Pyridoxamine protects against mechanical defects in cardiac ageing in rats: studies on load dependence of myocardial relaxation.

Our team demonstrated in the past that pyridoxamine attenuated arterial stiffening by targeting the pathogenic formation of glycated collagen cross-links in aged rats. Herein, we examined whether pyridoxamine therapy can protect against mechanical defects in myocardial relaxation by improving arterial wave properties and cardiac contractile performance in senescent animals. Fifteen-month-old male Fisher 344 rats were treated daily with pyridoxamine (1 g l(-1) in drinking water) for 5 months and compared with age-matched untreated control animals (20 months old). Arterial wave properties were characterized by wave transit time (τw) and wave reflection factor (Rf). We measured the contractile status of the myocardium in an intact heart as the left ventricular (LV) end-systolic elastance (Ees). Myocardial relaxation was described according to the time constant of the LV isovolumic pressure decay (τe). Pyridoxamine therapy prevented the age-associated prolongation in LV τe and the diminished Ees in senescent rats. The drug also attenuated the age-related augmentation in afterload imposed on the heart, as evidenced by the increased τw and decreased Rf. We found that the LV τe was significantly influenced by both the arterial τw and Rf (τe = 16.3902 + 8.3123 × Rf - 0.4739 × τw; r = 0.7048, P < 0.005). In the meantime, the LV τe and the LV Ees showed a significant inverse linear correlation (τe = 13.9807 - 0.0068 × Ees; r = 0.6451, P < 0.0005). All these findings suggested that long-term treatment with pyridoxamine might ameliorate myocardial relaxation rate, at least partly through its ability to enhance myocardial contractile performance, increase wave transit time and decrease wave reflection factor in aged rats.

Enhanced aortic nerve growth factor expression and nerve sprouting in rats following gastric perforation.

BACKGROUND: Nerve growth factor (NGF) up-regulation during inflammation has been demonstrated to occur in several different tissues. Herein, the expression of aortic nerve growth factor and its association with nerve sprouting in a rodent model of self-limited peritonitis were investigated. MATERIALS AND METHODS: Male Wistar rats were randomized into one of three groups: gastric perforation (GP), sham group, and GP group treated with methylprednisolone (GP-M). Aortic expression of NGF and growth associated protein 43 (GAP43) were evaluated at several different time points (range, 6 h to 2 wk) after GP or sham. RESULTS: Compared with the sham group, expression of NGF was significantly elevated during the inflammatory period (the first week post-GP) in GP rats. The GP group also had enhanced nerve sprouting, which persisted after the peritonitis recovered. Methylprednisolone abrogated NGF up-regulation and nerve sprouting induced by GP. CONCLUSIONS: GP resulted in up-regulation of aortic NGF that coincided with aortic nerve sprouting. Methylprednisolone effectively blocked GP-induced NGF up-regulation. Further studies are necessary to decipher the causality of these observed changes.

Plasma leptin response to oral glucose tolerance and fasting/re-feeding tests in rats with fructose-induced metabolic derangements.

The aim of this study was to compare the postprandial leptin response in rats with and without metabolic syndrome induced by a fructose-enriched diet. The effect of aging and the association between variations in metabolic substrates was also evaluated. Oral glucose tolerance test (OGTT) and fasting/re-feeding test were used to evaluate the responses of leptin and to explore the dynamic relationship between endogenous leptin and metabolic substrates, including glucose, insulin and triglycerides (TG). At the 7th week, plasma leptin was unchanged in control rats after oral glucose loading. However, plasma leptin levels increased in fructose-fed rats with insulin resistant OGTT curves. At the 11th month, plasma leptin level was reduced during starvation and returned to the level prior to starvation during re-feeding in control rats. In contrast, the starvation-induced reduction in leptin showed a potentially larger rebound effect during re-feeding in fructose-fed rats. Analysis of covariance demonstrated that there alone was no interactive effect of dietary manipulation between leptin and TG, suggesting that fructose diet-induced insulin resistance-related metabolic syndrome may concomitantly elevate leptin and TG. Furthermore, multiple regression analysis suggests TG was the primary correlative determinant of endogenous leptin concentration. Our data showed that there are different patterns of leptin response to OGTT and fasting/re-feeding tests in rats with and without metabolic syndrome. The results suggest that these effects may be related to a TG-mediated impairment of leptin function and a protective mechanism to reduce lipid-induced tissue damage in patients with metabolic syndrome.

Methylprednisolone Protects Cardiac Pumping Mechanics from Deteriorating in Lipopolysaccharide-Treated Rats.

It has been shown that a prolonged low-dose corticosteroid treatment attenuates the severity of inflammation and the intensity and duration of organ system failure. In the present study, we determined whether low-dose methylprednisolone (a synthetic glucocorticoid) can protect male Wistar rats against cardiac pumping defects caused by lipopolysaccharide-induced chronic inflammation. For the induction of chronic inflammation, a slow-release ALZET osmotic pump was subcutaneously implanted to infuse lipopolysaccharide (1 mg kg(-1) d(-1)) for 2 weeks. The lipopolysaccharide-challenged rats were treated on a daily basis with intraperitoneal injection of methylprednisolone (5 mg kg(-1) d(-1)) for 2 weeks. Under conditions of anesthesia and open chest, we recorded left ventricular (LV) pressure and ascending aortic flow signals to calculate the maximal systolic elastance (E max) and the theoretical maximum flow (Q max), using the elastance-resistance model. Physically, E max reflects the contractility of the myocardium as an intact heart, whereas Q max has an inverse relationship with the LV internal resistance. Compared with the sham rats, the cardiodynamic condition was characterized by a decline in E max associated with the increased Q max in the lipopolysaccharide-treated rats. Methylprednisolone therapy increased E max, which suggests that the drug may have protected the contractile status from deteriorating in the inflamed heart. By contrast, methylprednisolone therapy considerably reduced Q max, indicating that the drug may have normalized the LV internal resistance. In parallel, the benefits of methylprednisolone on the LV systolic pumping mechanics were associated with the reduced cardiac levels of negative inotropic molecules such as peroxynitrite, malondialdehyde, and high-mobility group box 1 protein. Based on these data, we suggested that low-dose methylprednisolone might prevent lipopolysaccharide-induced decline in cardiac intrinsic contractility and LV internal resistance, possibly through its ability to reduce the aforementioned myocardial depressant substances. However, since our results were obtained in anesthetized open-chest rats, extrapolation to what may occur in conscious intact animals should be done with caution.

Prevention of arterial stiffening by using low-dose atorvastatin in diabetes is associated with decreased malondialdehyde.

INTRODUCTION: Without affecting the lipid profile, a low-dose treatment with atorvastatin contributes to the reduction of oxidative stress, inflammation, and adverse cardiovascular events in diabetes. In this study, we investigated whether low-dose atorvastatin exerts any beneficial effect on vascular dynamics in streptozotocin (STZ)-induced diabetes in male Wistar rats. METHODS: Diabetes was induced using a single tail-vein injection of STZ at 55 mg kg-1. The diabetic rats were treated daily with atorvastatin (10 mg kg-1 by oral gavage) for 6 weeks. They were also compared with untreated age-matched diabetic controls. Arterial wave reflection was derived using the impulse response function of the filtered aortic input impedance spectra. A thiobarbituric acid reactive substances measurement was used to estimate the malondialdehyde content. RESULTS: The high plasma level of total cholesterol in the diabetic rats did not change in response to this low-dose treatment with atorvastatin. Atorvastatin resulted in a significant increase of 15.4% in wave transit time and a decrease of 33.5% in wave reflection factor, suggesting that atorvastatin may attenuate the diabetes-induced deterioration in systolic loads imposed on the heart. This was in parallel with its lowering of malondialdehyde content in plasma and aortic walls in diabetes. Atorvastatin therapy also prevented the diabetes-related cardiac hypertrophy, as evidenced by the diminished ratio of left ventricular weight to body weight. CONCLUSION: These findings indicate that low-dose atorvastatin might protect diabetic vasculature against diabetes-associated deterioration in aorta stiffness and cardiac hypertrophy, possibly through its decrease of lipid oxidation-derived malondialdehyde.

Methylprednisolone stiffens aortas in lipopolysaccharide-induced chronic inflammation in rats.

INTRODUCTION: Glucocorticoids are commonly used as therapeutic agents in many acute and chronic inflammatory and auto-immune diseases. The current study investigated the effects of methylprednisolone (a synthetic glucocorticoid) on aortic distensibility and vascular resistance in lipopolysaccharide-induced chronic inflammation in male Wistar rats. METHODS: Chronic inflammation was induced by implanting a subcutaneous slow-release ALZET osmotic pump (1 mg kg(-1) day(-1) lipopolysaccharide) for either 2 or 4 weeks. Arterial wave transit time (τ) was derived to describe the elastic properties of aortas using the impulse response function of the filtered aortic input impedance spectra. RESULTS: Long-term lipopolysaccharide challenge enhanced the expression of advanced glycation end products (AGEs) in the aortas. Lipopolysaccharide also upregulated the inducible form of nitric oxide synthase to produce high levels of nitric oxide (NO), which resulted in vasodilation, as evidenced by the fall in total peripheral resistance (Rp ). However, lipopolysaccharide challenge did not influence the elastic properties of aortas, as shown by the unaltered τ. The NO-mediated vascular relaxation may counterbalance the AGEs-induced arterial stiffening so that the aortic distensibility remained unaltered. Treating lipopolysaccharide-challenged rats with methylprednisolone prevented peripheral vasodilation because of its ability to increase Rp . However, methylprednisolone produced an increase in aorta stiffness, as manifested by the significant decline in τ. The diminished aortic distensibility by methylprednisolone paralleled a significant reduction in NO plasma levels, in the absence of any significant changes in AGEs content. CONCLUSION: Methylprednisolone stiffens aortas and elastic arteries in lipopolysaccharide-induced chronic inflammation in rats, for NO activity may be dominant as a counteraction of AGEs.

Enhanced expression of cardiac nerve growth factor and nerve sprouting markers in rats following gastric perforation: the association with cardiac sympathovagal balance.

Endotoxemia and/or systemic inflammation may lead to disturbances in the cardiac autonomic nervous system and consequent arrhythmia. The underlying mechanism remains unclear. Therefore, we investigated the expression of nerve growth factor (NGF) and its association with cardiac sympathovagal balance in a rodent model of self-limited peritonitis. Male Wistar rats were randomized into the following groups: normal control, sham, gastric perforation (GP), and GP treated with methylprednisolone. Cardiac expression of NGF, growth-associated protein 43 (GAP43), along with other nerve markers were evaluated at several time points (6 h to 2 weeks) after GP. An autoregressive process was performed on each detrended electrocardiogram to calculate the heart rate power spectrum. Compared with the normal control and sham groups, expression of NGF was significantly elevated for 1 week after GP. We also found the up-regulated GAP43 and tyrosine hydroxylase protein levels in the GP group, which persisted after recovery from peritonitis. Gastric perforation caused a biphasic change in the ratio of low-frequency to high-frequency power (an index of sympathovagal balance), with an initial decrease followed by recovery at 24 h. Increased NGF and cardiac sympathetic marker expression were temporally associated with the restoration of the cardiac sympathovagal balance. Methylprednisolone abrogated the NGF up-regulation induced by GP and delayed the resumption of sympathovagal balance. We conclude that GP resulted in up-regulation of cardiac NGF, GAP43, and tyrosine hydroxylase expression that coincided with recovery of cardiac sympathovagal balance. Moreover, methylprednisolone can effectively block GP-induced NGF up-regulation.