Inhibition of Angiotensin Converting Enzyme, Angiotensin II Receptor Blocking, and Blood Pressure Lowering Bioactivity across Plant Families.

Hypertension is a major risk factor for coronary heart disease, kidney disease, and stroke. Interest in medicinal or nutraceutical plant bioactives to reduce hypertension has increased dramatically. The main biological regulation of mammalian blood pressure is via the renin-angiotensin-aldosterone system. The key enzyme is angiotensin converting enzyme (ACE) that converts angiotensin I into the powerful vasoconstrictor, angiotensin II. Angiotensin II binds to its receptors (AT1) on smooth muscle cells of the arteriole vasculature causing vasoconstriction and elevation of blood pressure. This review focuses on the in vitro and in vivo reports of plant-derived extracts that inhibit ACE activity, block angiotensin II receptor binding and demonstrate hypotensive activity in animal or human studies. We describe 74 families of plants that exhibited significant ACE inhibitory activity and 16 plant families with potential AT1 receptor blocking activity, according to in vitro studies. From 43 plant families including some of those with in vitro bioactivity, the extracts from 73 plant species lowered blood pressure in various normotensive or hypertensive in vivo models by the oral route. Of these, 19 species from 15 families lowered human BP when administered orally. Some of the active plant extracts, isolated bioactives and BP-lowering mechanisms are discussed.

Bioequivalence of n-3 fatty acids from microencapsulated fish oil formulations in human subjects.

Fish oil n-3 fatty acids (FA) have known health benefits. Microencapsulation stabilises and protects fish oil from oxidation, enabling its incorporation into foods. The aim of the present study was to compare the bioavailability of n-3 FA delivered as two microencapsulated fish oil-formulated powders or fish oil gel capsules (FOGC) taken with a flavoured milk in healthy participants. Formulation 1 (F1) composed of a heated mixture of milk protein-sugar as an encapsulant, and formulation 2 (F2) comprised a heated mixture of milk protein-sugar-resistant starch as an encapsulant. Participants consumed 4 g fish oil (approximately 1·0 g EPA and DHA equivalent per dose). Bioavailability was assessed acutely after ingestion of a single dose by measuring total plasma FA composition over a period of 48 h (n 14) using a randomised cross-over design, and over the short term for a period of 4 weeks using an unblinded parallel design (after daily supplementation) by measuring total plasma and erythrocyte FA composition at baseline and at 2 and 4 weeks (n 47). In the acute study, F1 greatly increased (% Δ) plasma EPA and total n-3 FA levels at 2 and 4 h and DHA levels at 4 h compared with FOGC. The time to reach maximal plasma values (T(max)) was shorter for F1 than for FOGC or F2. In the short-term study, increases in plasma and erythrocyte n-3 FA values were similar for all treatments and achieved an omega-3 index in the range of 5·8-6·3 % after 4 weeks. Overall, the results demonstrated human bioequivalence for microencapsulated fish oil powder compared with FOGC.

Role of ω3 long-chain polyunsaturated fatty acids in reducing cardio-metabolic risk factors.

Cardiovascular disease is the leading cause of mortality in many economically developed nations, and its incidence is increasing at a rapid rate in emerging economies. Diet and lifestyle issues are closely associated with a myriad of cardiovascular disease risk factors including abnormal plasma lipids, hypertension, insulin resistance, diabetes and obesity, suggesting that diet-based approaches may be of benefit. Omega-3 longchain-polyunsaturated fatty acids (ω3 LC-PUFA) are increasingly being used in the prevention and management of several cardiovascular risk factors. Both the ω3 and ω6 PUFA families are considered essential, as the human body is itself unable to synthesize them. The conversion of the two precursor fatty acids - linoleic acid (18:2ω6) and α-linoleic acid (α18:3ω3) - of these two pathways to longer (≥C(20)) PUFA is inefficient. Although there is an abundance of ω6 PUFA in the food supply; in many populations the relative intake of ω3 LC-PUFA is low with health authorities advocating increased consumption. Fish oil, rich in eicosapentaenoic (EPA, 20:5ω3) and docosahexaenoic (DHA, 22:6ω3) acids, has been found to cause a modest reduction in blood pressure at a dose level of >3g/d both in untreated and treated hypertensives. Whilst a multitude of mechanisms may contribute to the blood pressure lowering action of ω3 LC-PUFA, improved vascular endothelial cell function appears to play a central role. Recent studies which evaluated the potential benefits of fish oil in type-2 diabetes have helped to alleviate concerns raised in some previous studies which used relatively large dose (5-8 g/d) and reported a worsening of glycemic control. Several meta-analyses have confirmed that the most consistent action of ω3 LC-PUFA in insulin resistance and type-2 diabetes is the reduction in triglycerides. In some studies, fish oil has been found to cause a small rise in LDL-cholesterol, but a change in the LDL particle size, from the smaller more atherogenic form to the larger, less damaging particle size, have also been noted. ω3 LC-PUFA are effective modulators of the inflammation that accompanies several cardio-metabolic abnormalities. Taking into consideration the pleiotropic nature of their actions, it can be concluded that dietary supplementation with ω3 LC-PUFA will lead to improvements in cardio-metabolic health parameters. These fatty acids pose only minor side effects and more importantly, do not interact adversely with the common drug therapies used in the management and treatment of hypertension, dyslipidemia, type-2 diabetes, and obesity/metabolic syndrome, but in some instances work synergistically, thereby providing additional cardiovascular benefits.

Site specific delivery of microencapsulated fish oil to the gastrointestinal tract of the rat.

The aim of this study was to design food grade matrices to deliver microencapsulated fish oil to the large bowel of the rat where the potential exists to retard inflammation and cancer development. Digestion in simulated gastric fluid and intestinal fluid demonstrated that only 4-6% of oil was released from the following dried emulsion formulations: 50% fish oil encapsulated in heated casein-glucose-dried glucose syrup (1:1:1) (Cas-Glu-DGS-50); 25% fish oil in casein-modified resistant starch (Hylon VII) (1:1) (Cas-Hylon-25); or 25% fish oil in Cas-Glu-Hylon (1:1:1) (Cas-Glu-Hylon-25). A short-term gavage study (0-12 h) with fish oil and Cas-Glu-DGS-50 demonstrated the appearance of fish oil long chain (LC) n-3 polyunsaturated fatty acids (PUFA) into the plasma indicating specific small intestinal absorption with little LC n-3 PUFA reaching the large bowel. In a 2-week-long term, daily gavage study, the bioavailability of fish oil and fish oil in Cas-Glu-DGS-50 or Cas-Hylon-25 demonstrated that fish oil and Cas-Glu-DGS-50 LC n-3 PUFA were incorporated into the tissue of the small intestine and colon, whereas Cas-Hylon-25 was resistant to degradation in the small intestine. The use of modified Hylon VII for targeted colonic delivery was confirmed in the final short-term gavage study (0-14 h) using Cas-Glu-Hylon-25 with [(14)C]-trilinolenin as a marker incorporated into the microcapsules, where up to 60% of the labeled oil reached the large bowel. Depending on the microencapsulating matrix employed, fish oil can be delivered selectively to the small intestine or to a high degree to the large bowel.

Dietary fish oil dose-response effects on ileal phospholipid fatty acids and contractility.

We have reported that dietary fish oil (FO) leads to the incorporation of long-chain n-3 PUFA into the gut tissue of small animal models, affecting contractility, particularly of rat ileum. This study examined the FO dose response for the incorporation of n-3 PUFA into ileal tissue and how this correlated with in vitro contractility. Groups of ten to twelve 13-wk-old Wistar-Kyoto rats were fed 0, 1, 2.5, and 5% FO-supplemented diets balanced with sunflower seed oil for 4 wk, after which ileal total phospholipid FA were determined and in vitro contractility assessed. For the total phospholipid fraction, increasing the dietary FO levels led to a significant increase first evident at 1% FO, with a stepwise, nonsaturating six-fold increase in n-3 PUFA as EPA (20:5n-3), DPA (docosapentaenoic acid, 22:5n-3), and DHA, but mainly as DHA (22:6n-3), replacing the n-6 PUFA linoleic acid (18:2n-6) and arachidonic acid (20:4n-6) over the dosage range. There was no difference in KCl-induced depolarization-driven contractility. However, a significant increase in receptor-dependent maximal contractility occurred at 1% FO for carbachol and at 2.5% FO for prostaglandin E2, with a concomitant increase in sensitivity for prostaglandin E2 at 2.5 and 5% FO. These results demonstrate that significant increases in ileal membrane n-3 PUFA occurred at relatively low doses of dietary FO, with differential receptor-dependent increases in contractility observed for muscarinic and prostanoid agonists.

Restoration of depressed prostanoid-induced ileal contraction in spontaneously hypertensive rats by dietary fish oil.

We have reported that dietary fish oil (FO) rich in n-3 PUFA modulates gut contractility. It was further demonstrated that the gut of spontaneously hypertensive rats (SHR) has a depressed contractility response to prostaglandins (PG) compared with normotensive Wistar-Kyoto (WKY) rats. We investigated whether feeding diets supplemented with n-3 PUFA increased gut contractility and restored the depressed prostanoid response in SHR gut. Thirteen-week-old SHR were fed diets containing fat at 5 g/100 g as coconut oil (CO), lard, canola oil containing 10% (w/w) n-3 FA as alpha-linolenic acid (1 8:3n-3), or FO (as HiDHA, 22:6n-3) for 12 wk. A control WKY group was fed 5 g/100 g CO in the diet. As confirmed, the SHR CO group had a significantly lower gut response to PGE2 and PGF2alpha compared with the WKY CO group. Feeding FO increased the maximal contraction response to acetylcholine in the ileum compared with all diets and in the colon compared with lard, and restored the depressed response to PGE2 and PGF2alpha in the ileum but not the colon of SHR. FO feeding also led to a significant increase in gut total phospholipid n-3 PUFA as DHA (22:6n-3) with lower n-6 PUFA as arachidonic acid (20:4n-6). Canola feeding led to a small increase in ileal EPA (20:5n-3) and DHA and in colonic DHA without affecting contractility. However, there was no change in ileal membrane muscarinic binding properties due to FO feeding. This report confirms that dietary FO increases muscarinic- and eicosanoid receptor-induced contractility in ileum and that the depressed prostanoid response in SHR ileum, but not colon, is restored by tissue incorporation of DHA as the active nutrient.

Depressed prostanoid-induced contractility of the gut in spontaneously hypertensive rats (SHR) is not affected by the level of dietary fat.

Dietary saturated fat (SF) has adverse effects on cardiac and vascular smooth muscle (VSM) contractility. Furthermore, VSM of spontaneously hypertensive rats (SHR) is overreactive to various biological stimuli. The aim of this study was to investigate the effects of increasing dietary fat as lard on gut contractility in SHR. Control Wistar-Kyoto (WKY) rats and SHR (13 wk old) were fed for 12 wk a diet containing 3% sunflower oil [low fat (LF), 3% total fat] or diets supplemented with 7% lard [medium fat (MF), 10% total fat] or 27% lard [high fat (HF), 30% total fat]. For ileal and colonic tissues (WKY and SHR), there was a lower total phospholipid PUFA (n-6)/(n-3) ratio with increased dietary SF (P < 0.003). For WKY, increasing SF led to lower levels of the major SCFA and lower total SCFA levels in cecal digesta (P < 0.01). This trend was evident in SHR but significant only for butyrate (P < 0.01). Contractility responses were unaltered in ileum. In colon, there was a change of sensitivity (50% effective concentration) to angiotensin II in WKY (P < 0.05) due to increased SF and a change of sensitivity to prostaglandin (PG)E(2) and carbachol in SHR (P < 0.05). When the 3 dietary groups were combined, there was lower sensitivity (P < 0.01) and lower maximal contraction (P < 0.05) in ileum and lower maximal contraction in colon of SHR in response to PGF(2alpha) (P < 0.05) and PGE(2) (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.