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We hypothesize that a "Faustian bargain"-the trading of increased SARS-CoV2 viral infection with a concurrent potential for prevention of life-threatening lower lung infection explains the previous and future morbidity and mortality from COVID-19. Further, this trade-off is made feasible by fundamental principles of thermodynamics and receptor affinity., (© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

We have developed a mechanistic model of SARS-CoV-2 and SARS-CoV infection, exploring the relationship between the viral diffusion in the mucosa and viral affinity for the angiotensin converting enzyme 2 (ACE2) target. Utilising the structural similarity of SARS-CoV and SARS-CoV-2 and a shared viral target receptor (ACE2), but a dramatic difference in upper or lower respiratory tract infectivity, we were able to generate insights into the linkage of mucosal diffusion and target receptor affinity in determining the pathophysiological pathways of these two viruses. Our analysis reveals that for SARS-CoV-2 the higher affinity of ACE2 binding, the faster and more complete the mucosal diffusion in its transport from the upper airway to the region of the ACE2 target on the epithelium. This diffusional process is essential for the presentation of this virus to the furin catalysed highly efficient entry and infection process in the upper respiratory tract epithelial cells. A failure of SARS-CoV to follow this path is associated with lower respiratory tract infection and decreased infectivity. Thus, our analysis supports the view that through tropism SARS-CoV-2 has evolved a highly efficient membrane entry process that can act in concert with a high binding affinity of this virus and its variants for its ACE2 which in turn promotes enhanced movement of the virus from airway to epithelium. In this way ongoing mutations yielding higher affinities of SARS-CoV-2 for the ACE2 target becomes the basis for higher upper respiratory tract infectivity and greater viral spread. It is concluded that SARS-CoV-2 is constrained in the extent of its activities by the fundamental laws of physics and thermodynamics. Laws that describe diffusion and molecular binding. Moreover it can be speculated that the very earliest contact of this virus with the human mucosa defines the pathogenesis of this infection., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Why a systems analysis view of this pandemic? The current pandemic has inflicted almost unimaginable grief, sorrow, loss, and terror at a global scale. One of the great ironies with the COVID-19 pandemic, particularly early on, is counter intuitive. The speed at which specialized basic and clinical sciences described the details of the damage to humans in COVID-19 disease has been impressive. Equally, the development of vaccines in an amazingly short time interval has been extraordinary. However, what has been less well understood has been the fundamental elements that underpin the progression of COVID-19 in an individual and in populations. We have used systems analysis approaches with human physiology and pharmacology to explore the fundamental underpinnings of COVID-19 disease. Pharmacology powerfully captures the thermodynamic characteristics of molecular binding with an exogenous entity such as a virus and its consequences on the living processes well described by human physiology. Thus, we have documented the passage of SARS-CoV-2 from infection of a single cell to species jump, to tropism, variant emergence and widespread population infection. During the course of this review, the recurrent observation was the efficiency and simplicity of one critical function of this virus. The lethality of SARS-CoV-2 is due primarily to its ability to possess and use a variable surface for binding to a specific human target with high affinity. This binding liberates Gibbs free energy (GFE) such that it satisfies the criteria for thermodynamic spontaneity. Its binding is the prelude to human host cellular entry and replication by the appropriation of host cell constituent molecules that have been produced with a prior energy investment by the host cell. It is also a binding that permits viral tropism to lead to high levels of distribution across populations with newly formed virions. This thermodynamic spontaneity is repeated endlessly as infection of a single host cell spreads to bystander cells, to tissues, to humans in close proximity and then to global populations. The principal antagonism of this process comes from SARS-CoV-2 itself, with its relentless changing of its viral surface configuration, associated with the inevitable emergence of variants better configured to resist immune sequestration and importantly with a greater affinity for the host target and higher infectivity. The great value of this physiological and pharmacological perspective is that it reveals the fundamental thermodynamic underpinnings of SARS-CoV-2 infection., (© 2022 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

The application of science to human nutrition over the centuries has served societies well. One example is the identification of key nutrients to overcome nutritional deficiencies, which has enhanced life expectancy. Enhanced life expectancy, however, is associated with an increased prevalence of chronic disorders related to food and nutrition. Findings of studies indicating that individual responses to nutrients differ substantially between individuals make it necessary to re-examine the relationship between nutrition and human health. The emergence of new genomic-based technologies illustrates the complexity and scale of the interactions between nutrition and genetic factors. Epigenetic modifications resulting from interactions of the genetic profile, aging, and lifestyle can influence the time course of chronic disorders and contribute to human variability in response to nutritional interventions. Developing a better understanding of human variability as it applies to human nutrition will involve embracing the approaches and principles of complex science., (© The Author(s) 2020. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

OBJECTIVE Patient-reported outcomes (PROs) such as the Oswestry Disability Index (ODI) and EuroQol-5D (EQ-5D) are widely used to evaluate treatment outcomes following spine surgery for degenerative conditions. The goal of this study was to use the Charlson Comorbidity Index (CCMI) as a measure of general health status, for comparison with standard PROs. METHODS The authors examined serial CCMI scores, complications, and PROs in 371 patients treated surgically for degenerative lumbar spine conditions who were enrolled in the Quality and Outcomes Database from a single center. The cohort included 152 males (41%) with a mean age of 58.7 years. Patients with no, minor, or major complications were compared at baseline and at 1 year postoperatively. RESULTS Minor complications were observed in 177 patients (48%), and major complications in 34 (9%). There were no significant differences in preoperative ODI, EQ-5D, or CCMI among the 3 groups. At 1 year, there was a significantly greater deterioration in CCMI in the major complication group (1.03) compared with the minor (0.66) and no complication groups (0.44, p < 0.006), but no significant difference in ODI or EQ-5D. CONCLUSIONS Despite equivalent improvements in PROs, patients with major complications actually had greater deterioration in their general health status, as evidenced by worse CCMI scores. Because CCMI is predictive of medical and surgical risk, patients who sustained a major complication now carry a greater likelihood of adverse outcomes with future interventions, including subsequent spine surgery. Although PRO scores are a key metric, they fail to adequately reflect the potential long-term impact of major perioperative complications.

O(6)-methyl guanine (O(6)MeG) adducts are major toxic, promutagenic, and procarcinogenic adducts involved in colorectal carcinogenesis. Resistant starch and its colonic metabolite butyrate are known to protect against oncogenesis in the colon. In this study, we hypothesized that a dietary intervention that specifically delivers butyrate to the large bowel (notably butyrylated high-amylose maize starch [HAMSB]) would reduce colonic levels of O(6)MeG in rats shortly after exposure to the deoxyribonucleic acid (DNA) alkylating agent azoxymethane (AOM) when compared with a low-amylose maize starch (LAMS). A further objective was to validate an immunohistochemistry (IHC) method for quantifying O(6)MeG against a high-performance liquid chromatography method using fluorescence and diode array detection. Rats were fed either LAMS or HAMSB diets for 4 weeks followed by a single injection of AOM or saline and killed 6 hours later. After AOM exposure, both IHC and high-performance liquid chromatography method using fluorescence and diode array detection measured a substantially increased quantity of DNA adducts in the colon (P<.001). Both techniques demonstrated equally that consumption of HAMSB provided a protective effect by reducing colonic adduct load compared with the LAMS diet (P<.05). In addition, IHC allowed visualization of the O(6)MeG distribution, where adduct load was reduced in the lower third of the crypt compartment in HAMSB-fed rats (P=.036). The apoptotic response to AOM was higher in the HAMSB-fed rats (P=.002). In conclusion, the reduction in O(6)MeG levels and enhancement of the apoptotic response to DNA damage in the colonic epithelium through consumption of HAMSB provide mechanistic insights into how HAMSB protects against colorectal tumorigenesis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Azoxymethane (AOM) is an alkylating agent that generates mutagenic and carcinogenic O(6)-methylguanine (O(6)meG) adducts in DNA. O(6)meG has been detected in human colonic DNA; hence, understanding the innate cellular events occurring in response to the formation of O(6)meG is important in developing preventive strategies for colorectal cancer. We explored the time-course, dose-response, and kinetics of O(6)meG formation and its removal by the DNA repair protein, O(6)-methylguanine DNA methyltransferase (MGMT), and apoptosis. In rats given AOM (10 mg/kg), the formation of O(6)meG occurs within 2 h of exposure, accompanied by rapid depletion of MGMT activity and followed by the induction of an acute apoptotic response that peaks at 6-8 h. MGMT repair and apoptosis are dependent on AOM dose and O(6)meG load. Apoptosis is initiated only when a high O(6)meG load is present and MGMT activity is fully depleted. AOM, 10 mg/kg, overwhelms MGMT repair for about 96 h and renewed MGMT activity is only observed once O(6)meG is no longer detectable. A threshold for apoptosis is observed at 6 h after 6 mg/kg AOM, when a high O(6)meG persists and MGMT activity is very low. These data suggest that apoptosis is probably triggered by O(6)meG, but only once the capacity of MGMT to repair O(6)meG is exhausted. In the colonic epithelium, apoptosis may be complementary to MGMT, in terms of minimising potentially mutagenic events and maintaining a healthy genome., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is an epidemic facing the entire world. Increased knowledge gained during the past 25 years indicates that AD falls along a clinical and neuropathological spectrum represented as a continuum that extends from preclinical disease in which there are no symptoms, through early symptomatic phases, and finally to AD dementia. The Alzheimer's research community recognizes that imaging, body fluids, and cognitive biomarkers contribute to enhanced diagnostic confidence for AD. There has also been emerging consensus regarding the use of AD biomarkers in clinical trials. The use of biomarkers in clinical trials and practice is hampered by the lack of standardization. In response to the emerging need for standardization, an international meeting of AD researchers was held in Melbourne, Australia, in March 2012 to bring together key researchers, clinicians, industry, and regulatory stakeholders with the aim of generating consensus on standardization and validation of cognitive, imaging, and fluid biomarkers, as well as lifestyle parameters used in research centers worldwide., (Copyright © 2013 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Butyrate and its analogues have long been investigated as potential chemotherapeutic agents. Our previous structure-activity relationship studies of butyrate analogues revealed that 4-benzoylbutyrate had comparable in vitro effects to butyrate when used to treat HT29 and HCT116 colorectal cancer cell lines. The aim of this study was to identify potential mechanisms associated with the antitumorigenic effects of 4-benzoylbutyrate. In this study, butyrate, 3-hydroxybutyrate and 4-benzoylbutyrate were also investigated for their effects on histone deacetylase (HDAC) activity and histone H4 acetylation in HT29 and HCT116 cells. The biological effects of these analogues on HT29 cells were further investigated using quantitative proteomics to determine the proteins potentially involved in their apoptotic and antiproliferative effects. Because 3-hydroxybutyrate had minimal to no effect on apoptosis, proliferation or HDAC activity, this analogue was used to identify differentially expressed proteins that were potentially specific to the apoptotic effects of butyrate and/or 4-benzoylbutyrate. Butyrate treatment inhibited HDAC activity and induced H4 acetylation. 4-Benzoylbutyrate inhibited HDAC activity but failed to enhance H4 acetylation. Proteomic analysis revealed 20 proteins whose levels were similarly altered by both butyrate and 4-benzoylbutyrate. Proteins that showed common patterns of differential regulation in the presence of either butyrate or 4-benzoylbutyrate included c-Myc transcriptional targets, proteins involved in ER homeostasis, signal transduction pathways and cell energy metabolism. Although an additional 23 proteins were altered by 4-benzoylbutyrate uniquely, further work is required to understand the mechanisms involved in its apoptotic effects.

The in vitro activity of human recombinant β-secretase (BACE1) was studied using a fluorogenic substrate based on the cleavage site for the enzyme in the Swedish mutation of amyloid precursor protein. The enzyme was inhibited by a control peptide inhibitor with good repeatability. The enzyme preparation comprised a mixture of pro-enzyme or zymogen and mature enzyme whereby the pro-enzyme sequence forms a 'flap' that can obstruct the binding site. 'Open flap' forms of the zymogen and mature enzyme are active, but the 'closed flap' form of the zymogen is inactive. This mixture of enzyme populations permitted apparent stimulation of enzyme activity under particular conditions, presumably due to facilitating flap-opening of the zymogen. As reported for heparin, enzyme activation was stimulated in the presence of low concentrations of Tween 20 and dimethylsulfoxide before becoming inhibited at higher concentrations. Dietary plant extracts either consistently inhibited (e.g. clove, tea, cinammon) or consistently stimulated (e.g. mushroom, parsley, asparagus) BACE1. Common structural features identified by Fourier transform infrared spectroscopy revealed that BACE1 activity could be explained by differential interactions of either small molecule or polymeric species with mature versus zymogen forms of the enzyme, respectively. Further, enzyme activity could be reversed by mixtures of high and low mass species. These results may have implications for the regulation of β-secretase activity in vivo by either endogenous or possibly dietary factors and for a potential role of BACE1 in stimulation of the production of amyloid beta peptide in sporadic Alzheimer's disease., (© 2012 CSIRO. Journal compilation © 2012 FEBS.)

Colorectal cancer is the second leading cause of cancer death in Australia. Nutrition, particularly intake of vegetables and certain plant components, has been reported to have a major role in cancer risk reduction. Recently, there has been a growing research interest in rosemary, a common household plant grown in many parts of the world. This study aims to review scientific evidence from all studies, published from 1996 to March 2010 that examined the protective effects of rosemary on colorectal cancer and other types of cancer. Literature evidence from animal and cell culture studies demonstrates the anticancer potential of rosemary extract, carnosol, carnosic acid, ursolic acid, and rosmarinic acid. No evidence for other rosemary constituents was found. The reported anticancer properties were found to arise through the molecular changes in the multiple-stage process of cancer development, which are dose related and not tissue or species specific. This is evidenced by the ability of rosemary to suppress the development of tumors in several organs including the colon, breast, liver, stomach, as well as melanoma and leukemia cells. The results suggested that the different molecular targets modulated by rosemary and its active constituents are useful indicators of success in clinical cancer chemo-prevention trials.

It is the purpose of this article to discuss the development and application of a logic model in the context of a large scientific research program within the Commonwealth Scientific and Industrial Research Organisation (CSIRO). CSIRO is Australia's national science agency and is a publicly funded part of Australia's innovation system. It conducts mission-driven scientific research focussed on delivering results with relevance and impact for Australia, where impact is defined and measured in economic, environmental and social terms at the national level. The Australian Government has recently signalled an increasing emphasis on performance assessment and evaluation, which in the CSIRO context implies an increasing emphasis on ensuring and demonstrating the impact of its research programs. CSIRO continues to develop and improve its approaches to impact planning and evaluation, including conducting a trial of a program logic approach in the CSIRO Preventative Health National Research Flagship. During the trial, improvements were observed in clarity of the research goals and path to impact, as well as in alignment of science and support function activities with national challenge goals. Further benefits were observed in terms of communication of the goals and expected impact of CSIRO's research programs both within CSIRO and externally. The key lesson learned was that significant value was achieved through the process itself, as well as the outcome. Recommendations based on the CSIRO trial may be of interest to managers of scientific research considering developing similar logic models for their research projects. The CSIRO experience has shown that there are significant benefits to be gained, especially if the project participants have a major role in the process of developing the logic model., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Azoxymethane (AOM) is a methylating agent capable of inducing mutations in DNA by forming adducts with DNA bases. It has been used to understand the mechanisms involved in colon carcinogenesis. Of the adducts formed in response to AOM, O(6)-methyl-2'-deoxy-guanosine (O(6)-mdGua) is the most mutagenic. Based on studies in rodents of the abundance and persistence of DNA adducts in various tissues after treatment with alkylating agents, previous results suggest, as a generalization, that the longer O(6)-mdGua adducts remain unrepaired in the cells of a tissue, the greater the risk for tumorigenesis. To test this hypothesis, we have built on these studies, expanding the number of tissues in which O(6)-mdGua abundance and persistence were examined and correlating these data with tumour distribution and abundance in rats maintained for 26 weeks after the treatment with AOM. Our study revealed firstly the existence of groups of tissues that developed relatively large amounts (proximal and distal colon, proximal small intestine (SI), liver and kidney) and relatively low levels (stomach, distal SI, bladder, spleen, blood and lung) of O(6)-mdGua after AOM exposure. Secondly, while all tissues showed an increase in adduct levels at 6h after mutagen treatment and most showed a significant drop in adduct levels between 6h and 48h (stomach, proximal and distal SI, liver, spleen, blood and lung), one group of tissues displayed O(6)-mdGua levels that did not decrease at 48h (proximal and distal colon, kidney and bladder). Predictably, the colon displayed tumours 26 weeks after treatment. Interestingly, however, the proximal SI also displayed significant tumour formation at that time. Our findings demonstrate (1) a direct association between exposure to O(6)-mdGua and tumours of the distal colon and (2) a dissociation of the relationship between adduct clearance and tumorigenesis in the SI. This diversity of response in the gastrointestinal tract warrants further analysis., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background and Aims: Chronic opioid analgesia has the debilitating side-effect of constipation in human patients. The major aims of this study were to: 1) characterize the opioid-specific antagonism of morphine-induced inhibition of electrically driven contraction of the small intestine of mice, rats, and guinea pigs; and 2) test if the oral delivery of small milk-derived opioid antagonist peptides could block morphine-induced inhibition of intestinal transit in mice., Methods: Mouse, rat, and guinea pig intact ileal sections were electrically stimulated to contract and inhibited with morphine in vitro. Morphine inhibition was then blocked by opioid subtype antagonists in the mouse and guinea pig. Using a polymeric dye, Poly R-478, the opioid antagonists casoxin 4 and lactoferroxin A were tested orally for blocking activity of morphine inhibition of gut transit in vivo by single or double gavage techniques., Results: The guinea pig tissue was more sensitive to morphine inhibition compared with the mouse or the rat (IC(50) [half maximal inhibitory concentration] values as nmol/L ± SEM were 34 ± 3, 230 ± 13, and 310 ± 14 respectively) (P < 0.01). The inhibitory influence of opioid agonists (IC(50)) in electrically driven ileal mouse preparations were DADLE ([D-Ala(2), D-Leu(5)]-enkephalin) ≥ met-enkephalin ≥ dynorphin A ≥ DAMGO ([D-Ala(2), N-Me-Phe(4), Glyol(5)]-enkephalin) > morphine > morphiceptin as nmol/L 13.9, 17.3, 19.5, 23.3, 230, and 403 respectively. The mouse demonstrated predominantly κ- and δ-opioid receptor activity with a smaller μ-opioid receptor component. Both mouse and guinea pig tissue were sensitive to casoxin 4 antagonism of morphine inhibition of contraction. In contrast to naloxone, relatively high oral doses of the μ-opioid receptor antagonists, casoxin 4 and lactoferroxin A, applied before and after morphine injection were unable to antagonize morphine inhibition of gut transit., Conclusions: Casoxin 4 reverses morphine-induced inhibition of contraction in mice and guinea pigs in vitro but fails to influence morphine inhibition of mouse small intestinal transit by the oral route.

1. Butyrate, a bacteria fermentative product in the colonic lumen, has been shown to produce a wide variety of biological effects in human cancer cells in vitro. However, there are pharmacological drawbacks associated with the use of butyrate therapy and there are limited published data on the structure-activity relationship of butyrate analogues in colorectal cancer cells. Previously, we determined structure-activity relationship using HT-29 human colorectal cancer cells. However, it was viewed as important to explore similar relationships in another colorectal cancer cell line. 2. Therefore, in the present study, the in vitro structure-activity relationship of butyrate analogues was examined by investigating their effects on apoptosis, cell proliferation, histone deacetylase (HDAC) activity and lactate dehydrogenase (LDH) leakage as a measure of cell toxicity in HCT-116 human colorectal cancer cells. 3. Of the 32 analogues tested, only 4-benzoylbutyrate, 3-benzo-ylpropionate, 4-(4-nitrophenyl)butyrate and 3-(4-fluorobenzoyl)propionate exhibited comparable biological effects to butyrate. The common structural properties of the compounds of interest were to lack amino or hydroxyl substitutions at the 2-, 3- and/or 4-position of the aliphatic moiety of butyrate. 4. The present study reveals a dissociation between the induction of apoptosis, inhibition of cell proliferation, HDAC activity and LDH leakage. The results indicate differential responses of butyrate analogues in HT-29 and HCT-116 colorectal cancer cells.

1. Butyrate is a well known product of starch fermentation by colonic bacteria and is of interest owing to its ability to induce in vitro apoptosis and cell differentiation, as well as to inhibit cell growth in colorectal and other cancer cells. Synthetic analogues of butyrate may also possess cellular activities in a variety of cultured cells. The aim of the present study was to evaluate the effects of butyrate analogues on apoptosis, proliferation and histone deacetylase (HDAC) activity in HT-29 colorectal cancer cells. In addition, the effects of these analogues on lactate dehydrogenase leakage, as a measure of non-specific cytotoxicity, were evaluated in HT-29 cells. 2. Of the 26 analogues examined, four (propionate, 4-benzoylbutyrate, 4-(4-aminophenyl)butyrate and benzyloxyacetate) exhibited comparable effects to butyrate. Interestingly, no activity was noted for compounds carrying amino, hydroxyl or methyl substitutions at the 2-, 3- or 4-position of the aliphatic moiety of butyrate. 3. In conclusion, chemical changes to the structure of butyrate can significantly modify the biological activity assayed in HT-29 colorectal cancer cells in vitro.

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.

Interleukin-6 (IL-6) is a multifunctional pro-inflammatory cytokine that is tightly regulated and expressed at low levels in healthy individuals. Increased IL-6 expression has been associated with a variety of diseases, including inflammatory conditions such as atherosclerosis and cardiovascular disease (obesity, myocardial infarction and type II diabetes). Cytokines including IL-6 and tumour necrosis factor alpha as well as acute phase proteins such as C-reactive protein (CRP) and fibrinogen are key biochemical risk factors for the development of these disease conditions. IL-6 is the key cytokine responsible for the stimulus of synthesis and secretion of CRP. IL-6 activates cell surface signalling via the assembly of IL-6, the IL-6 receptor (IL-6R) and the signalling receptor gp130. Assembly of the (hexameric) signalling complex of IL-6, IL-6R and gp130 occurs in a sequential manner and therefore this signalling complex lends itself to several potential sites for drug targeting. This review discusses some of the mechanisms of IL-6 signalling on various aspects of cardiovascular biology as well as some recent developments in drug targeting of this complex.

Colorectal cancer (CRC) is the 3rd leading cause of cancer death in the United States and the 2nd leading cause of cancer death in Australia. Environmental factors play important roles in the multiple-stage process of CRC and nutritional intervention has been identified as playing a major role in its prevention. The aim of this study was to review systematically the scientific evidence from all studies conducted over the last decade that examined effects of garlic on CRC. Levels of evidence were ranked from level I to level V according to study designs and the quality of each study was assessed against a set of quality criteria based on those used by the National Health and Medical Research Council in Australia. One randomized controlled trial (RCT, level II) reported a statistically significant 29% reduction in both size and number of colon adenomas in CRC patients taking aged garlic extract. Five of 8 case control/cohort studies (level III) suggested a protective effect of high intake of raw/cooked garlic and 2 of 8 of these studies suggested a protective effect for distal colon. A published meta-analysis (level III) of 7 of these studies confirmed this inverse association, with a 30% reduction in relative risk. Eleven animal studies (level V) demonstrated a significant anticarcinogenic effect of garlic and/or its active constituents. On balance, there is consistent scientific evidence derived from RCT of animal studies reporting protective effects of garlic on CRC despite great heterogeneity of measures of intakes among human epidemiological studies.

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 N(omega)-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.

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 Nomega-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 (TxA ) receptor antagonist SQ29548 induced a complete reversal of the abnormal constriction. In contrast, thromboxane synthetase inhibition had no effect, ruling out any involvement of TxA 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 PGG /H and endothelium-derived free radicals rather than TxA per se appear to contribute to the NOLA-dependent TxA -like vasoconstriction.

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.

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 N(omega)-nitro-L-arginine (NOLA). Dietary alpha -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, alpha-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., (Copyright 2001 Harcourt Publishers Ltd.)

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 F(2 alpha), leukotriene C(4), 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 alpha -linolenic acids (alpha 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., (Copyright 2001 Harcourt Publishers Ltd.)

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 (IC(50) values, nM): [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]-enkephalin (DAMGO) (15)>[D-Ala(2),D-Leu(5)]-enkephalin (DADLE) (35)> or =morphine (46)> or =[D-Ala(2)]-met-enkephalinamide (55)>[D-Ala(2)]-beta-casomorphin[1--4] amide (122)>beta-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-Ala(2)]-met-enkephalinamide=morphine (4700)>[D-Ala(2)]-beta-casomorphin[1--4] amide (29000). beta-Casomorphin[1--4] amide, leu-enkephalin and met-enkephalin are mostly inactive when applied luminally. Furthermore, the opioid antagonists, casoxin 4 and [D-Ala(2)]-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.

The influence of diets containing gamma-linolenic acid (GLA; 18:3n-6) on sciatic nerve conduction velocity (NCV) was determined in diabetic rats. NCV was lower in diabetic rats fed diets supplemented with olive oil or sunflower seed oil than in nondiabetic rats; rats supplemented with GLA during a 5-wk diabetic period, however, did not exhibit significantly lower NCV. The mean proportion of the phospholipid fatty acid linoleic acid (18:2n-6) was higher in the sciatic nerves of diabetic rats than in the nondiabetic groups irrespective of dietary lipid treatment. Additionally, the proportion of linoleic acid was higher in the diabetic rats fed sunflower oil than in all other groups. Dietary GLA supplementation did not significantly influence the fatty acid composition of nerve membrane phospholipids and there was no obvious correlation between the fatty acid composition of nerve membrane phospholipids and NCV. The content of fructose and glucose in sciatic nerves was higher, whereas that of myo-inositol was lower, in diabetic rats than in nondiabetic rats; however, this was not significantly influenced by dietary GLA. GLA administration did not significantly influence Na(+)-K(+)-exchanging ATPase or ouabain binding activity in sciatic nerve preparations, both of which remained nonsignificantly different in the diabetic and nondiabetic groups. The results suggest that dietary GLA can prevent the deficit in NCV induced by diabetes and that this effect is independent of the nerve phospholipid fatty acid profile, sugar and polyol content, Na(+)-K(+)-exchanging ATPase activity, and ouabain binding. GLA may prevent the deficit in NCV indirectly, possibly by its role as a precursor of vasodilatory prostaglandins. These results confirm that GLA is the active component of evening primrose oil.

There is considerable interest in the possibility that diet-derived isoflavonoids may help in protection against a number of chronic diseases common in Western society. Based on animal studies, however, concerns have been raised that consumption of isoflavonoids by infants and young children may be undesirable. Clover contains isoflavonoids and therefore may represent, via milk, a source of isoflavonoids in the human diet. In this study the concentrations of daidzein (7, 4'-dihydroxyisoflavone), genistein (5, 7, 4'-trihydroxyisoflavone) and equol (7-hydroxy-(4'-hydroxyphenyl)chroman) were measured using HPLC in cows' milk samples obtained from 76 farms in three Australian states. In addition, concentrations were measured in samples collected from one South Australian factory both before and after pasteurization. Concentrations in all samples were found to be extremely low. The mean daidzein concentration was < 5 ng/ml. Mean genistein concentrations ranged from just detectable (approximately 2 ng/ml) in Victorian samples collected during summer to 20-30 ng/ml in samples from all states collected during spring when isoflavonoid-containing clover is most dominant in pasture. Mean equol concentrations ranged from 45 +/- 10 ng/ml in Victorian farm samples collected during summer to 293 +/- 52 ng/ml in Western Australian samples collected in spring. The mean concentrations of genistein and equol in post-pasteurization samples collected in spring were approximately double those for samples collected in autumn. Pasteurization had no effect on isoflavonoid concentrations. We conclude that the concentrations of isoflavonoids in Australian cows' milk are low and are therefore unlikely to have any pronounced biological effects in human consumers.

1. 5-Hydroxytryptamine (5-HT) exerts both contractile and relaxant effects in the marmoset isolated aorta, actions that are unaffected by the 5-HT2 antagonist ketanserin. The aim of the present study was to define the receptors mediating the contractile activity of 5-HT in the marmoset aorta. 2. Contractile responses were elicited in aortic rings that were either: (i) precontracted submaximally with the thromboxane A2 agonist U44069 in order to amplify the responses; or (ii) exposed to N(omega)-nitro-L-arginine (100 micromol/L) plus LY 53857 (0.1 micromol/L; a 5-HT2 receptor antagonist shown previously to inhibit relaxation). The effect of 5-HT on adenosine 3',5'-cyclic monophosphate (cAMP) formation was also investigated. 3. The effects of agonists and antagonists comprised: (i) agonist potencies in the order 5-carboxamidotryptamine > 5-HT > sumatriptan > 8-hydroxy-2-(di-n-propylamino)tetralin; (ii) inhibition of contractile action of 5-HT by the 5-HT1D antagonist GR 127935; (iii) a contractile response to methysergide; (iv) a lack of effect of tropisetron, an antagonist of 5-HT3 and 5-HT4 receptors; and (v) inhibition of forskolin-stimulated cAMP formation by 5-HT (in the presence of LY 53857), indicative of negative coupling to adenylate cyclase. 4. The above effects fulfill the criteria for a 5-HT1-like receptor. In view of the previous finding that this contractile response is insensitive to ketanserin, it is concluded that the contractile effects of 5-HT in the marmoset aorta are mediated exclusively by a 5-HT1-like receptor.

Young adult male Hooded Wistar rats were rendered diabetic by administration of streptozotocin and maintained for 5 weeks on a diet containing either 6% olive oil as the total source of fat (OO diet), or purified gamma-linolenic acid (GLA) at a concentration of 0.5% with the remaining 5.5% provided by olive oil (GLA diet). Rats were treated with the angiotensin converting inhibitor, cilazapril, administered in the drinking water at a dose of 20 mg kg-1 body weight day-1. For the OO diet groups, sciatic nerve conduction velocity (NCV) in diabetic rats was reduced by 32% (p < 0.01) in comparison with nondiabetic (vehicle-treated) rats and 27.5% (p < 0.05) in comparison with diabetic rats treated with cilazapril. Diabetic, cilazapril-treated rats showed no reduction in NCV. For the nondiabetic, diabetic, and diabetic plus cilazapril groups fed GLA, the NCV was not significantly different, indicating that dietary GLA also prevented the deficit in the NCV induced by the diabetic state. Analysis of the sciatic nerve endoneurial phospholipid fatty acids revealed a significant reduction in the proportion of GLA and an elevation in the proportion of linoleic acid in the diabetic groups compared with the nondiabetic groups and this was independent of the cilazapril treatment or the dietary lipid supplement. Sciatic nerve myo-inositol content was unaltered while mannose, fructose, glucose, and sorbitol levels were elevated in the diabetic groups and these changes were independent of the cilazapril treatment or the dietary lipid supplement. These results indicate that in the rat, cilazapril treatment or dietary GLA, at the doses tested, are effective in preventing the deficit in the NCV induced by diabetes.

Consumption of soy products has been linked to a reduced mortality and morbidity from a number of cancers. Genistein, one of the principal soy isoflavones, has been shown to inhibit the growth of a number of tumour cell lines in vitro; however, a role of genistein in retarding tumour growth in vivo is less well documented. In this study, in addition to examining the effects of genistein on the growth of murine B16 melanoma cells in vitro, we have examined the effects of feeding a genistein-rich diet on s.c. growth of these tumour cells in mice. In vitro, the melanoma cells showed an increase in sensitivity to genistein with increasing time of exposure, culminating in a 50% growth inhibition (IC50) at 12.5 microM after 7 days. Genistein at 25 microM induced micronucleus formation after 24 hr and at concentrations as low as 2.5 microM induced morphological changes indicative of differentiation. Growth of solid tumours implanted into female C57BL/6J mice was inhibited by 50% when mice were fed genistein for 1 week before and for 1 week after inoculation with B16 melanoma cells. Plasma genistein concentrations at the time of tumour removal were 1.1 microM, which is similar to levels reported in humans consuming diets high in soybeans or soybean products, while control animals had no detectable genistein in plasma. Our results provide additional in vivo evidence suggesting that genistein retards the growth of implanted tumours, adding further to studies suggesting that this isoflavonoid is a biologically active component of soy foods.

1. Na+/H+ antiporter/exchange activity (NHE) in human cheek epithelial cells was assessed in 288 female twins and siblings. The genetic contribution of factors to NHE activity was assessed in 128 matched twin pairs (76 monozygotic (MZ); 52 dizygotic (DZ)). 2. There was a small reduction in NHE with age and body mass index. The significant correlations (+/-their standard error (SE)) within MZ and DZ pairs of twins were 0.54 +/- 0.08 and 0.26 +/- 0.13, respectively, implying that genetic factors accounted for 54% of the variance in age-adjusted NHE. There was no cross-sectional relationship between NHE and measures of blood pressure. Based on within-pair differences, however, there was a weak negative association (r = 0.22; P < 0.05) between mean arterial pressure and NHE. 3. It remains to be determined whether NHE in cheek cells is associated with blood pressure tracking over time in young females.

Several cardiovascular risk factors including, hypercholesterolaemia and hypertension, lead to diseased blood vessels due to endothelial cell dysfunction. Recent studies also indicate that such alterations in blood vessel function may involve free radical related mechanism(s). Therefore, in the present study, two different preparations of palm oils with variable antioxidant profiles, as well as a purified antioxidant fraction extracted from unprocessed palm oil (tocotrienol-rich-factor; TRF), were tested for their ability to influence blood vessel dysfunction in the spontaneously hypertensive rat (SHR). Adult SHRs were fed a synthetic diet supplemented (5% w/w) with either physically refined palm oil (PO), golden palm cooking oil (Nutrolein; GPO) or olive oil (OO; control diet). Antioxidant rich diet (TRF diet) was prepared by supplementing the OO diet with 0.2% (w/w) TRF. After 12 weeks of pre-feeding, segments of thoracic aorta were used to evaluate vascular function. Compared to the normotensive Wistar-Kyoto (WKY) control rats, aortic rings from the SHR showed impaired endothelium dependent relaxation to acetylcholine (ACh) which was restored by dietary TRF (p<0.05, ANOVA and Tukey's test). In addition, the paradoxical increase in tension in control hypertensive vessels observed at higher doses of ACh was prevented by TRF and also by the PO and GPO diets. Although the development of thromboxane-like constrictor response, after the inhibition of nitric oxide in hypertensive vessels, was unaffected by test diets, both TRF and GPO feeding prevented the amplification of this unwanted constriction by a threshold dose (7.2x10-10 M) of noradrenaline. Results suggest a modulatory role for minor constituents of edible oils and are in agreement with the recently reported benefits of natural antioxidants against cardiovascular diseases.

Proton-dependent, ethylisopropylamiloride (EIPA)-sensitive Na+ uptake (Na+/H+ antiporter) studies were performed to examine if saliva, and ionophores which alter cellular electrolyte balance, could influence the activity of the cheek cell Na+/H+ antiporter. Using the standard conditions of 1 mmol/l Na+, and a 65:1 (inside:outside) proton gradient in the assay, the uniport ionophores valinomycin (K+) and gramicidin (Na+) increased EIPA-sensitive Na+ uptake by 177% (p < 0.01) and 227% (p < 0.01), respectively. The dual antiporter ionophore nigericin (K(+)-H+) increased EIPA-sensitive Na+ uptake by 654% (p < 0.01), with maximal Na+ uptake achieved by 1 min and at an ionophore concentration of 50 mumol/l, with an EC50 value 6.4 mumol/l. Pre-incubation of cheek cells with saliva or the low molecular weight (MW) components of saliva (saliva activating factors, SAF) for 2 h at 37 degrees C, also significantly stimulated EIPA-sensitive Na+ uptake. This stimulation could be mimicked by pre-incubation with 25 mmol/l KCl or K(+)-phosphate buffer. Pre-incubating cheek cells with SAF and the inclusion of 20 mumol/l nigericin in the assay, produced maximum EIPA-sensitive Na+ uptake. After pre-incubation with water, 25 mmol/l K(+)-phosphate or SAF, with nigericin in all assays, the initial rate of proton-gradient dependent, EIPA-sensitive Na+ uptake was saturable with respect to external Na+, with Km values of 0.9, 1.7, and 1.8 mmol/l, and Vmax values of 13.4, 25.8, and 31.1 nmol/mg protein/30 sec, respectively. With 20 mumol/l nigericin in the assay, Na+ uptake was inhibited by either increasing the [K+]o in the assay, with an ID50 of 3 mmol/l. These results indicate that nigericin can facilitate K+i exchange for H+o and the attending re-acidification of the cheek cell amplifies 22Na+ uptake via the Na+/H+ antiporter. The degree of stimulation of proton-dependent, EIPA-sensitive Na+ uptake is therefore dependent, in part, on the intracellular [K+]i.

Rodent models have been used to study the anticarcinogenic properties of the soy isoflavones, particularly genistein, but there is little information regarding the pharmacokinetics of the absorption and excretion of genistein. In this study, rats were given a single oral dose of genistein (20 mg/kg body weight) or an equivalent dose of its glycone forms, as an isoflavone-rich soy extract. Concentrations of genistein were measured in plasma, urine and feces at intervals up to 48 h after dosing. Plasma genistein concentration at 2 h after dosing was 11.0 +/- 2.3 mumol/L in genistein-treated rats compared with 4.93 +/- 0.22 mumol/L (P = 0.025) in soy extract-treated rats, but there were no significant differences at 8 h and later times. The mean urinary excretion rate during the first 2 h after dosing was more than 10 times higher in the genistein group compared with the soy extract group (0.27 +/- 0.08 mumol/h and 0.020 +/- 0.011 mumol/h, respectively, P = 0.017) but the percentage of dose recovered in urine over 48 h was not different between groups (19.9 +/- 2.4% genistein treated; 17.5 +/- 1.1% soy extract treated). There were no significant differences between groups in the recovery of genistein in feces (21.9 +/- 2.8% and 21.1 +/- 2.5% of dose, respectively). Only 6.1 +/- 0.9% of the daidzein from the soy extract was recovered in the feces. The results suggest that the extent of absorption of genistein is similar for the glycone and aglycone forms. Although higher initial plasma concentrations may be achieved with the aglycone, similar long-term concentrations exist for both forms of isoflavone.

1. Human cheek cell Na+/H+ antiporter activity (measured as the rate of proton-dependent 22Na+ uptake) was determined in seven normotensive (NT) and four hypertensive (HT) subjects following preincubation of cheek cells with a low molecular weight fraction isolated from NT saliva together with the ionophore, nigericin. 2. Cheek cells preincubated in this manner exhibited greater Na+/H+ antiporter activity with the mean values being 4.2 nmol Na+.mg protein.5 min for the NT group and 1.7 for the HT group. 3. It is possible that stimulation of Na+ transport is due to cellular accumulation of K+ ions during preincubation which, in the presence of the K+/H+ selective ionophore, nigericin, can cause cellular reacidification promoting further 22Na+ uptake via the Na+/H+ antiporter.

Treatment of spontaneously hypertensive rats (SHR) with alpha-adrenoceptor antagonists failed to alter the development of hypertension in this animal model. However, agents such as captopril (CAP) and losartan (LOS) which interfere with the renin-angiotensin system effectively prevented the development of hypertension. When tolerance occurred in the presence of doxazosin (DOX) or phenoxybenzamine, there was an enhanced sensitivity to the blood pressure lowering influence of LOS. In the presence of CAP, at a dose that did not retard the development of blood pressure in the SHR, DOX treatment significantly offset the development of hypertension in this strain. These results suggest that a functional tolerance to agents that interfere with the sympathetic nervous system is mediated by the renin-angiotensin system. Angiotensin-converting enzyme inhibition was associated with a normalization of the enhanced contraction of the mesenteric vascular bed seen in preparations from the SHR and a suppression in the development of the vascular amplifier. The results suggest that the sympathetic nervous system is unable to maintain an elevated blood pressure in the SHR during interference with the functioning of the renin-angiotensin system. Conversely, under conditions of alpha-adrenoceptor blockade, angiotensin II can maintain an elevated blood pressure in the SHR.

1. The levels of the neurotrophic factor, nerve growth factor (NGF) in the mesenteric vascular bed of the spontaneously hypertensive rat (SHR) were greater than those in the corresponding vascular bed of normotensive Wistar-Kyoto rats (WKY). 2. Administration of angiotensin II (200 ng/kg per min, by minipump) for 2 weeks to juvenile WKY rats increased the levels of NGF in the mesenteric vasculature to those seen in untreated SHR. 3. Administration of the angiotensin II receptor antagonists losartan (30 mg/kg per day, p.o.) or PD144277 (10 mg/kg per day, p.o.) to juvenile SHR for 4 weeks reduced the levels of NGF such that they were indistinguishable from the values obtained for normotensive WKY rats. 4. The results confirm the elevated level of NGF in the mesenteric vasculature of the SHR and suggest that angiotensin II may play a role in regulating the abnormal concentrations of the protein in this tissue.