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CSIRO Health Sciences & Nutrition, Adelaide, South Australia 5000, Australia
2To whom correspondence should be addressed. E-mail: glen.patten{at}csiro.au.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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(P < 0.05) and PGE2 (P < 0.01) compared with WKY. Unlike (n-3) PUFA, dietary SF had little overall effect on gut contractility. However, this is the first report of a defect in PG responsiveness from gut tissue from hypertensive rats.
KEY WORDS: • hypertensive rats • saturated fat • gut contractility • prostanoid defect
Dietary saturated fat (SF)3 has long been known to influence lipoprotein metabolism and the development of atherogenesis (1,2). Recent findings indicate that dietary lipids including SF may also modulate contractility of cardiac, vascular, and bronchopulmonary smooth muscle cells and the tracheal airway (3–5). For example, compared with (n-3) and (n-6) polyunsaturated oils, dietary SF was associated with a lower ejection fraction and a reduction in myocardial energy efficiency in a nonhuman primate model (6). Similarly, dietary PUFA were reported to modulate bronchopulmonary and vascular smooth muscle (VSM) cell function (5). In addition, we showed recently that dietary (n-3) PUFA from fish oil may have beneficial effects on gut smooth muscle contractility in small animals (7,8). Fish oil feeding also reduces vascular hypercontractility in hypertension in both animal models (4,9) and humans (10,11), resulting in lower blood pressure (BP) (12). In contrast to a reduction in reactivity in hypertensive rats, fish oil feeding led to an increased contractility in normal rat gut tissue that was not affected by relatively low levels of SF or (n-6) PUFA (7). Taken together, these observations support the notion that dietary lipid effects on contractility are dependent not only on the type of smooth muscle preparation, but are also influenced by the underlying disease state. Therefore, the aim of this study was to investigate the role of dietary SF as lard on gut contractility in spontaneously hypertensive rats (SHR) in which VSM function is compromised.
Dietary SF and PUFA exert their pleiotropic physiologic actions by initially altering membrane fatty acid composition; this can modify mediator profiles such as eicosanoids and also affect physiologic responses to exogenous agonists (7). In the present investigation, Wistar-Kyoto (WKY) rats and SHR were fed a base diet of 3% sunflower oil supplemented with 0, 3, or 27% saturated animal fat as lard (up to 
53% of total energy as fat), and we examined the effects of SF on gut physiology. Lard was chosen as the source of fat because, although only 36% saturated fat, the sn-2 position of the triacylglycerol contains 71% as SFA (mainly as palmitic acid, 18:0) and may influence membrane phospholipid fatty acid profiles (13).
In particular, we investigated the role of increasing dietary SF on intestinal fatty acid composition, cecal digesta SCFA levels, and the in vitro contractile responses of isolated ileum and colon to muscarinic and eicosanoid agonists of gastrointestinal contractility that are important to bowel homeostasis and motility (14–17). We also investigated the effects of the potent gastrointestinal agonist, angiotensin II (Ang II) (18), which plays a key role in the renin-angiotensin system, especially as it relates to hypertension and the development of disease (19–21).
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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5% fat (SF03–025 Low n3 Rat and Mouse Cubes, Glen Forrest Stockfeeders) and water ad libitum. They were subjected to a 12-h light:dark cycle at 23°C. Each strain was then distributed into 3 groups of 10–12 rats and fed the following diets containing 3% sunflower oil for 12 wk: low fat with 73% carbohydrate (LF); medium fat with 7% lard and 66% carbohydrate (MF); and high fat with 27% lard and 46% carbohydrate (HF) (Table 1). The total fat levels of the diets were 3, 10, and 30%, giving energy as fat as 7, 22, and 53% respectively. The rats were housed and the experiment conducted with the approval of the CSIRO HS&N animal ethics committee. The rats were weighed weekly for the duration of the feeding trial.
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Tissue collection. At the completion of the 12-wk feeding experiment, the rats were weighed, anesthetized with Nembutal (sodium pentobarbitone, 60 mg/kg i.p.), and killed by exsanguination (7,8). Any effects of Nembutal on gut contractility were removed in the initial tissue wash-out periods (23). The small intestine and colon were removed and prepared for physiologic recordings as described (7,8). The total cecal digesta were snap-frozen in liquid nitrogen and stored at –80°C for later pH and SCFA analysis.
Total phospholipid fatty acid analysis of ileal and colonic tissue. Small frozen sections (150 mg) of ileum or colon were ground in a glass homogenizer and total lipids extracted in methanol:chloroform:water (2:4:1) and separated by TLC; the fatty acids were methylated and analyzed by GLC as described previously (7,24).
Cecal digesta pH and SCFA analysis. A standard mixture of SCFA and heptanoic acid was used to calibrate the GLC and pH and SCFA analysis of cecal digesta was undertaken as described previously (7).
Physiologic recording of ileal and colonic contractility. Sections of the ileum, proximal, or distal colon (0.03–0.04 m) were secured in an organ chamber with buffer conditions, organ chamber mechanics, and contraction properties determined as previously described (7,8,25). Ileal and colonic tissues were assayed in parallel. Results are given as volts per gram of (gut) tissue (V/g).
Contraction of quiescent ileum and colon.
The gastrointestinally active agonists were added sequentially to the bath containing ileal or colonic tissue. Dose-response curves were generated as described (7,8). The order of agonists was maintained for each tissue from each rat and the responsiveness of the tissue was tested at the end of each assay by the addition of acetylcholine (7,8). Because the colon is not affected by U-46619 and does not tolerate multiple additions as well, the order of agonists was as follows: proximal colon acetylcholine, Ang II, 8-iso-prostaglandin (PG)E2, and distal colon carbachol, PGF2 and PGE2.
Pharmacologic agents and suppliers.
The pharmacologic agents (concentration range in nmol/L used in organ bath) and the suppliers were as follows: acetylcholine (10–15000), human Ang II (0.1–1000), carbamylcholine chloride (carbachol) (10–15000), and fine chemicals were from Sigma Chemical; PGF2 (1–5000), PGE2 (1–5000), 8-iso-PGE2 (5–5000), and U-46619 (5–5000) were from Sapphire Bioscience. For the ileum, the order of agonists was acetylcholine, Ang II, 8-iso-PGE2, PGF2, PGE2, and U-46619.
Data analysis. Data are shown as means ± SEM. Statistical evaluation was performed by two-way ANOVA using GraphPad Prism 3.01 (GraphPad Software) to determine whether significant differences existed due to diet or strain. The P-values were then determined by ANOVA and Bonferroni multiple comparison post-tests performed when the F-test was significant at P < 0.05 using GraphPad Instat 3.0 (GraphPad Software). Differences between the strains at various PG doses were tested by ANOVA. The 50% effective concentrations (EC50; nmol/L) and maximal contractions (V/g of tissue) were determined using graph fits in GraphPad Prism 3.01 with R2 values > 0.99.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Fatty acid content of total phospholipids of ileum and colon. In WKY and SHR ileal tissue, there was an increase in the levels of 18:0 (P < 0.02) and 22:6(n-3) (docosahexaenoic acid; DHA) (P < 0.005) with a subsequent decrease in the (n-6)/(n-3) ratio (P < 0.003) with increasing levels of dietary SF (Table 2). In WKY, there were subtle decreases in ileal (n-6) (P < 0.03) and increases in (n-3) fatty acids (P < 0.006). For SHR, there were small increases in ileal (n-3) fatty acids (P < 0.02). In colonic tissue, the increase in the lard content of the diet decreased the 24:0 level (P < 0.03) (results not shown) and lowered the (n-6)/(n-3) ratio in both WKY and SHR (Table 2) (P < 0.05).
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and PGE2 shown, Table 4). However, in colon of WKY rats, there was a difference in sensitivity (EC50) for Ang II (LF > MF) (P < 0.05) and in colon of SHR there were differences in sensitivity for PGE2 (LF < MF and HF) (P < 0.01) and carbachol (LF < MF and HF) (P < 0.05).
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and PGE2, there were trends for lower EC50 and higher V/g in WKY compared with SHR with differences in the EC50 in rats fed MF (P < 0.004) and in V/g in rats fed LF for PGF2 (P < 0.03). The EC50 for PGE2 differed in ileum of rats fed LF and MF (P < 0.04) as did the V/g in those fed HF (P < 0.05) (Table 4). Similarly, in colon, there was a trend for higher V/g in WKY compared with SHR for PGF2. The EC50 for PGE2 was higher in colon for SHR fed LF (P < 0.02) and lower for those fed HF (P < 0.03) while V/g was lower for those fed HF diet (P < 0.01) (Table 4).
Because there were no differences in agonist-induced contractility due to diets but differences between WKY and SHR strains for the ileum, all of the data from the 3 diet groups were pooled to discern potential effects of hypertension on gut smooth muscle contractility (Table 5). For comparison, this was also done with the colon data (Table 5) where some differences in sensitivity due diet were noted. In ileum, lower PGF2 and PGE2 had lower EC50 and higher V/g values in WKY than in SHR (Fig. 1). In the colon, PGF2 and PGE2 had higher V/g in WKY than in SHR (Fig. 1).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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, PGE2, U-46619) effectors because these classes of agonist were reported to play a major role in GI homeostasis and contractility (20,28). We report here that there were no changes in maximal contraction (V/g) due to increasing levels of dietary SF supplementation in ileum or colon in response to the agonists used. Lard is particularly high in SFA in the sn-2 position of the triacylglycerol molecule, which results in membrane phospholipid fatty acid compositional changes that may be implicated in regulating cell signaling and second messengers systems (13). Although it is not possible to distinguish between the effects of total dietary fat from SFA in this study, the relative proportion of monounsaturated fats remained fairly constant (24–31%). Although monounsaturated fat has health benefits on plasma lipid and oxidation profiles (29), little has been reported for contractility. However, it is important to note that the level of polyunsaturated fat in the diet was almost halved (from 64 to 35%) with the 3% up to 30% total dietary fat.
The results of this study are in contrast to the effects of (n-3) PUFA from fish oil which led to increased ileal, but not colonic contraction (7). However, there were changes in sensitivity (EC50) in proximal colon in WKY for Ang II and in distal colon in SHR for PGE2 and carbachol. Ang II and PGE2 were recently implicated in the development of colon tumors (21), and this increased sensitivity due to dietary SF may have some relevance to the progression of the disease (30,31). Carbachol is a stable analog of acetylcholine, the major neurotransmitter in the GI tract (32). The increase in sensitivity to this muscarinic agonist mimetic is difficult to explain, but the upregulation of smooth muscle M3 receptors has been associated with diverticular disease (33). However, these observations were not seen for the natural muscarinic agonist, acetylcholine, in the proximal colon where its functionality may be different (34).
Because there were significant differences and trends for PGF2 and PGE2 when WKY was compared with SHR across diets, the results for the 3 dietary groups were combined (Table 5). This revealed a significantly lower sensitivity and lower V/g response to PGF2 and PGE2 in the ileum of the SHR compared with WKY. This trend was also observed for V/g in the colon. For the agonists used, this finding was prostanoid specific and was not evident for muscarinic, Ang II, or other eicosanoids tested. This is the first report of a specific defect in PG reactivity in the gut of hypertensive rats.
Increasing the amount of dietary SF significantly lowered the major SCFA (acetate, propionate and butyrate) and total SCFA in cecal digesta from WKY rats with a subsequent increase in pH, a trend we observed previously for Sprague-Dawley rats (7). These changes were significant only for butyrate and pH in the SHR with a trend for lower acetate and propionate. This may be explained by the concomitant decrease in dietary cornstarch with increasing fat, which could contribute to less resistant starch reaching the cecum and less fermentation to SCFA (35). Depending on the animal model or dietary supplement employed, decreased cecal pH was associated with increased GI transit time, whereas a lowered colonic pH was implicated in reduced large bowel transit and disease (36,37). SCFA were implicated in the control of contractility in many sections of the gut (38) but the role of saturated dietary fat on GI transit was not examined in this study. With the discovery of specific SCFA receptors (39), the role of intestinal SCFA in GI contractility and motility may be better understood (40).
Feeding animals cholesterol or high levels of SF has varying effects on GI motility (41). The diets used in this study had SF levels of 0.4 to 27.4%. However, ileal and colonic phospholipid fatty acid levels were resistant to change, and tissue levels of monounsaturated, PUFA or SFA were not affected in WKY or SHR. Also, there were no major fatty acid compositional differences due to diets for ileum or colon of WKY compared with SHR. Subtle changes that did occur in fatty acid composition due to diet were increased stearic acid (18:0) and DHA [22:6(n-3)] in the ileum with total (n-3) levels increasing. This resulted in a decrease in the (n-6)/(n-3) ratio. Similar trends were found for the colon. In agreement with other workers, we found previously that dietary supplementation of a small amount of (n-3) PUFA from fish oil fed to animals resulted in significant increases in gut tissue phospholipid (n-3) PUFA incorporation and dramatically lowered the (n-6)/(n-3) ratio at the expense of (n-6) PUFA (7,8,25,42). The small changes in tissue fatty acid composition described in this study cannot explain the changes in sensitivity of the WKY colon to Ang II and the SHR colon to PGE2 and carbachol that were not evident in the ileum. The increase in sensitivity in the SHR colon could be associated with the relatively small decrease in the (n-6)/(n-3) phospholipid fatty acid ratio. However, it was observed that the dietary response in SHR colon to carbachol was not paralleled by the natural muscarinic agonist, acetylcholine.
PGs may act via the G protein–coupled receptor systems on the cell membranes that regulate cellular function (43). PG receptor binding studies of gut tissue from WKY and SHR may explain this defect. However, the abnormality may be a postreceptor event that may involve, for example, smooth muscle calcium handling (44).
Because PGs are important for GI tract homoeostasis (13–16), SHR may be a useful model for the study of impaired intestinal function as it relates to health and disease. Chronic inflammatory bowel diseases, e.g., Crohn’s disease and ulcerative colitis, were reported to involve the overproduction of specific PGs (45). Recently, it was concluded that PGE2 works to prevent inflammatory bowel disease (IBD) initiation and progression and that in knockout mice, only EP4-deficient mice developed severe colitis with dextran sodium sulfate treatment (46). Although patients with IBD rarely have hypertension (47), this prostanoid defect in the SHR gut may be a useful model for investigating bowel inflammation. We are now investigating whether dietary long-chain (n-3) PUFA from fish oil (7,8) can reverse this depressed gut prostanoid response in the SHR strain. It is also likely that dietary (n-3) PUFA can improve gut contractility in genetic (48) and chemically induced models of IBD (49) without pharmacologic intervention (50).
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FOOTNOTES |
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3 Abbreviations used: Ang II, Angiotension II; BP, blood pressure; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; EC50, 50% effective concentration; GI, gastrointestinal; HF, high fat; IBD, inflammatory bowel disease; LC, long chain; LF, low fat; MF, medium fat; PG, prostaglandin; SF, saturated fat; SHR, spontaneously hypertensive rats; VSM, vascular smooth muscle; WKY, Wistar-Kyoto.
Manuscript received 7 June 2004. Initial review completed 28 June 2004. Revision accepted 13 August 2004.
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). Results are combined data from rats fed LF, MF, and SF diets. Values are means ± SEM, n = 33–35 rats. Asterisks indicate a difference from SHR: *P < 0.05, **P < 0.01, ***P < 0.001.