Pharmacology

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Age- and hypertension-induced changes in abnormal contractions in rat aorta
(Lippincott Williams & Wilkins, 2002) Abeywardena, M.; Jablonskis, L.; Head, R.
The current investigation explored the potential age-dependant modulation of abnormal spontaneous constrictions (thromboxane-like) in the spontaneously hypertensive rat (SHR) aorta, observed only after the inhibition of endogenous production of nitric oxide (NO). Aortic rings from SHR and Wistar-Kyoto (WKY) control rats of varying ages (4, 8, 12, and 18 months) were mounted in organ baths, and changes in tension were monitored. Inhibition of NO with Nω-nitro-L-arginine (NOLA) unmasked a slow contraction, which appeared to be age dependent (p < 0.05). This contraction was found in SHRs of all age groups and in older WKY rats. Denuding the endothelium in young SHRs did not influence the constriction, confirming a nonendothelial cell origin, while in the older groups this led to a 30–40% reduction in contraction. Comparable attenuation of the constrictor response was observed after incubation of endothelium intact rings with superoxide dismutase (100 U/ml) or 3-amino-1,2,4-triazole. Of the residual activity that was unaffected by free radical scavengers or de-endothelialization, 60–70% was sensitive to cyclooxygenase inhibition by indomethacin and/or ibuprofen. The thromboxane (TxA2) receptor antagonist SQ29548 induced a complete reversal of the abnormal constriction. In contrast, thromboxane synthetase inhibition had no effect, ruling out any involvement of TxA2 in mediating this abnormality. Collectively, these observations support the view that as compared with the normotensive setting, contraction induced by NO inhibition in the SHR develops prematurely and deteriorates more rapidly during the aging process. In aged rats, prostaglandin endoperoxide intermediates PGG2/H2 and endothelium-derived free radicals rather than TxA2 per se appear to contribute to the NOLA-dependent TxA2-like vasoconstriction.
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An apparatus to assay opioid activity in the infused lumen of the intact isolated guinea pig ileum
(Elsevier Science Inc, 2001) Patten, G.; Head, R.; Abeywardena, M.; McMurchie, E.
A modified apparatus is described that provides for the simultaneous bathing of the serosa of an intact piece of isolated guinea pig ileum while allowing infusion of the isolated lumen. The comparative compartmental potency of the opioid agonists morphine, casomorphins, and enkephalins to inhibit electrically driven contractions are described in this system. The rank-order potency for serosally applied opioid agonists was (IC50 values, nM): [d-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin (DAMGO) (15)>[d-Ala2,d-Leu5]-enkephalin (DADLE) (35)≥morphine (46)≥[d-Ala2]-met-enkephalinamide (55)>[d-Ala2]-β-casomorphin[1–4] amide (122)>β-casomorphin[1–4] amide (940)>met- and leu-enkephalin (>6000). This contrasted to the rank-order potency for the luminally applied opioid agonists: DADLE (63)>DAMGO (135)>[d-Ala2]-met-enkephalinamide=morphine (4700)>[d-Ala2]-β-casomorphin[1–4] amide (29000). β-Casomorphin[1–4] amide, leu-enkephalin and met-enkephalin are mostly inactive when applied luminally. Furthermore, the opioid antagonists, casoxin 4 and [d-Ala2]-casoxin 4, when infused into the lumen, significantly overcame the inhibitory effect of morphine added to the serosal side. This model provides an assay and screening system to differentiate between the effects of chemical agents applied via the blood stream (serosa) or food side (lumen) on quiescent or electrically driven gut activity of the nervous plexi or receptor systems of the ileum.
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Dietary fish oil alters the sensitivity of guinea pig ileum to electrically driven contractions and 8-iso-PGE2
(Pergamon-Elsevier Science Ltd, 2002) Patten, G.; Bird, A.; Topping, D.; Abeywardena, M.
Dietary fish oil rich in n-3 polyunsaturated fatty acids (PUFA) have been positively implicated in bowel health. This was investigated in relation to newborn guinea pig growth, caecal digesta pH and SCFA profile, ileal total phospholipid fatty acid content and particularly for in vitro ileal contractility. A newly formulated commercial rice porridge (congee) preparation supplemented with essential nutrients, standard chow for palatability and 3% fat as safflower oil or tuna fish oil was fed to new born guinea pigs and their mothers. After two months of feeding, while the mean body weight and weight and length of small intestine of the fish oil supplemented group were significantly lower (P < 0.05) compared to the safflower supplemented group there was no difference in final small intestine density. Substitution of safflower oil with tuna fish oil led to significantly lower oleic acid content of ileum total phospholipid with a concomitant increase in the n-3 PUFA ALA, EPA and DHA (P < 0.05). The fish oil supplemented group had a significantly higher caecal digesta pH (P < 0.03) with a significantly lower propionate concentration (P < 0.04). Significantly less voltage was required to initiate contraction of the ileum of the fish oil supplemented group (P < 0.03). There was no significant difference in the sensitivity (EC50) and maximal contraction induced by acetylcholine, histamine, serotonin, and prostaglandins PGE2 or PGF2α. However, the sensitivity to the isoprostane, 8-iso-PGE2 of the fish oil supplemented group was significantly reduced (P < 0.04). These results warrant further investigation into the physiological role that dietary n-3 PUFA may play in bowel contractility and health. © 2002 Elsevier Science Inc. All rights reserved.
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Dietary n-3 and n-6 polyunsaturated oils and airway contractility
(Churchill Livingstone, 2001) Abeywardena, M.; Jablonskis, L.; Head, R.
Recent reports suggest modulation of chronic obstructive pulmonary disease by dietary polyunsaturated fatty acids. In the present study, we re-examined this possibility by using an established animal model of pulmonary sensitisation. Adult guinea pigs were fed diets supplemented (10% w/w) with either olive, canola or safflower oil for 4 weeks before sensitising with ovalbumin and continuing on various diets for a further 6 week period. Neither the contraction following ovalbumin challenge, nor the responses to histamine, carbachol and various eicosanoid mediators – prostaglandin F2α, leukotriene C4, thromboxane mimetic U44619 – of isolated segments of airway tissue were altered (P>0.05, ANOVA) by the dietary lipid treatment. Lipid analysis showed changes in membrane linoleic acid (18:2n-6) and α -linolenic acids (α 18:3n-3) in lung phospholipids consistent with dietary intakes. However, no significant further desaturation/elongation of these dietary precursors was evident. Ovalbumin induced contraction was fully reversed by the lipoxygenase inhibitor esculetin whilst indomethacin resulted in a slight increase possibly due to the inhibition of bronchodilator prostanoids. Results confirm that under the conditions employed airway function was not influenced by the variable dietary intakes of n-3 and n-6 PUFA.
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Dietary polyunsaturated fatty acid and antioxidant modulation of vascular dysfunction in the spontaneously hypertensive rat
(Churchill Livingstone, 2001) Abeywardena, M.; Head, R.
Two currently available edible oils–olive and canola–and two oil blends of plant origin having different n-3/n-6 polyunsaturated fatty acid (PUFA) ratios were evaluated for their ability to modify vascular dysfunction in the spontaneously hypertensive rat (SHR). Synthetic diets supplemented with test oils (5% w/w) were fed for 12 weeks, and segments of thoracic aorta used to assess vascular function. Vessels from the SHR displayed a spontaneous constrictor response after the inhibition of endothelial cell nitric oxide (NO) with Nω-nitro-L-arginine (NOLA). Dietary α -linoleate enrichment led to a reduction (P<0.05) in this abnormality with a dietary n-3/n-6 PUFA ratio of 1.0 (blend-1) yielding the best outcome. Relaxation to acetylcholine (ACh) was unaffected by dietary lipid supplementation. NOLA treated rings also displayed contractions to ACh that were abolished by indomethacin, thromboxane antagonists SQ29548, picotamide and flavonoids kaempferol and quercetin. In contrast, α -tocopherol, rutin and the lipoxygenase inhibitor esculetin resulted in only partial (30–55%) inhibition, and were ineffective against the NOLA-induced contraction suggesting the operation of different biochemical mechanisms in mediating the spontaneous and Ach-induced contractions. Results implicate plant-based oils and antioxidants as potential modulators of vascular function.
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Effects of convenience rice congee supplemented diets on guinea pig whole animal and gut growth, caecal digesta SCFA and in vitro ileal contractility
(H E C Press, 2004) Patten, G.; Bird, A.; Topping, D.; Abeywardena, M.
The aim of the study was to feed convenience baby food brown rice (BC) and white rice (WC) congee diets compared to egg custard (EC) and baked bean (BB) diets to newborn guinea pig pups. Diets were isocaloric and formulated to contain equal macronutrient content of carbohydrate, protein, fat and fibre. Diets were supplemented with essential nutrients, fruit and vegetables and decrementally with standard chow for palatability. We investigated the acceptability of the diets and specifically whether the different natural fibre content of these diets could influence whole animal and small intestinal growth, caecal digesta properties and specifically in vitro ileal contractility. After 8 weeks of feeding, the mean body weight of WC group was significantly lower than the BB group. WC group had lower small intestine weight than both BC group and BB group resulting in lower small intestine density compared to BB group. Caecal digesta pH and total short chain fatty acid (SCFA) concentration were similar. However, butyrate was higher in the BB group compared to the other diets. Contractility studies revealed a small but significantly higher voltage was required to initiate ileal contraction of BC group compared to both the EC and BB groups. All dietary groups responded similarly to acetylcholine, histamine, serotonin, PGE(2), PGF(2alpha), and 8-iso-PGE(2). There were no differences on inhibition of electrically-driven contraction by morphine or epinephrine. The newborn guinea pig model was an effective system for testing, with limitations, supplemented convenience baby foods with variable natural fibre content that demonstrated significant effects on animal growth, caecal digesta SCFA and intestinal contractility.
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Effects of edible tropical plant extracts on inhibiting copper-mediated low-density lipoprotein oxidation and upregulating low-density lipoprotein receptor in HepG2 cells
(Harwood Acad Publ GMBH, 2003) Salleh, M.; Runnie, I.; Roach, P.; Mohamed, S.; Head, R.; Abeywardena, M.
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Longchain n-3 polyunsaturated fatty acids and blood vessel function
(Elsevier Science BV, 2001) Abeywardena, M.; Head, R.
The cardiovascular health benefits of longchain n−3 polyunsaturated fatty acids (PUFAs) have been reported to exert at several different cellular control mechanisms. These include, effects on lipoprotein metabolism, haemostatic function, platelet/vessel wall interactions, anti-arrhythmic actions and also inhibition of proliferation of smooth muscle cells and therefore growth of the atherosclerotic plaque. Fish oil feeding has also been found to result in moderate reductions in blood pressure and to modify vascular neuroeffector mechanisms. The majority of such cardiovascular benefits of n−3 PUFAs are likely to be mediated in the vascular wall and at the vascular endothelium level, since this monolayer of cells plays a central role in the regulation and maintenance of cardiovascular homeostasis and function. While these processes include endothelium-derived vasorelaxant and vasoconstrictor compounds, the vascular endothelium also plays host to many receptors, binding proteins, transporters and signalling mechanisms. Accordingly, endothelial dysfunction, which underlies many cardiovascular disease conditions, can trigger acute vascular events including vasospasm, thrombosis or restenosis leading to ischaemia. The longchain n−3 PUFAs have been reported to possess several properties that may positively influence vascular function. These include favourable mediator profiles (nitric oxide, eicosanoids) that influence vascular reactivity, change in vascular tone via actions on selective ion channels, and maintenance of vascular integrity. In addition to direct effects on contractility, n−3 PUFAs may affect vascular function, and the process of atherogenesis, via inhibition of vascular smooth muscle cell proliferation at the gene expression level, and by modifying expression of inflammatory cytokinesis and adhesion molecules. Collectively, these properties are consistent with pleiotropic actions of longchain n−3 PUFAs, and may explain the beneficial cardiovascular protection of this family of fatty acids that have been clearly evident through epidemiological data as well from more recent large-scale clinical trials.
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Polyphenol-enriched extract of oil palm fronds (Elaeis guineensis) promotes vascular relaxation via endothelium-dependent mechanisms
(Blackwell Science Asia, 2002) Abeywardena, M.; Runnie, I.; Nizar, M.; Momamed, S.; Head, R.
Plant-based polyphenolic compounds have been reported to possess cardiovascular health benefits. Several dietary sources, including herbs and spices, fruits and vegetables, and tea and wine, contain an array of biologically active compounds that have been shown to be effective in retarding oxidation of low-density lipoproteins (LDL) and promoting vascular relaxation. In the present study four different plant sources, both edible and non-edible, were evaluated for potential activity. Organic extracts enriched in polyphenols were prepared from palm fronds (Elaesis guineensis); lemongrass (Cymbopogon citrates); papaya shoots (Carica papaya) and green chilli (Capsicum frutescenes) and tested for their ability to prevent in vitro oxidation of LDL, and for potential vascular relaxation actions. Rings of rat thoracic aorta and isolated perfused mesenteric vascular beds were mounted in organ baths, contracted using a half-maximal dose of noradrenaline and exposed to cumulative additions of test extracts. Palm frond extract resulted in considerable relaxation (>75%) in both preparations and was found to be endothelium-dependent as removal of endothelium or inhibition of endogenous nitric oxide (NO) led to a total loss in relaxant activity. Lemongrass extract caused a greater relaxation action in the mesenteric preparation compared to aortic rings, and appears to be mediated via NO-independent and non-prostanoid mechanisms. Of the extracts tested, palm fronds also demonstrated the highest antioxidant capacity, as determined by the ferric reducing activity/potential assay, and resulted in a significant delay (P < 0.05) in the oxidation of LDL. Collectively, these preliminary findings lend further support to the potential cardiovascular actions of plant polyphenols and also identify oil palm fronds as containing constituents that promote vascular relaxation via endothelium-dependent mechanisms
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Restoration of depressed prostanoid-induced ileal contraction in spontaneously hypertensive rats by dietary fish oil
(Amer Oil Chemists Soc A O C S Press, 2005) Patten, G.; Adams, M.; Dallimore, J.; Rogers, P.; Topping, D.; Abeywardena, M.
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 α-linolenic acid (18∶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 PGF2α 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 PGF2α 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.
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The cardiovascular protective role of docosahexaenoic acid.
(ELSEVIER, 1996) McLennan, P.; Howe, P.; Abeywardena, M.; Muggli, R.; Raederstorff, D.; Mano, M.; Rayner, T.; Head, R.
Dietary fish oils rich in n-3 polyunsaturated fatty acids can modulate a diverse range of factors contributing to cardiovascular disease. This study examined the relative roles of eicosapentaenoic acid (20:5 n-3; EPA) and docosahexaenoic acid (22:6 n-3; DHA) which are the principal n-3 polyunsaturated fatty acids regarded as candidates for cardioprotective actions. At low dietary intakes (0.4–1.1% of energy (%en)), docosahexaenoic acid but not eicosapentaenoic acid inhibited ischaemia-induced cardiac arrhythmias. At intakes of 3.9–10.0%en, docosahexaenoic acid was more effective than eicosapentaenoic acid at retarding hypertension development in spontaneously hypertensive rats (SHR) and inhibiting thromboxane-like vasoconstrictor responses in aortas from SHR. In stroke-prone SHR with established hypertension, docosahexaenoic acid (3.9–10.0%en) retarded the development of salt-loading induced proteinuria but eicosapentaenoic acid alone was ineffective. The results demonstrate that purified n-3 polyunsaturated fatty acids mimic the cardiovascular actions of fish oils and imply that docosahexaenoic acid may be the principal active component conferring cardiovascular protection.
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Vasorelaxation induced by common edible tropical plant extracts in isolated rat aorta and mesenteric vascular bed
(Elsevier Sci Ltd, 2004) Runnie, I.; Salleh, M.; Mohamed, S.; Head, R.; Abeywardena, M.
In this study, the vasodilatory actions of nine edible tropical plant extracts were investigated. Ipomoea batatas (sweet potato leaf), Piper betle (betel leaf), Anacardium occidentale (cashew leaf), Gynandropsis gynandra (maman leaf), Carica papaya (papaya leaf), and Mentha arvensis (mint leaf) extracts exhibited more than 50% relaxing effect on aortic ring preparations, while Piper betle and Cymbopogon citratus (lemongrass stalk) showed comparable vasorelaxation on isolated perfused mesenteric artery preparation. The vascular effect on the aortic ring preparations were mainly endothelium-dependent, and mediated by nitric oxide (NO) as supported by the inhibition of action in the presence of Nω-nitro-l-arginine (NOLA), an nitric oxide synthase (NOS) inhibitor, or by the removal of endothelium. In contrast, vasodilatory actions in resistance vessels (perfused mesenteric vascular beds) appear to involve several biochemical mediators, including NO, prostanoids, and endothelium-dependent hyperpolarizing factors (EDHFs). Total phenolic contents and antioxidant capacities varied among different extracts and found to be independent of vascular relaxation effects. This study demonstrates that many edible plants common in Asian diets to possess potential health benefits, affording protection at the vascular endothelium level.

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