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Clinical and Experimental Hypertension, 2012; 34(2): 99106 Copyright Informa Healthcare USA, Inc.

. ISSN 1064-1963 print /1525-6006 online DOI: 10.3109/10641963.2011.618196

Sodium Alginate Oligosaccharides Attenuate Hypertension and Associated Kidney Damage in Dahl Salt-Sensitive Rats Fed a High-Salt Diet
Shouko Terakado,1 Mai Ueno,1 Yuki Tamura,1 Natsuko Toda,1 Mariko Yoshinaga,1 Kie Otsuka,1 Atsushi Numabe,2 Yukari Kawabata,3 Itsuki Murota,4 Nobuyuki Sato,4 Yoshio Uehara1
1 Department 2 Department

of Clinical Nutrition, Faculty of Home Economics, Kyoritsu Womens University, Tokyo, Japan, of Clinical and Laboratory Medicine, Dokkyo University School of Medicine, Mibu, Japan, 3 Health Service Center, University of Tokyo, Tokyo, Japan, 4 Central Research Institute, Maruha Nichiro Holdings, Inc., Tsukuba, Japan

Abstract
Objectives: In this article, the antihypertensive effects of sodium alginate oligosaccharides, enzymatic products of high molecular natural alginate from sea weeds, in Dahl salt-sensitive (Dahl S) rats were investigated. Material and Methods: Dahl S rats fed a high-salt (4% NaCl) diet were treated with sodium alginate oligosaccharides (4% or 8% w/w) for 7 weeks. Systolic blood pressure (SBP) was measured by the tail-cuff method, and hypertensive cardiovascular benets and kidney damage were assessed. Glomerular function and morphological sclerosis were determined. Results: SBP increased in an age-dependent manner in the untreated Dahl S rats. Sodium alginate oligosaccharide treatment attenuated the increase in SBP in a dose-dependent manner. The heart and aortic walls weighed less in the rats treated with sodium alginate oligosaccharides than in the untreated rats. The SBP reduction was associated with a decrease in urinary protein excretion and an increase in the creatinine clearance rate. Sodium alginate oligosaccharides signicantly attenuated hypertensive glomerular sclerosis and arterial injury in the kidney. Fractional excretion of sodium (FENa) decreased in low-salt Dahl S rats and increased with a salt challenge. The alginate oligosaccharides decreased FENa in high-salt Dahl S rats. Conclusions: The results of this study suggest that sodium alginate oligosaccharides attenuate salt-induced hypertension in Dahl S rats. This reduction is associated with decreases in cardiovascular and renal damage. Keywords: alginate, salt-induced hypertension, kidney, Dahl rats

INTRODUCTION Alginate is a polysaccharide rich in ber produced from seaweeds including kombu and giant kelp. Alginate is essentially composed of the anionic sugars -L-guluronate and -D-mannuronate (Figure 1) (1,2). These sugars bind to one another by way of a 1,4-glycoside bond. The molecular weight averages 500 000 daltons, and the long-chain alginate is viscous and water insoluble. It is not digested or absorbed in the intestine. Thus, it is believed that the chemical properties of alginate somehow retard or inhibit absorption of cholesterol or sodium in the intestine (3). Adhesion to the viscous moiety or more specic ionic binding may be possible mechanisms for the binding. In this context, it has been noted that the sugars have a carboxylic acid and alginate has the capacity to bind Na+ , K+ , or

Ca2+ . The ionic exchange between H+ and Na+ , K+ , or Ca2+ presumably decreases absorption of Na+ in the intestine, thereby attenuating high blood pressure (3). This explanation seems acceptable as the antihypertensive effects of alginate. Unfortunately, however, the mechanisms of the antihypertensive effects of alginate are not well understood (2). Alginate is usually extracted and puried as sodium alginate, and it has less capacity for Na+ binding than theoretically expected while this form of alginate decreases blood pressure. Moreover, the low molecular weight alginate (40 00060 000 daltons) produced by physiological techniques is water soluble, and this is also reported to decrease cholesterol and glucose absorption (3,4). These data seemingly oppose the traditional explanation of the mechanism of the long-chain alginate in the

Address correspondence to Yoshio Uehara, MD, PhD, Department of Clinical Nutrition, Faculty of Home Economics, Kyoritsu Womens University, 2-2-1 Hitotsubashi, Chiyoda-ku, Tokyo 101-8437, Japan. E-mail: yuehara@kyoritsu-wu.ac.jp Received 31 January 2011; revised 31 March 2011; accepted 3 April 2011.

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100 S. Terakado et al.

(A)

(B)

Figure 1 . Chemical structure of alginate. (A) Natural alginate is a polysaccharide ber rich in seaweeds including kombu and giant kelp. Natural alginate is essentially composed of anionic sugars of -L-guluronate and -D-mannuronate. (B) Sodium alginate oligosaccharides used in this study are composed of unsaturated uronic acids (dU) and -L-guluronate (G) and/or -D-mannuronate (M).

regulation of absorption of nutrients or antihypertensive action. In this context, an enzymatic method that high molecular weight alginate can be cleaved into very small oligosaccharides with 23 sugars (including unsaturated uronic acid and 3-L-guluronate and/or -Dmannuronate) was established recently (Figure 1) (5,6). Uronic acid is an unsaturated form of 3-L-guluronate or -D-mannuronate. The resulting alginate oligosaccharides are around 500 daltons in the molecular weight and water soluble. While alginate is cleaved, the oligosaccharides are saturated with Na+ . In addition, more than 40% of the cleaved oligosaccharides orally administered are absorbed in the intestine and then excreted in urine (unpublished data). Thus, in order to understand the sodium-binding mechanism of alginate, it is interesting to examine whether very small molecular weight sodium alginate oligosaccharides are able to attenuate elevated blood pressure in salt-dependent hypertension. According to previous studies on alginate, it may be possible that the retardation/inhibition of sodium absorption is due to -L-guluronate and -Dmannuronate sugars rather than the high molecular or low molecular weight of the alginate (57). To test this hypothesis, the effects of oral administration of sodium alginate oligosaccharides on salt-induced hypertension and associated kidney damage were investigated in Dahl salt-sensitive (Dahl S) rats. MATERIALS AND METHODS
Experimental Design

Dahl S/Jr Sea rats (Dahl S rats) were originally obtained from the colony of Mollegard Co. Ltd. (Copenhagen, Denmark). The strain was maintained at Seak Co. Ltd. (Mie, Japan) and then kept as an inbred colony by Kudo Co. Ltd. (Mie, Japan). Dahl S rats were divided into four groups: (i) eight Dahl S rats fed a low-salt (0.3% NaCl) diet (DSlow), (ii) eight Dahl S rats fed a high-salt (4% NaCl) diet (DS-high), (iii) eight Dahl S rats fed a high-salt (4% NaCl) diet containing 4% w/w sodium alginate oligosaccharides (TX-low), and (iv) eight Dahl S rats fed a high-salt (4% NaCl) diet containing 8% w/w sodium alginate oligosaccharides (TX-high). All rats were maintained on the diet for 7 weeks. Water was available ad libitum throughout the experiment. Twenty-four-hour urine samples were collected every 2 weeks using a metabolic cage. Urine samples were stored at 80 C until assayed. Systolic blood pressure (SBP) was measured using the tail-cuff method of Friedman and Freed (8) with a modication in the detection system (Natsume Seisakujo Model KN-210-1; Tokyo, Japan). The same investigator measured blood pressure in all animals in a quiet, warm room. At the end of the experiment, SBP was measured. Under pentobarbital anesthesia (75 mg/kg body weight), blood samples and kidneys were obtained from each animal. Blood samples were drawn into syringes containing ethylenediaminetetraacetic acid (EDTA)disodium, and plasma was quickly separated using a refrigerated centrifuge. The samples were stored at 80 C until assayed. The kidneys were placed in 10% formalin solution for morphological examination.

This study followed the guidelines for experimental animal handling and was approved by the Animal Care Committee of the Kyoritsu Womens University. A total of 32 4-week-old male Dahl S (Dahl S/Jr Sea) rats were purchased from SRL Ltd. (Tokyo, Japan). The

Biomarkers of Renal Damage

Plasma and urinary creatinine levels and urinary sodium excretion were measured using an autoanalyzer (Model Hitachi 736; Hitachi Co., Ltd., Tokyo, Japan). Urinary
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Alginate and Antihypertension 101

protein concentrations were measured using a protein assay kit (BioRad, Hercules, CA, USA). Glomerular sclerosis was semi-quantitatively assessed according to a method reported previously (9,10). Briey, each kidney was immediately xed in 3.5% formalin, and sagittal slices were cut and embedded in parafn. Sections (2 m thickness) were cut and stained with Azan and periodic acid Schiff (PAS). At least 100 glomeruli were examined in each specimen. Glomerular sclerotic lesions were intensely stained by PAS. The severity of these lesions was graded according to the percentage of total glomeruli involved: no lesions, grade 0; 1%25% sclerosis, grade 1; 26%50% sclerosis, grade 2; 51%75% sclerosis, grade 3; and 76%100% sclerosis, grade 4. An overall glomerular sclerosis score was calculated by multiplying the severity score (04) by the percentage of glomeruli affected and totaling the values from all glomeruli for each specimen. The severity of arterial injury was graded as follows: 0, normal artery; I, medial and intimal hyperplasia or necrosis with luminal narrowing; II, medial necrosis with inammatory cell inltration; and III, medial and intimal hyperplasia or necrosis with inammatory cell inltration and thrombus formation. The overall arterial injury score (AI score) was obtained by multiplying the severity score (03) by the percentage of arteries displaying the same degree of injury and these scores were all added together.
Statistical Analysis

420 DS-low TX-low 360 300

** *

Body weights (g)

** ** ** * *

** *
DS-high

240 180 120 60 Start 1

TX-high

** *

2 3 4 5 Experimental period (wk)

Figure 2. Alterations of body weights. Abbreviations: DS-low Dahl S rats fed a low-salt diet (open square); DS-high Dahl S rats fed a high-salt diet (open circle); TX-low Dahl S rats fed a high-salt diet and given low-dose sodium alginate oligosaccharides (closed diamond); TX-high Dahl S rats fed a high-salt diet and given high-dose sodium alginate oligosaccharides (closed circle). Group differences were assessed by one-way factorial ANOVA analysis of variance, followed by post hoc LSD test. *P < .05 versus the respective values of DS-high, **P < .05 versus the respective values of DS-low.

All statistical analyses were performed using STATISTICA software (StatSoft, Tulsa, OK, USA). Values were expressed as means SD. Differences were assessed by one-way factorial analysis of variance (ANOVA) followed by post hoc least signicant difference (LSD) test or non-parametric KruskalWallis test followed by a MannWhitney U test with Bonferroni correction. P values less than .05 were considered statistically signicant.
Guidelines for Handling Rats for Experiments

weight was increased to control DS-low and higher than the untreated DS-high. In low-dose alginate oligosaccharide treatment, the body weight was almost the same as the control DS-low during the study. In DS-high rats, both heart and aortic walls weights signicantly increased compared with DS-low rats. The increase was attenuated with the oligosaccharide treatments (Table 1). Similarly, kidney weights were higher in DShigh compared with DS-low rats. The increase in kidney weights signicantly decreased with the oligosaccharide treatments.
Changes in SBP

Alterations of SBP are shown in Figure 3. Systolic blood pressure increased in an age-dependent manner with a
Table 1. Organ weights Organ weight Experimental groups DS-low DS-high TX-low TX-high P value Heart (g) 1.19 0.03* 1.70 0.15 1.58 0.07* 1.50 0.76* <.001 Aortic walls (mg/mm2 ) 0.22 0.06 0.25 0.03 0.22 0.02 0.21 0.03* <.05 Kidney (g) 1.80 0.09* 2.68 0.41 2.56 0.20 2.54 0.22 <.001

This study was approved by the Institutional Review Committee of the University of Tokyo for animal studies. The experiment was conducted in accordance with the National Institutes of Health guidelines. RESULTS
Body Weights and Organ Weights

Dahl S rats fed a low-salt diet (DS-low) showed an age-dependent increase in body weight throughout the study (Figure 2). In untreated Dahl S rats fed a high-salt diet (DS-high), body weight was signicantly decreased compared with DS-low rats throughout the study. In high-dose alginate oligosaccharides treatment, the body weight was lowered compared with the untreated DS-high; however, during the last 2 weeks the body
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Abbreviations: DS-low Dahl S rats fed a low-salt diet; DShigh Dahl S rats fed a high-salt diet; TX-low Dahl S rats fed a high-salt diet and given low-dose sodium alginate oligosaccharides; TX-high Dahl S rats fed a high-salt diet and given high-dose sodium alginate oligosaccharides. Group differences were assessed by one-way factorial ANOVA analysis of variance, (as indicated by P value in the table) followed by post hoc LSD test. *P < .05 versus DS-high.

102 S. Terakado et al.


260 Systolic blood pressure (mm Hg) 240 220 DS-high 200 180 160 140 120 100 Start TX-low

* * * *

* *
TX-high

level of DS-low rats, suggesting that sodium was likely reabsorbed with the sodium alginate oligosaccharide treatment (3.21 1.16 for TX-low, P < .005 vs. DS-high and 2.40 1.26 for TX-high, P < .001 vs. DS-high).
Kidney Damage

* * * *
1 2 3 4

*
DS-low

Experimental period (wk)

The inuence of alginate oligosaccharide treatments on kidney damage was examined in Dahl S rats. As shown in Figure 4A, urinary protein excretion increased with high-salt loading, and this increase was signicantly attenuated by the alginate oligosaccharide treatments. Similarly, the creatinine clearance rate signicantly decreased in DS-high rats, and this

Urinary excretions of protein (mg/day)

Figure 3. Alterations of systolic blood pressure. Abbreviations: DS-low Dahl S rats fed a low-salt diet (open square); DShigh Dahl S rats fed a high-salt diet (open circle); TX-low Dahl S rats fed a high-salt diet and given low-dose sodium alginate oligosaccharides (closed diamond); TX-high Dahl S rats fed a high-salt diet and given high-dose sodium alginate oligosaccharides (closed circle). Group differences were assessed by one-way factorial ANOVA analysis of variance, followed by post hoc LSD test. *P < .05 versus the respective values of DS-high.

(A) 1000 800 600 400 200 0

* *

high-salt challenge, and SBP rose to 234 6 mm Hg 7 weeks after the challenge. Sodium alginate oligosaccharide treatments signicantly attenuated the rise in blood pressure in a dose-dependent manner.
Alterations in Urinary Sodium Excretions

Start

Creatinine clearance rate (mL/day)

Urinary sodium excretion was signicantly greater in DS-high compared with DS-low rats. Moreover, the sodium excretion tended to decrease with alginate oligosaccharide treatment (Table 2). This decrease was also seen in the estimated fractional excretion of sodium (FENa). Fractional excretion of sodium was less than 0.1% in DS-low rats, and signicantly increased with a high-salt challenge (0.06 0.03 vs. 5.05 1.51, P < .0001). The increased FENa was attenuated with sodium alginate oligosaccharide treatments toward the
Table 2. Urinary sodium excretions Urinary sodium excretions (mg/day) Experimental groups DS-low DS-high TX-low TX-high P value Start 1.9 0.4 1.9 0.3 2.3 0.6 2.6 0.7* <.05 4 wk 8.0 2.5* 284.2 62.4 267.6 55.8 290.2 48.2 <.001 7 wk 10.6 4.4* 541.7 112.6 393.8 91.0* 380.0 100.9* <.001

4 wk Experiment period

7 wk

(B) 1800 1600 1400 1200 1000 800 600 400 200 0 DS-low DS-high TX-low Experimental groups TX-high

* *

Abbreviations: DS-low Dahl S rats fed a low-salt diet; DS-high Dahl S rats fed a high-salt diet; TX-low Dahl S rats fed a highsalt diet and given low-dose sodium alginate oligosaccharides; TX-high Dahl S rats fed a high-salt diet and given highdose sodium alginate oligosaccharides. Group differences were assessed by one-way factorial ANOVA analysis of variance, (as indicated by P value in the table) followed by post hoc LSD test. *P < .05 versus DS-high.

Figure 4. (A) Biomarker of kidney injury urinary excretions of protein and (B) creatinine clearance rate (Ccr). In (A), urinary protein excretions in DS-low were far below the detection limit represented by open column (the left), and those in DS-high are shown in the solid bar. The excretions in TX-low are represented by the left slashed bar, and those in TX-high by the right slashed bar. Abbreviations: DS-low Dahl S rats fed a lowsalt diet; DS-high Dahl S rats fed a high-salt diet; TX-low Dahl S rats fed a high-salt diet and given low-dose sodium alginate oligosaccharides; TX-high Dahl S rats fed a high-salt diet and given high-dose sodium alginate oligosaccharides. Group differences were assessed by one-way factorial ANOVA analysis of variance, followed by post hoc LSD test. *P < .05 versus DS-high.
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Alginate and Antihypertension 103

decrease was attenuated to the normal level of DS-low rats (Figure 4B). Morphological changes of glomeruli were seen in the kidneys of Dahl S rats (Figure 5). High-salt loading shifted the glomerular sclerosis pattern toward grade III or grade IV, as shown in Figure 6A(i) and (ii). The alginate oligosaccharide treatments signicantly attenuated the severity of glomerular sclerosis (Figure 6A(iii) and (iv)). Such trends were more marked when glomerular sclerosis score was calculated according to the formula described in the text (Figure 6B). The high-salt challenge increased the score more than twofold compared with DS-low rats. This increase signicantly decreased with the alginate oligosaccharide treatment. Similarly, the effects of alginate oligosaccharide treatment on the arterial injury in the kidney were assessed. In normotensive Dahl S-low rats the arteries appeared almost normal, and the high-salt challenge increased the injury up to 146 (Figure 7). The alginate oligosaccharide treatments signicantly attenuated the arterial injury in the kidney. The renal tubular damage was seemingly attenuated (9,10).

DISCUSSION In this study, the authors attempted to postulate that the sodium alginate oligosaccharide indeed attenuates

blood pressure elevation in salt-induced hypertension because this oligosaccharide was originally produced enzymatically by the coinvestigators of this study, and the pharmacological effects are not clear (6). The oligosaccharide is produced from natural alginate, and the oligosaccharide tested in this study does not contain the natural or low molecular alginate at all. The highand low molecular alginates that have been investigated are characterized of water insoluble, highly viciousness, and stickiness. This makes it hard to take them orally. The authors rstly succeeded in cleaving alginate enzymatically to very small oligosaccharide that is very water soluble (more than 0.5 g oligosaccharide/mL). In fact, in this study, it was demonstrated that sodium alginate oligosaccharide treatments attenuated salt-induced hypertension in Dahl S rats in a dosedependent manner. The blood pressure signicantly declined 3 weeks after the treatment began, and the reduction was maintained throughout the experiment. The blood pressure reduction at the end of the experiment with the high-dose sodium alginate treatment was almost similar to the levels of blood pressure reduction achieved by the antihypertensive drugs, diuretic indapamide, or calcium channel blocker benidipine (11,12). Indeed, the reduction in blood pressure was associated with decreases in the weights of the heart and aortic walls. These results suggest that the decrease in blood pressure in sodium alginate oligosaccharide-treated rats

Figure 5. Micrographs of representative glomerular injury in Dahl S rats fed a low-salt diet and a high-salt diet. In Dahl S rats fed a low-salt diet, a signicant number of glomeruli appeared almost normal as shown in (A), and in untreated Dahl S rats fed a high-salt diet, a signicant number of glomeruli were injured severely as shown in (B) (75%100% sclerosis). Glomerular lesions of the kidney from sodium alginate oligosaccharide treatments were shown in (C) (0%25% sclerosis, a high-dose sodium alginate oligosaccharide) and (D) (25%50% sclerosis, a high-dose sodium alginate oligosaccharide). The slices were stained with Periodic acid Shiff (PAS). Magnication 10 40. Solid bars represent 50 M.
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(A) i Percentage of glomeruli injured 70 55 40 25 10 5 (A) ii Percentage of glomeruli injured GS0% GS25% GS50% GS75% Severity of glomeruli injured GS100% 70 55 40 25 10 5

GS0%

GS50% GS75% GS25% Severity of glomeruli injured

GS100%

(A) iii 70 55 40 25 10 5

(A) iv 70 Percentage of glomeruli injured GS0% GS25% GS50% GS75% Severity of glomeruli injured (B) 350 300 GS score (0400) 250 200 150 100 50 0 DS-low DS-high TX-low Experimental groups TX-high GS100%

Percentage of glomeruli Injured

55

40

25

10

GS0%

GS25%

GS50%

GS75%

GS100%

* * *

Figure 6. (A) Protection of glomerular injury with oligo-alginate treatments. This gure showed the distribution pattern of the injured glomeruli in each experimental group. Groups 0, I, II, III, and IV represent intact, 0%25%, 25%50%, 50%75%, and 75%100% sclerotic glomeruli, respectively. The ordinate axis represents percent number of glomeruli assigned to each degree of injury ((i) DS-low; (ii) DS-high; (iii) TX-low; (iv) TX-high). Differences were assessed by non-parametric sign test and Wilcoxons matched pairs test. The group differences were less than 0.001 for each categorized damage. (B) Glomerular sclerosis (GS) score was estimated according to the equation described in the text. The ordinate axis represents the score ranging from 0 (all intact glomeruli) to 400 (all obsolescence glomeruli). Differences were assessed by non-parametric KruskalWallis test followed by MannWhitney U test with Bonferroni correction. Abbreviations: DS-low Dahl S rats fed a low-salt diet; DS-high Dahl S rats fed a high-salt diet; TX-low Dahl S rats fed a high-salt diet and given low-dose sodium alginate oligosaccharides; TX-high Dahl S rats fed a high-salt diet and given high-dose sodium alginate oligosaccharides. *P < .05 versus DS-high.

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Alginate and Antihypertension 105


300 250 AI score (0300) 200 150

*
100 50 0

* *
DS-low DS-high TX-low TX-high Experimental groups

Figure 7. The effects of alginate oligosaccharide treatments on arterial injury in the kidney This gure showed the effects of alginate oligosaccharide treatment on arterial injury in the kidney. The arterial injury score (AI score) was calculated according to the equation described in the text. The ordinate axis represents the score ranging from 0 to 300. Abbreviations: DS-low Dahl S rats fed a low-salt diet; DS-high Dahl S rats fed a highsalt diet; TX-low Dahl S rats fed a high-salt diet and given low-dose sodium alginate oligosaccharides; TX-high Dahl S rats fed a high-salt diet and given high-dose sodium alginate oligosaccharides. Differences were assessed by non-parametric KruskalWallis test followed by MannWhitney U test with Bonferroni correction. *P < .001 versus DS-high.

resulted in a decrease in cardiovascular stress induced by a high-salt challenge. Moreover, this is the rst report to demonstrate that sodium alginate oligosaccharide treatment attenuated kidney damage in salt-induced hypertension. The treatment was associated with a decrease in urinary protein excretion and an increase in the creatinine clearance rate, strongly suggesting attenuation of glomerular injury in Dahl S rats. Morphological investigation revealed a decrease in the number of glomeruli with severe damage and decreases in the glomerular sclerosis score and arterial injury score in hypertensive Dahl S rats with sodium oligosaccharide treatment. These data suggest that sodium alginate oligosaccharide treatment attenuated salt-induced hypertension in association with a decrease in cardiovascular hypertrophy and hypertensive kidney injury. In this context, it has been reported that treatment with natural alginate with a high molecular weight of 500 000 daltons decreased blood pressure in spontaneously hypertensive rats or rats with salt-induced hypertension (5,13). Since Na+ may replace either K+ or Ca2+ in natural alginate, the alginate somehow has the capacity to bond to sodium molecules in the intestine. This possibility seems to be of interest; however, it has not been proven thus far yet. In fact, Tsuji et al. (5) reported that blood pressure similarly declined with alginate treatment when the carboxylic acids were completely blocked with Na+ , K+ , or Ca2+ . Chen et al. (7) very recently published an
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article reporting that low molecular weight potassium alginate attenuates blood pressure elevation with an increase in urinary sodium excretion in deoxycorticosterone acetate (DOCA)-salt hypertensive model. Moreover, in this study, sodium alginate oligosaccharides composed of only 23 molecules of -L-guluronic acids and -D-mannuronate were utilized and the carboxylic acids were completely neutralized with Na+ ions during the enzymatic process. Such properties seemingly contradict the classical explanation of the antihypertensive effects of high molecular weight alginate. In this study, evidence against the high molecular weight alginate was provided, and the data strongly suggested that the oligosaccharides -L-guluronic acids and -D-mannuronate with their reduced form of uronic acid participated in the antihypertensive action. Most importantly, the antihypertensive effects were different from the mechanism addressed thus far. It was not certain, then, how the oligosaccharides contributed to the decrease in blood pressure with attenuation of kidney injury in Dahl S rats. In this context, there were no differences in body weight among the three high-salt Dahl S groups, thereby suggesting that salt intake might be the same. However, urinary excretions of sodium were lower in sodium alginate oligosaccharide-treated Dahl S rats. More markedly, FENa was increased in Dahl S rats with the high-salt challenge, and the increase was attenuated with the oligosaccharide treatment. Accurately speaking, the food intake was not determined, and so, the Na metabolism in the alginate treatment was better assessed more carefully. However, the experimental conditions were the same except for the contents of salt in the diet and whether sodium alginate oligosaccharide was given. Considering these, it was conceivable that the net sodium loading was lower in the treated rats. If this is true, the changes might be due to retardation or inhibition of sodium absorption in the intestine. These changes would be attainable with direct action of the oligosaccharides on sodium absorption in the intestine (14). In this context, preliminary data suggest that about 40% of the oligosaccharides given orally are absorbed in the intestine (unpublished data). This may indicate the route via circulating blood as well as intestinal inhibition. Sodium alginate oligosaccharides included several sugar molecules. At this time, the oligosaccharides responsible for the antihypertensive action could not be addressed. However, since this story is very promising, further studies to disclose the mechanisms are required. In conclusion, this study demonstrated that treatment with very low molecular weight sodium alginate oligosaccharides attenuated salt-induced hypertension in Dahl S rats, and this was associated with decreases in cardiovascular hypertrophy and kidney damage. The underlying mechanisms may be speculative at this time. In this study, the antihypertensive action of sodium alginate oligosaccharide was postulated, and now, the effects of the oligosaccharide on Na absorption in

106 S. Terakado et al.

intestine or the possibility of direct vasorelaxation of the oligosaccharide are being investigated. Additional studies are needed to elucidate the mechanism of the effects of sodium alginate oligosaccharides for antihypertensive action in salt-induced hypertension. ACKNOWLEDGMENT The authors acknowledge Ms. Naoko Suzuki for morphological investigation. Declaration of interest: The authors report no conicts of interest. The authors alone are responsible for the content and writing of the paper. REFERENCES

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[11] [1] Gacesa P. Alginates. Carbohydr Polym 1988; 8:161182. [2] Suzuki I, ed. D. Facts about Food Additives, 6th ed. Tokyo: Hirokawa Book Store, 1992, 7685. [3] Hiura N, Chaki T, Ogawa H. Antihypertensive effects of sodium alginate oligosaccharides. Nippon Nogeikagaku Kaishi 2001; 75:783785. (abstract in English). [4] Asaoka T. Benets and effects of low-molecular weight alginate sodium. New Food Ind 2001; 43:1319. (available in Japanese). [5] Tsuji K, Tsuji E, Nakagawa Y, Suzuki S. Effects of Na-binding capacity of dietary bers on blood pressure in spontaneously

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hypertensive rats. Nihon Kaseigaku Kaishi 1988; 39:187195. (abstract in English). Chaki T, Baba T, Hiura N, Kobayashi M. Purication and characterization of alginate lyase from Pseudoalteromonas sp. strain no. 1786. J Appl Glycosci 2008; 55:8188. Chen YY, Ji W, Du JR, et al. Preventive effects of low molecular mass potassium alginate extracted from brown algae on DOCA salt-induced hypertension in rats. Biomed Pharmacother 2010; 64:291295. Friedman M, Freed SC. Microphonic manometer for indirect determination of systolic blood pressure in the rat. Proc Soc Exp Biol Med 1949; 70:670672. Hirawa N, Uehara Y, Kawabata Y, et al. Mechanistic analysis of renal protection by angiotensin converting enzyme inhibitor in Dahl salt-sensitive rats. J Hypertens 1994; 12:909918. Hirawa N, Uehara Y, Kawabata Y, et al. Subpressor dose of angiotensin II increases susceptibility to the haemodynamic injury of blood pressure in Dahl salt-sensitive rats. J Hypertens 1995; 13:8190. Uehara Y, Kawabata Y, Shirahase H, et al. Radical scavenging properties of indapamide and renal protection in Dahl salt-sensitive rats. Hyperten Res 1992; 15:1726. Uehara Y, Hirawa N, Takeda T, et al. Possible linkage between renal injury and cardiac remodeling in Dahl salt-sensitive rats treated with the calcium channel antagonist benidipine. Hypertens Res 1995; 18:245253. Kimura S, Xhang G-X, Nishiyama A, et al. A-allose, an all-cis aldo-hexose, suppresses development of salt-induced hypertension in Dahl rats. J Hypertens 2005; 23:18871894. Ganong WF. Review of Medical Physiology. Los Altos, CA: LANGE Medical Publishing, 2005.

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