Oxidative stress and inflammation in COVID-19: potential application OF GLP-1 receptor agonists.

COVID-19 is a global pandemic with devastating economic and public health impacts, which is particularly associated with increased incidence of respiratory and cardiovascular disease together with inflammation and oxidative stress as essential underlying features. Glucagon-Like Peptide-1 (GLP-1) receptor agonists are now routinely used for the clinical management of type 2 diabetes due to their established glucose-dependent insulinotropic actions. However, these agents also display a variety of pleiotropic functions, including the promotion of anti-inflammatory and antioxidant responses, highlighting likely therapeutic applications beyond glycemic control. Given that COVID-19 is particularly linked with adverse modulation of inflammatory and oxidative signaling, which are known to be impacted by GLP-1 receptor activation, it seems logical that GLP-1 receptor agonists may be beneficial for the clinical management of patients with SARS-CoV-2 infection. In this review, we discuss the specific role of inflammation and oxidative stress associated with COVID-19, including underlying pathogenic mechanisms, as the basis for the potential therapeutic application of GLP-1 receptor agonists to combat both acute and chronic complications of this devastating disease.

The influence of vestibular stimulation on metabolism and body composition.

Obesity, diabetes and metabolic disease represent an ongoing and rapidly worsening public health issue in both the developed, and much of the developing world. Although there are many factors that influence fat storage, it has been clearly demonstrated that the homeostatic cornerstone of metabolism lies within the hypothalamus. Moreover, neuronal damage to vital areas of the hypothalamus can drive reregulation or dysregulation of endocrine function, energy expenditure and appetite, thereby promoting a shift in overall metabolic function towards a state of obesity. Therefore, identification of treatments that influence the hypothalamus to improve obesity and associated metabolic diseases has long been a medical goal. Interestingly, evidence from animal studies suggests that activating the vestibular system, specifically the macular gravity receptor, influences the hypothalamus in a way that decreases body fat storage and causes a metabolic shift towards a leaner state. Given that the macular element of the vestibular system has been shown to activate with transdermal electrical stimulation applied to the mastoids, this may be a potential therapeutic approach for obesity, diabetes or related metabolic diseases, whereby repetitive stimulation of the vestibular system influences hypothalamic control of metabolic homeostasis, thereby encouraging decreased fat storage. Here, we present an up-to-date review of the current literature surrounding the vestibular influence of the hypothalamus and associated homeostatic sites in the context of current and novel therapeutic approaches for improved clinical management of obesity and diabetes.

Facilitated self-reported anaesthetic medication errors before and after implementation of a safety bundle and barcode-based safety system.

BACKGROUND: Anaesthetic medication administration errors are a significant threat to patient safety. In 2002, we began collecting data about the rate and nature of anaesthetic medication errors and implemented a variety of measures to reduce errors. METHODS: Facilitated self-reporting of errors was carried out in 2002-2003. Subsequently, a medication safety bundle including 'smart' infusion pumps were implemented. During 2014 facilitated self-reporting commenced again. A barcode-based medication safety system was then implemented and the facilitated self-reporting was continued through 2015. RESULTS: During 2002-2003, a total of 11 709 paper forms were returned. There were 73 reports of errors (0.62% of anaesthetics) and 27 reports of intercepted errors (0.23%). During 2014, 14 572 computerised forms were completed. There were 57 reports of errors (0.39%) and 11 reports of intercepted errors (0.075%). Errors associated with medication infusions were reduced in comparison with those recorded in 2002-2003 (P<0.001). The rate of syringe swap error was also reduced (P=0.001). The reduction in error rate between 2002-2003 and 2014 was statistically significant (P=0.0076 and P=0.001 for errors and intercepted errors, respectively). From December 2014 through December 2015, 24 264 computerised forms were completed after implementation of a barcode-based medication safety system. There were 56 reports of errors (0.23%) and six reports of intercepted errors (0.025%). Vial swap errors in 2014-2015 were significantly reduced compared with those in 2014 (P=0.004). The reduction in error rate after implementation of the barcode-based medication safety system was statistically significant (P=0.0045 and P=0.021 for errors and intercepted errors, respectively). CONCLUSIONS: Reforms intended to reduce medication errors were associated with substantial improvement.

Chronic treatment with a stable obestatin analog significantly alters plasma triglyceride levels but fails to influence food intake; fluid intake; body weight; or body composition in rats.

Obestatin (OB(1-23) is a 23 amino acid peptide encoded on the preproghrelin gene, originally reported to have metabolic actions related to food intake, gastric emptying and body weight. The biological instability of OB(1-23) has recently been highlighted by studies demonstrating its rapid enzymatic cleavage in a number of biological matrices. We assessed the stability of both OB(1-23) and an N-terminally PEGylated analog (PEG-OB(1-23)) before conducting chronic in vivo studies. Peptides were incubated in rat liver homogenate and degradation monitored by LC-MS. PEG-OB(1-23) was approximately 3-times more stable than OB(1-23). Following a 14 day infusion of Sprague-Dawley rats with 50 nmol/kg/day of OB(1-23) or a N-terminally PEGylated analog (PEG-OB(1-23)), we found no changes in food/fluid intake, body weight and plasma glucose or cholesterol between groups. Furthermore, morphometric liver, muscle and white adipose tissue (WAT) weights and tissue triglyceride concentrations remained unaltered between groups. However, with stabilized PEG-OB(1-23) we observed a 40% reduction in plasma triglycerides. These findings indicate that PEG-OB(1-23) is an OB(1-23) analog with significantly enhanced stability and suggest that obestatin could play a role in modulating physiological lipid metabolism, although it does not appear to be involved in regulation of food/fluid intake, body weight or fat deposition.

A national survey of infection control practice by New Zealand anaesthetists.

Anaesthetists have an important role in preventing nosocomial infection. Failures in this role have resulted in critical reports in the media. We ascertained the current practices of New Zealand anaesthetists relating to infection control, by distributing a questionnaire to all 450 anaesthetists practising in New Zealand. Sixty-one percent responded. Just over half the respondents had never read their hospital policy on infection control and over a third had never read the Australian and New Zealand College of Anaesthetists policy document on infection control. It was found that 3.4% rarely changed gloves if they became contaminated and 2.2% occasionally used the same syringe to administer drugs to more than one patient. The majority (86.3%) of respondents split one drug ampoule between more than one patient, 41.3% used multidose vials for more than one patient and 2.2% used pre-filled syringes for more than one patient. The majority complied with the College infection control policy for performing arterial cannulation (85.7%), central venous cannulation (77.4%) and regional blockade (65.1%). Respondents ranked the overall risk of the anaesthetist contributing to the transmission of infectious agents on a scale from 0 to 10 (10=highest risk). The median response was 7, the modal response was 10 and interquartile range was 4 to 8. There was a high level of awareness of the risks of contributing to cross-infection inherent in anaesthesia, most anaesthetists reporting that they followed recommended guidelines in this context. However, these data suggest more effort is required to promote compliance with appropriate guidelines.

Oxidative stress and heart failure.

Despite advances in treatment, chronic congestive heart failure carries a poor prognosis and remains a leading cause of cardiovascular death. Accumulating evidence suggests that reactive oxygen species (ROS) play an important role in the development and progression of heart failure, regardless of the etiology. Under pathophysiological conditions, ROS have the potential to cause cellular damage and dysfunction. Whether the effects are beneficial or harmful will depend upon site, source and amount of ROS produced, and the overall redox status of the cell. All cardiovascular cell types are capable of producing ROS, and the major enzymatic sources in heart failure are mitochondria, xanthine oxidases and the nonphagocytic NADPH oxidases (Noxs). As well as direct effects on cellular enzymatic and protein function, ROS have been implicated in the development of agonist-induced cardiac hypertrophy, cardiomyocyte apoptosis and remodelling of the failing myocardium. These alterations in phenotype are driven by redox-sensitive gene expression, and in this way ROS may act a potent intracellular second messengers. Recent experimental studies have suggested a possible causal role for increased ROS in the development of contractile dysfunction following myocardial infarction and pressure overload, however the precise contribution of different cellular and enzymatic sources involved remain under investigation.

Radiological insertion of gastrostomy in patients in whom endoscopy was unsuccessful.

INTRODUCTION: Endoscopy is the standard technique of percutaneous gastrostomy placement, but failure of placement may occur due to difficulty with intubation or previous abdominal surgery. A review of personal experience is made. PATIENTS AND METHODS: Between January 1997 and May 1998, 90 gastrostomy devices were successfully placed endoscopically in our unit. Endoscopic placement was unsuccessful in 3 patients and not attempted in a further 7 because of oro-pharyngeal obstruction. These 10 patients (6 male, 4 female, aged 51-84 years) had advanced neuro-degenerative disease or malignancy of the head and neck or oesophagus. All patients underwent radiological insertion of a gastrostomy tube by the 'push' method after insufflation of air into the stomach via a naso-gastric tube. RESULTS: Radiological insertion of gastrostomy device was successful in 9 out of 10 patients. Failure occurred in 1 patient due to inability to pass a naso-gastric tube and surgical gastrostomy was required. Pain at the gastrostomy site was the most common problem post-procedure and 4 patients still required analgesia on discharge. One patient developed a wound infection. There were no procedure-related deaths. The 30-day mortality due to all causes was 20%. Only 1 patient remained alive at 6 months. DISCUSSION: Availability of a radiologist trained in the placement of percutaneous gastrostomy allowed 99% of such devices to be placed percutaneously, even in those patients in whom endoscopy was not possible. However advanced underlying disease in this patient group results in a high mortality.

Impaired endothelial regulation of ventricular relaxation in cardiac hypertrophy: role of reactive oxygen species and NADPH oxidase.

BACKGROUND: Endothelium-derived nitric oxide (NO) selectively enhances myocardial relaxation. In experimental left ventricular hypertrophy (LVH), this endothelium-dependent LV relaxant response is impaired despite a preserved response to exogenous NO. We investigated the potential role of reactive oxygen species (ROS) in this defect. METHODS AND RESULTS: Short-term treatment with the antioxidants vitamin C (10 micromol/L) or deferoxamine (500 micromol/L) restored LV relaxant responses to the NO agonists bradykinin (10 nmol/L) and substance P (100 nmol/L) in isolated ejecting hearts of aortic-banded guinea pigs. Substance P decreased the time to onset of LV relaxation (tdP/dt(min)) by -6.8+/-1.7 ms in the presence of vitamin C and by -8.9+/-2.2 ms in the presence of deferoxamine compared with -0.8+/-2.2 ms in the absence of antioxidants (P<0.05 either antioxidant versus control). A similar restoration of relaxant response to substance P was observed in the presence of the superoxide dismutase mimetic, Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (10 micromol/L), but not with tetrahydrobiopterin or L-arginine. Protein expression of the NADPH oxidase subunits gp91-phox and p67-phox and myocardial NADPH oxidase activity were significantly increased (P<0.05) in the banded group compared with shams. CONCLUSIONS: An increase in ROS, most likely derived at least in part from NADPH oxidase, is responsible for the impaired endothelial regulation of LV relaxation in LVH. These are the first data to potentially link increased NADPH oxidase-derived ROS with a defect in cardiac contractile function in a pathological setting.

A variable inertial system for measuring the contractile properties of human muscle.

PURPOSE: A flywheel system of variable inertia is described for inferring the mechanical properties of human muscle during a single explosive movement. METHODS: The system consists of a lightweight aluminum disk mounted on a shaft onto which a driving cog is mounted. The inertia of the system can be varied from 0.024 to 0.69 kg.m(2) by attaching semicircular steel plates to the disk. A rotary encoder detects displacement of the wheel with a resolution of 1 degrees. Digital signals from the encoder are collected using an A/D converter interfaced to a PC. The data are then processed for the calculation of torque, velocity, power, work done, and acceleration. The mechanical properties of the muscles employed are inferred from calculations of flywheel displacement, time, and force. In addition, a pretension release mechanism can be incorporated into the system to allow isometric force to be developed before movement. This can increase power generation at the low inertias where the time of contraction is typically less than 200 ms. Seven subjects were test-retested using the device. Measures of both average and peak power were made. RESULTS: When mounted in the apparatus described by Bassey and Short, the maximum values for peak and average power were on average 965 +/- 103 and 448 +/- 47 W, respectively. Upon retesting, these results were found to be reliable (cv = 3.3% and 3.0%, respectively). CONCLUSIONS: The inertial system described has been shown to have validity in reproducibility and provided a suitable method of determining a number of muscle output properties during short-term single exertions. This tool could prove useful in a research or clinical setting and may also prove useful as a training device as it negates the need for a strain gauge or goniometer attachment.

A randomized trial of thermal ablative therapy versus expandable metal stents in the palliative treatment of patients with esophageal carcinoma.

BACKGROUND: Expandable metal stent insertion and thermal tumor ablation (TTA) both improve dysphagia in patients with advanced esophageal cancer, but no direct comparison study of their efficacy on health-related quality of life has been published. The aim of this study was to compare survival, relief of dysphagia, quality of life, and cost in patients treated by thermal ablation or stent insertion. METHODS: Sixty-five patients with histologically proven, inoperable esophageal and esophagogastric cancer were initially assessed by endoscopy, barium contrast radiography, and CT of the thorax and abdomen. Dysphagia and quality of life were serially assessed at monthly intervals. Patients were randomized to either repeated TTA or insertion of an expandable metal stent. RESULTS: Median survival was significantly longer for patients who underwent TTA; 125 days (17-546) versus 68 days (8-602) for those in whom a stent was inserted (p < 0.05), although relief of dysphagia was disappointing in both groups. Several patients in both groups had serious treatment-related complications and required further therapy. Median length of hospital stay and cost were greater for patients treated by TTA. Health-related quality of life was globally impaired in both groups at randomization and deteriorated significantly in the stent group. Pain was reported more commonly by patients with stents. CONCLUSIONS: The palliation of patients with advanced esophageal and esophagogastric cancer remains unsatisfactory. Health-related quality of life deteriorated in the stent group but not in the TTA group. Patients treated by TTA live longer than patients treated by stent insertion, but the cost of TTA is higher.

Divergent biological actions of coronary endothelial nitric oxide during progression of cardiac hypertrophy.

Coronary endothelial NO synthase expression and NO bioactivity were investigated at sequential stages during the progression of left ventricular hypertrophy. Male guinea pigs underwent abdominal aortic banding or sham operation. Left ventricular contractile function was quantified in isolated ejecting hearts. Coronary endothelial and vasodilator function were assessed in isolated isovolumic hearts in response to boluses of bradykinin (0.001 to 10 micromol/L), substance P (0.01 to 100 micromol/L), diethylamine NONOate (DEA-NO) (0.1 to 1000 micromol/L), N(G)-monomethyl-L-arginine monoacetate (L-NMMA) (10 mmol/L), and adenosine (10 mmol/L). At a stage of compensated left ventricular hypertrophy (3 weeks), left ventricular endothelial NO synthase protein expression was unaltered (Western blot and immunocytochemistry). Vasoconstriction in response to L-NMMA was increased in banded animals compared with sham-operated animals (13.8+/-2.1% versus 6.2+/-1.3%, n=10; P<0.05), but agonist- and DEA-NO-induced vasodilation was similar in the 2 groups. At a stage of decompensated left ventricular hypertrophy (8 to 10 weeks), left ventricular endothelial NO synthase protein expression was significantly lower in banded animals (on Western analysis: banded animals, 7.8+/-0.4 densitometric units; sham-operated animals, 12.2+/-1.7 densitometric units; n=5; P<0.05). At this time point, vasoconstriction in response to L-NMMA was similar in the 2 groups, but vasodilatation in response to bradykinin (30.9+/-2.4% versus 39.7+/-2.2%, n=10; P<0.05), DEA-NO (26.2+/-1.8% versus 34.6+/-1.8%, n=10; P<0.05), and adenosine (24.3+/-2.0% versus 35.7+/-2.0%, n=10; P<0.01) was attenuated in banded animals. These findings indicate that there is an increase in the basal activity of NO (without a significant change in endothelial NO synthase expression) in early compensated left ventricular hypertrophy, followed by a decrease in both endothelial NO synthase expression and NO bioactivity during the transition to myocardial failure.

The interaction between oxidised chylomicron remnants and the aorta of rats fed a normocholesterolaemic or hypercholesterolaemic diet.

The effects of oxidised chylomicron remnants on endothelium-dependent relaxation and lipoprotein uptake were studied in both the normocholesterolaemic and hypercholesterolaemic rat aorta in vitro. Incubation of aortic rings taken from normocholesterolaemic animals with oxidised (by treatment with copper sulphate) chylomicron remnant particles resulted in a reduction in both vessel sensitivity and maximum percent relaxation in response to carbachol (CCh) and ATP, without affecting responses to A23187 and S-nitroso-N-acetylpenicillamine (SNAP). Studies comparing control vessels and those taken from fat-fed rats confirmed that hypercholesterolaemia significantly decreased relaxations in response to CCh and potentiated contractions in response to phenylephrine (PE) via a nitric oxide (NO)-dependent mechanism. Perfusion of the aorta of these hypercholesterolaemic rats for 2 h with (125)I-labelled oxidised chylomicron remnants showed that significantly greater amounts of lipoprotein became associated with the artery wall, as compared to control normocholesterolaemic animals. However, there was no significant difference in the uptake of native chylomicron remnant particles between control and hypercholesterolaemic vessels. Taken together, the findings of this study suggest that incorporation of lipoproteins of dietary origin into the arterial wall may contribute to endothelial dysfunction and that their contribution may be enhanced by hypercholesterolaemia. These data also support the putative involvement of oxidative modification in the atherosclerotic process, although the presence of oxidised chylomicron remnants in vivo and their role in atherogenesis remains to be established.

Chylomicron remnants potentiate phenylephrine-induced contractions of rat aorta by an endothelium-dependent mechanism.

The effects of chylomicron remnants on endothelium-dependent contraction of rat aorta were studied in vitro. Chylomicron remnant particles were prepared in vivo from male Wistar rats and were incubated with aortic rings for 45 min before concentration contraction response curves were constructed to phenylephrine. Both native and oxidised chylomicron remnants significantly increased vessel sensitivity to this agonist. Oxidised chylomicron remnants also significantly increased the maximum response. This potentiation was abolished by endothelial removal, but was still evident in the presence of Nomega-nitro-L-arginine, with or without cyclo (D-alpha-aspartyl-L-prolyl-D-valyl-L-leucyl-D-tryptophyl) (BQ-123), indomethacin or superoxide dismutase. The study demonstrates, for the first time, that lipoprotein particles of dietary origin potentiate vascular contractions. This effect is endothelium-dependent, but is not due to inhibition of basal nitric oxide production or to stimulation of endothelin, superoxide or a cyclo-oxygenase-derived product.

Effects of oral propylthiouracil treatment on nitric oxide production in rat aorta.

The effects of oral propylthiouracil (PTU) treatment on vascular nitric oxide (NO) production were studied in the rat aorta. Rats were fed a standard low fat diet with or without 0.1% PTU, for 2 or 4 weeks, or for 2 weeks with additional thyroxine injections. Concentration response curves were then constructed to phenylephrine (PE) in both endothelium-intact and denuded aortic rings from these animals and after incubation with 0.1 mM L-N(G)nitroarginine (L-NOARG). In addition, expression of nitric oxide synthase (NOS) was analysed in sections of aorta from PTU-treated and control rats using rabbit polyclonal antibodies to both inducible NOS (iNOS) and endothelial NOS (eNOS). Oral PTU treatment resulted in a significant reduction in both the maximum response (control, 0.53+/-0.02; 2 week PTU, 0.20+/-0.07; 4 week PTU, 0.07+/-0.02 g mg(-1)) and vessel sensitivity (EC50 values: control, 9.10x10(-8)+/-0.67; 2 week PTU, 7.45x10(-7)+/-1.15; 4 week PTU, 9.73x10(-7)+/-0.45 M) to PE in endothelium-intact vessel rings, as compared to controls (P<0.05). Both endothelial removal and incubation with L-NOARG restored the maximum response after 2, but not 4 weeks, although, in general, vessel sensitivity was not altered by either treatment. Vessels from PTU-treated rats given thyroxine injections showed no significant differences between any of the dose response curve parameters. Immunohistochemical analysis suggested that labelling for eNOS may be increased after PTU treatment as compared to control animals, whereas iNOS antibody immunoreactivity was not different between the two groups. These results suggest that the hyporesponsiveness to PE observed after oral PTU treatment is, in part, due to enhanced nitric oxide (NO) production by the endothelium, and demonstrate for the first time that thyroid hormones may play a role in the regulation of eNOS activity in the rat aorta.

The ergoreflex in patients with chronic stable heart failure.

BACKGROUND: The main symptoms of chronic heart failure are breathlessness and fatigue on exertion. Abnormalities of skeletal muscle cause early metabolic distress on exercise, with resultant ergoreceptor stimulation causing increased ventilation. The aim of this study is to determine the extent of enhanced ergoreflex activity in chronic heart failure in the leg. METHODS: Ten patients with chronic stable heart failure (New York Heart Association class II-III) and nine healthy age-matched controls performed two bouts of ankle dorsiflexion. On one occasion a cuff was inflated round the thigh to suprasystolic levels for 3 min immediately post-exercise: regional circulatory occlusion. Recovery with regional circulatory occlusion was compared to recovery without it. RESULTS: Systolic and diastolic blood pressure and ventilation were higher after 3 min post-exercise regional circulatory occlusion than after 3 min control recovery in the patient group (184+/-13.3 vs. 165+/-12.5 mm Hg, P<0.01, 94+/-4.7 vs. 86+/-3.5 mm Hg, P<0.05, 9.8+/-0.7 vs. 7.9+/-0.36 l/min, P<0.01). Systolic and diastolic blood pressure were higher after post-exercise regional circulatory occlusion than after control recovery in the control group (149+/-7.8 vs. 138+/-5.7 mm Hg, P<0.01, 86+/-3.3 vs. 82+/-2.5 mm Hg, P<0.05), but this was not the case for ventilation (8.1+/-0.62 vs. 8.1+/-0.62 l/min). Ergoreflex activity was greater in the patient group than in the controls for systolic blood pressure (91 vs. 48%, P<0.001), diastolic blood pressure (86 vs. 49%, P<0.05) and ventilation (39 vs. -1%, P<0.05). CONCLUSIONS: Ergoreceptor stimulation contributes to an increased ventilation and blood pressure response to leg exercise in chronic heart failure patients, perhaps contributing to dyspnoea and exercise limitation. Peripheral factors such as skeletal muscle abnormalities contribute to the pathogenesis of symptoms in chronic heart failure.

Insurance and the risk of ruptured appendix in the adult.

BACKGROUND: Disparities in medical care related to the insurance status of patients have been reported. A retrospective analysis was performed to examine the insurance-related differences in the risk of appendiceal perforation in the Prince of Wales Hospital (POWH), New South Wales. METHODS: Computerized data of 1179 patient years who had a diagnosis of appendicitis and were admitted to the POWH over the preceding 10 years were examined. The outcome measure was appendiceal perforation. Patient variables examined were insurance status, sex, age, and socio-economic status (SES). Three hundred patients over the same period were identified who had an appendicectomy but not appendicitis. Multiple logistic regression and Fisher's exact test were used for statistical analysis. RESULTS: The overall perforation rate in 1179 patients was 17%. The only factor that was related to an increased risk of perforation was age over 50 years (odds ratio (OR) 1.57; 95% confidence interval (CI) 1.04-2.53). Sex, insurance status or SES were not associated with a higher risk of perforation. The overall rate of negative appendicectomy was 20% (300 of 1479 patients), and the rate was higher in the uninsured patients (22 vs 17%, P = 0.014, Fisher's exact test). CONCLUSIONS: Lack of health insurance was not associated with an increased incidence of appendiceal perforation at the POWH. Age over 50 years was identified as the only risk factor for appendiceal perforation. The lower negative appendicectomy rate in the insured group may be because of better diagnostic ability of consultants compared to registrars.

The influence of chylomicron remnants on endothelial cell function in the isolated perfused rat aorta.

A system for the perfusion of the isolated rat aorta which allowed the study of both the uptake of chylomicron remnants by the artery wall and their effects on endothelial function was developed. Perfusion for 2 h with 125I-labelled native or oxidised (by treatment with copper sulphate) chylomicron remnants showed that small amounts became associated with the artery wall (0.111 +/- 0.034 and 0.216 +/- 0.082 ng protein/mg tissue, respectively). Tests on endothelial function were carried out in vessel rings prepared after perfusion of the aortas in the presence or absence of chylomicron remnants for 2 h. After perfusion of the vessels with oxidised chylomicron remnants, the maximum response to phenylephrine (PE) was significantly increased (from 0.34 +/- 0.06 to 0.51 +/- 0.04 g/mg tissue; P < 0.05), while the maximum % relaxation to carbachol (CCh) was significantly decreased (from 91.6 +/- 2.4 to 71.5 +/- 7.2; P < 0.05) and the response to S-nitroso-N-acetylpenicillimine (SNAP) was unaffected. Perfusion with native chylomicron remnants showed a tendency to induce similar effects, although the changes observed did not reach statistical significance. As the lipoproteins were not present in the solution bathing the vessel rings during these tests, these effects can be attributed to perfusion of the aortas with chylomicron remnants, despite only small quantities being associated with the artery wall. The results suggest that oxidised chylomicron remnants influence vascular endothelial function by interfering with the L-arginine-nitric oxide (NO) pathway. The observed potentiation of contraction to PE may be due to inhibition of the basal release of NO or to the release of contractile factors. These findings support a role for dietary lipoproteins in the modulation of endothelial cell function which occurs in the pathogenesis of atherosclerosis.

Effects of chylomicrons and chylomicron remnants on endothelium-dependent relaxation of rat aorta.

The effects of chylomicrons and chylomicron remnants on endothelium-dependent relaxation of rat aorta were studied in vitro. Chylomicrons and chylomicron remnants were prepared in vivo. Aortic rings were incubated with the lipoproteins for 45 min before the vessels were constricted with phenylephrine and concentration relaxation response curves constructed to carbachol, ATP, A23187 and S-nitroso-N-acetylpenicillamine. Maximum % relaxations to carbachol were significantly reduced by both chylomicrons and chylomicron remnants but responses to ATP and S-nitroso-N-acetylpenicillamine were unaffected. In addition, chylomicrons significantly inhibited A23187-induced relaxation, causing an increase in the EC50 value. Chylomicron remnants cause selective inhibition of carbachol-induced relaxation suggesting an action at the receptor or G protein-coupled component of the receptor-mediated activation of the L-arginine-nitric oxide pathway. Chylomicrons appear to be less selective in their inhibition of the endothelium-dependent relaxation. This study demonstrates that lipoprotein particles of dietary origin may cause endothelial cell dysfunction.