved in the pathogenesis. We examined the ability of LNAME, a substance that can inhibit the dilatory actions of NO, to influence SBP and found a trend toward raised BP, more so in all the test groups. Accordingly, this supports the contention that a relatively depressed NO system is involved in sugar-induced hypertension 27
and that captopril, chromium, and fractions D and SX can enhance this system causing lower SBP.
Based upon previous findings, addition of Maitake SX to the diet of sucrose-eating rats would be expected to enhance insulin sensitivity, and we believe that to be the case here 11,13
. In the present study carried out on normotensive, female Sprague-Dawley rats, the circulating levels of fasting blood glucose (Table ) and the area under the curve in a glucose tolerance test (Table ), tended to be less, although not significantly so. More to the point, however, the challenge test to estimate insulin sensitivity did show a statistically improved activity in the SD ingesting fraction SX. Captopril and NBC were examined at the same time to act as positive controls. Ace inhibitor agents, like captopril, have been reported to have insulin-sensitizing abilities 36-39
and could theoretically reduce inflammation 40,41
, and this proved to be the case here. Captopril showed a trend toward enhancing insulin sensitivity, and NBC, previously shown to enhance insulin sensitivity, also did likewise. Somewhat surprising was the finding that Fraction D enhanced insulin sensitivity. It is not clear why this happened. Fraction D is known primarily for its immune enhancing properties 15
. It is unclear if the same substance or a difference substance in SX and D is responsible for the enhancement of insulin sensitivity and the inhibition of RAS.
To summarize some major points emanating from the present study, two commercial extracts of maitake mushroom (SX and D) are safe natural products that can favorably influence the progressive elevation of SBP over time, enhance insulin sensitivity, and lower circulating levels of a cytokine associated with inflammation - TNF-α. Accordingly, this makes the maitake mushroom and its commercial extracts excellent candidates to produce a long, healthful life span 42