Assessing the impact of mining on cyclic and linear methylsiloxane distribution in Tibetan soils: Source contribution and transport pattern.

The pervasive presence of methylsiloxanes (MSs), comprising linear and cyclic congeners, in the environment poses significant ecological risks, yet the understanding of their transport mechanisms and deposition patterns remains limited. This study analyzed the concentrations of 12 linear-MSs (L3-L14) and 7 cyclic-MSs (D3-D9) in 29 surface soil samples collected across varying altitudes (3726 to 4863 m) near the Jiama mining sector in Tibet, aiming to investigate the distribution and transport dynamics of MSs from the emission source. The distribution of total MS concentration (ranging from 50.1 to 593 ng/g) showed a remarkable correlation with proximity to the mining site, suggesting the emergent source of mining activities for the MSs in the remote environment of the Tibetan Plateau. Employing the innovative model of robust absolute principal component scores-robust geographically weighted regression (RAPCS-RGWR), the analysis predicted that the mining operations contributing 57.1 % of the total soil MSs, would significantly surpass contributions from traffic emissions (14.7 %), residential activities (13.2 %), and the environmental factor of total organic matter content (14.9 %). The Boltzmann equation effectively modeled the distribution pattern of soil MSs, highlighting atmospheric transport and gravitational settling as key distribution mechanisms. However, linear-MSs exhibited longer transport distances than cyclic-MSs and were more profoundly affected by prevailing wind directions, suggesting their differential environmental behaviors and risks. Our study underscored that the mining sector possibly emerged as a significant source of Tibetan MSs, and provided insights into the transport and fate of MSs in remote, high-altitude environments. The findings emphasize the need for targeted pollution control strategies to mitigate the environmental footprint of mining activities in Tibet and similar regions.

Apigenin targets fetuin-A to ameliorate obesity-induced insulin resistance.

Fetuin-A, a hepatokine secreted by hepatocytes, binds to insulin receptors and consequently impairs the activation of the insulin signaling pathway, leading to insulin resistance. Apigenin, a flavonoid isolated from plants, has beneficial effects on insulin resistance; however, its regulatory mechanisms are not fully understood. In the present study, we investigated the molecular mechanisms underlying the protective effects of apigenin on insulin resistance. In Huh7 cells, treatment with apigenin decreased the mRNA expression of fetuin-A by decreasing reactive oxygen species-mediated casein kinase 2α (CK2α)-nuclear factor kappa-light-chain-enhancer of activated B activation; besides, apigenin decreased the levels of CK2α-dependent fetuin-A phosphorylation and thus promoted fetuin-A degradation through the autophagic pathway, resulting in a decrease in the protein levels of fetuin-A. Moreover, apigenin prevented the formation of the fetuin-A-insulin receptor (IR) complex and thereby rescued the PA-induced impairment of the insulin signaling pathway, as evidenced by increased phosphorylation of IR substrate-1 and Akt, and translocation of glucose transporter 2 from the cytosol to the plasma membrane. Similar results were observed in the liver of HFD-fed mice treated with apigenin. Collectively, our findings revealed that apigenin ameliorates obesity-induced insulin resistance in the liver by targeting fetuin-A.

Selective brain perfusion improves the neurological outcomes after extracorporeal cardiopulmonary resuscitation in a rat model.

BACKGROUND: The major concern in patients who have suffered from cardiac arrest (CA) and undergone successful extracorporeal cardiopulmonary resuscitation (E-CPR) is poor neurological outcomes. In this study, we aimed to introduce a rat model of selective brain perfusion (SBP) during E-CPR to improve the neurological outcome after CA. METHODS: The rats underwent 7 min of untreated asphyxial CA and then were resuscitated with E-CPR for 30 min. The right external jugular vein and right femoral artery were separately cannulated to the E-CPR outflow and inflow. The right common carotid artery was cannulated from the proximal to the distal side for SBP. Subsequently, rats were removed from E-CPR, wounds were closed, and 90 min of intensive care were provided. Neurological deficit scores were tested after 4 h of recovery when the rats were mechanical ventilation-free. S100 calcium-binding protein B (S100B) and glial fibrillary acidic protein (GFAP) were detected through immunohistochemistry (IHC) of brain tissue. RESULTS: The rats that received SBP while resuscitated by E-CPR showed markedly better neurological performances after 4-h recovery than those resuscitated by E-CPR only. The IHC staining of GFAP and S100B in the hippocampus was low in the rats receiving SBP during E-CPR, but only GFAP showed significant differences. CONCLUSIONS: We successfully developed a novel and reproducible rat model of SBP while resuscitated by E-CPR to ameliorate the neurological performances after CA. This achievement might have opportunities for studying how to improve the neurological outcome in the clinical condition.

Advances in the molecular mechanisms of statins in regulating endothelial nitric oxide bioavailability: Interlocking biology between eNOS activity and L-arginine metabolism.

Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A, are widely used to treat hypercholesterolemia. In addition, statins have been suggested to reduce the risk of cardiovascular events owing to their pleiotropic effects on the vascular system, including vasodilation, anti-inflammation, anti-coagulation, anti-oxidation, and inhibition of vascular smooth muscle cell proliferation. The major beneficial effect of statins in maintaining vascular homeostasis is the induction of nitric oxide (NO) bioavailability by activating endothelial NO synthase (eNOS) in endothelial cells. The mechanisms underlying the increased NO bioavailability and eNOS activation by statins have been well-established in various fields, including transcriptional and post-transcriptional regulation, kinase-dependent phosphorylation and protein-protein interactions. However, the mechanism by which statins affect the metabolism of L-arginine, a precursor of NO biosynthesis, has rarely been discussed. Autophagy, which is crucial for energy homeostasis, regulates endothelial functions, including NO production and angiogenesis, and is a potential therapeutic target for cardiovascular diseases. In this review, in addition to summarizing the molecular mechanisms underlying increased NO bioavailability and eNOS activation by statins, we also discuss the effects of statins on the metabolism of L-arginine.

Aged polycyclic aromatic hydrocarbons as stratigraphic marker in the Anthropocene: Evidence from Tibetan Lake sediments.

Polycyclic aromatic hydrocarbons (PAHs) were supposed to serve as combustion marker reflecting the past energy use, but it was unclear whether their sediment records in the Anthropocene were "weathered" due to aging-induced formation of bound residues. In this study, the total concentration of PAHs (the sum of rapid desorption, slow desorption, and bound residue fractions) were determined in four dated sediment cores from eastern to central Tibet using multi-step sequential extraction method. The total 16 PAH concentrations were 11.8, 13.5, 18.9, and 29.4 ng/g dw (in average) in the Co Ngoin, Pung Co, Ahung Co, and Putok lakes, respectively. The stratigraphic records and estimated source contributions of PAHs in different areas of Tibet exhibited a coherent change in the mid-20th century in response to the Holocene-Anthropocene transition. The sediment PAHs also displayed a comparable pattern when the bound residue fraction was not accounted for, suggesting their effective retainability under natural aging conditions. This may be elucidated by the enduring forward and back conversions between slow desorption and bound residue fractions, which manifested similar time-dependent variations across PAH congeners. The distinct conversion tendencies of different congeners were predicted by the binding affinity of congeners to surface/inner regions of organic matter using molecular docking simulations. Our findings demonstrate the persistence of sediment PAH records under natural aging and validate the use of PAH documentary evidence for investigating the Anthropocene.

Primary emissions or environmental persistence contribute to the present DDTs: Evidence from sediment records in Tibetan lakes.

Dichlorodiphenyltrichloroethane (DDT) compounds are still circulating the global environment even though the technical DDT has been restricted in agriculture since the last century. The persistent presence of DDTs worldwide remains uncertain, as it is unclear whether their existence is primarily due to ongoing use or the prolonged persistence in soils and sediments that result in continuous reemission into the atmosphere. The present study applied a sequential extraction procedure to determine the DDT concentrations in rapid desorption, slow desorption, and bound residue fractions in the dated sediment cores from distinct regions of Tibet. The temporal variation of total DDTs (sum of three fractions) in sediments from southern and eastern Tibet respectively revealed the different DDT usage histories in India and China mainland. Nevertheless, the current application volumes of DDT-containing products in these regions were found to decrease significantly. The reversible transformations among three fractions of DDTs with aging time was observed along sediment profile, including the back conversion from bound residue. This process may be the key driver to prolong the half-life of sediment p,p'-DDT, resulting in the persistence of secondary sources of this persistent organic pollutant in the global environment for a longer duration than previously expected.

Aging affects isomer-specific occurrence of dechlorane plus in soil profiles: A case study in a geographically isolated landfill from the Tibetan Plateau.

Two major structural isomers in commercial dechlorane plus (DP) mixtures, anti-DP and syn-DP, generally displayed varied desorption and partitioning efficiencies in soils, which may be linked to their different aging rates. However, the molecular parameters that govern the degree of aging and its associated effects on the occurrence of DP isomers have not been comprehensively investigated. In this study, the relative abundance of rapid desorption concentration (Rrapid) was measured for anti-DP, syn-DP, anti-Cl11-DP, anti-Cl10-DP, Dechlorane-604 (Dec-604), and Dechlorane-602 (Dec-602) at a geographically isolated landfill area in the Tibetan Plateau. The Rrapid values were used as an indicator of aging degree, exhibiting a close correlation with the three-dimension conformation of the molecules for the dechlorane series compounds. This observation suggested that planar molecules may have a greater tendency to accumulate in the condensed phase of organic matter and undergo more rapid aging. The fractional abundances and dechlorinated products of anti-DP were found to be predominantly controlled by the aging degree of DP isomers. The multiple nonlinear regression model indicated that differences in aging between anti-CP and syn-DP were primarily driven by the total desorption concentration and soil organic matter content. Aging plays a significant role in both the transport processes and metabolism of DP isomers and should be taken into account to refine the assessment of their environmental behaviors.

Extracorporeal Life Support Enhances the Forward Pressure Wave to Cause a Mismatch between Cardiac Oxygen Demand and Supply.

Extracorporeal life support (ECLS) is a world-famous life-saving method. Until now, changes in arterial wave properties due to ECLS have remained unexamined. In this study, we determined the effects of ECLS on arterial wave properties and ventricular/arterial coupling in male Wistar rats with the measured aortic pressure alone. Ascending aortic pressure signals were measured before ECLS and at 30, 60, and 90 min after weaned off. The aortic pressure signal then calculated by fourth-order derivative to obtain an assumed triangular flow wave. The ratio of mean systolic pressure to mean diastolic pressure (Pms/Pmd), a parameter for evaluating the matching condition between myocardial oxygen demand and supply, was significantly higher after ECLS. The magnitude of forward pressure (|Pf|) augmented by ECLS prevailed over the backward pressure (|Pb|), leading to a decline in wave reflection factor. Pms/Pmd was positively linearly correlated with |Pf| (Pms/Pmd = 0.9177 + 0.0078 × |Pf|, r = 0.8677; P < 0.0001). These findings suggest that |Pf| was a predominant factor responsible for the mismatch between the myocardial oxygen demand and supply in rats after ECLS phase of experiment.

Quantification of cardiac pumping mechanics in rats by using the elastance-resistance model based solely on the measured left ventricular pressure and cardiac output.

The cardiac pumping mechanics can be characterized by both the maximal systolic elastance (Emax) and theoretical maximum flow (Qmax), which are generated using an elastance-resistance model. The signals required to fit the elastance-resistance model are the simultaneously recorded left ventricular (LV) pressure and aortic flow (Qm), followed by the isovolumic LV pressure. In this study, we evaluated a single-beat estimation technique for determining the Emax and Qmax by using the elastance-resistance model based solely on the measured LV pressure and cardiac output. The isovolumic LV pressure was estimated from the measured LV pressure by using a non-linear least-squares approximation technique. The measured Qm was approximated by an unknown triangular flow (Qtri), which was generated by using a fourth-order derivative of the LV pressure. The Qtri scale was calibrated using the cardiac output. Values of EmaxtriQ and QmaxtriQ obtained using Qtri were compared with those of EmaxmQ and QmaxmQ obtained from the measured Qm. Healthy rats and rats with chronic kidney disease or diabetes mellitus were examined. We found that the LV Emax and Qmax can be approximately calculated using the assumed Qtri, and they strongly correlated with the corresponding values derived from Qm (P < 0.0001; n = 78): EmaxtriQ = 51.9133 + 0.8992 × EmaxmQ (r2 = 0.8257; P < 0.0001); QmaxtriQ = 2.4053 + 0.9767 × QmaxmQ (r2 = 0.7798; P < 0.0001). Our findings suggest that the proposed technique can be a useful tool for determining Emax and Qmax by using a single LV pressure pulse together with cardiac output.

Quantification of contractile mechanics in the rat heart from ventricular pressure alone.

To quantitate the contractile mechanics of the heart, the ventricle is considered an elastic chamber with known end-systolic elastance (Ees ). Ees can be calculated from a single pressure-ejected volume curve, which requires simultaneous records of left ventricular (LV) pressure and the aortic flow (Qm). In clinical settings, it is helpful to evaluate patients' cardiac contractile status by using a minimally invasive approach to physiological signal monitoring, wherever possible, such as by using LV pressure alone. In this study, we evaluated a method for determining Ees on the basis of the measured LV pressure and an assumed aortic flow with a triangular wave shape (Qtri). Qtri was derived using a fourth-order derivative of the LV pressure to approximate its corresponding Qm. Values of EestriQ obtained using Qtri were compared with those of EesmQ obtained from the measured Qm. Healthy rats (NC; n = 28) and rats with type 1 diabetes (DM; n = 26) and chronic kidney disease (CKD; n = 20) were examined. The cardiodynamic conditions in both the DM and CKD groups were characterized by a decline in EesmQ and EestriQ. A significant regression line for Ees was observed (P < 0.0001): EestriQ = 2.6214 + 1.0209 × EesmQ (r2 = 0.9870; n = 74). Our finding indicates that the systolic pumping mechanics of the heart can be derived from a single LV pressure recording together with the assumed Qtri.

Defects in Vascular Mechanics Due to Aging in Rats: Studies on Arterial Wave Properties from a Single Aortic Pressure Pulse.

Changes in vascular mechanics due to aging include elevated vascular impedance, diminished aorta distensibility, and an accelerated return of pulse wave reflection, which may increase the systolic workload on the heart. Classically, the accurate measurement of vascular mechanics requires the simultaneous recording of aortic pressure and flow signals. In practice, it is feasible to estimate arterial wave properties in terms of wave transit time (τw) and wave reflection index (RI) by using aortic pressure signal alone. In this study, we determined the τ w and magnitudes of the forward (∣Pf ∣) and backward (∣Pb ∣) pressure waves in Long-Evans male rats aged 4 (n = 14), 6 (n = 17), 12 (n = 17), and 18 (n = 24) months, based on the measured aortic pressure and an assumed triangular flow (Qtri). The pulsatile pressure wave was the only signal recorded in the ascending aorta by using a high-fidelity pressure sensor. The base of the unknown Qtri was constructed using a duration, which equals to the ejection time. The timing at the peak of the triangle was derived using the fourth-order derivative of the aortic pressure waveform. In the 18-month-old rats, the ratio of τ w to left ventricular ejection time (LVET) decreased, indicating a decline in the distensibility of the aorta. The increased ∣Pb ∣ associated with unaltered ∣Pf ∣ enhanced the RI in the older rats. The augmentation index (AI) also increased significantly with age. A significant negative correlation between the AI and τ w /LVET was observed: AI = -0.7424 - 0.9026 × (τ w /LVET) (r = 0.4901; P < 0.0001). By contrast, RI was positively linearly correlated with the AI as follows: AI = -0.4844 + 2.3634 × RI (r = 0.8423; P < 0.0001). Both the decreased τ w /LVET and increased RI suggested that the aging process may increase the AI, thereby increasing the systolic hydraulic load on the heart. The novelty of the study is that Qtri is constructed using the measured aortic pressure wave to approximate its corresponding flow signal, and that calibration of Qtri is not essential in the analysis.

Investigation of the pathophysiology of cardiopulmonary bypass using rodent extracorporeal life support model.

BACKGROUND: Extracorporeal life support (ECLS) systems are life-saving devices used for treating patients with severe cardiopulmonary failure. In this study, we implemented a rat model of ECLS without the administration of inotropes or vasopressors. METHODS: The rats underwent 5 min of untreated asphyxial cardiac arrest and were resuscitated by ECLS for 30 min. The right external jugular vein and right femoral artery were separately cannulated to the ECLS outflow and inflow, respectively. Thereafter, ECLS was terminated, wounds were closed, and mechanical ventilation was provided for another 90 min. Subsequently, blood gas and hemodynamic analyses were performed. The plasma levels of C-reactive protein (CRP), interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha (TNF-α) were measured 120 min after reperfusion. RESULTS: The metabolic rate of lactate in the group of asphyxial cardiac arrest rescued by ECLS was slow; therefore, the pH at 120 min after reperfusion was significantly lower in this group than that in the group of normal rats treated with ECLS. The hemodynamic data showed no between-group differences. The plasma levels of CRP, IL-6, IL-10, and TNF-α increased after ECLS treatment. CONCLUSIONS: We successfully established a rodent ECLS model, which might be a useful approach for studying the pathophysiology induced by ECLS under clinical conditions.

Determining arterial wave transit time from a single aortic pressure pulse in rats: vascular impulse response analysis.

Arterial wave transit time (τw) in the lower body circulation is an effective biomarker of cardiovascular risk that substantially affects systolic workload imposed on the heart. This study evaluated a method for determining τw from the vascular impulse response on the basis of the measured aortic pressure and an assumed triangular flow (Qtri). The base of the unknown Qtri was constructed with a duration set equal to ejection time. The timing of the peak triangle was derived using a fourth-order derivative of the pressure waveform. Values of τws obtained using Qtri were compared with those obtained from the measure aortic flow wave (Qm). Healthy rats (n = 27), rats with chronic kidney disease (CKD; n = 22), and rats with type 1 (n = 22) or type 2 (n = 11) diabetes were analyzed. The cardiovascular conditions in the CKD rats and both diabetic groups were characterized by a decrease in τws. The following significant relation was observed (P < 0.0001): τwtriQ = -1.5709 + 1.0604 × τwmQ (r2 = 0.9641). Our finding indicates that aortic impulse response can be an effective method for the estimation of arterial τw by using a single pressure recording together with the assumed Qtri.

Systolic aortic pressure-time area is a useful index describing arterial wave properties in rats with diabetes.

The accurate measurement of arterial wave properties in terms of arterial wave transit time (τw) and wave reflection factor (Rf) requires simultaneous records of aortic pressure and flow signals. However, in clinical practice, it will be helpful to describe the pulsatile ventricular afterload using less-invasive parameters if possible. We investigated the possibility of systolic aortic pressure-time area (PTAs), calculated from the measured aortic pressure alone, acting as systolic workload imposed on the rat diabetic heart. Arterial wave reflections were derived using the impulse response function of the filtered aortic input impedance spectra. The cardiovascular condition in the rats with either type 1 or type 2 diabetes was characterized by (1) an elevation in PTAs; and (2) an increase in Rf and decrease in τw. We found that an inverse linear correlation between PTAs and arterial τw reached significance (τw = 38.5462 - 0.0022 × PTAs; r = 0.7708, P < 0.0001). By contrast, as the PTAs increased, the reflection intensity increased: Rf = -0.5439 + 0.0002 × PTAs; r = 0.8701; P <0 .0001. All these findings suggested that as diabetes stiffened aortas, the augmented aortic PTAs might act as a useful index describing the diabetes-related deterioration in systolic ventricular workload.

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.

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.

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.

Acetyl-l-carnitine and oxfenicine on cardiac pumping mechanics in streptozotocin-induced diabetes in male Wistar rats.

INTRODUCTION: In the treatment of patients with diabetes, one objective is an improvement of cardiac metabolism to alleviate the left ventricular (LV) function. For this study, we compared the effects of acetyl-l-carnitine (one of the carnitine derivatives) and of oxfenicine (a carnitine palmitoyltransferase-1 inhibitor) on cardiac pumping mechanics in streptozotocin-induced diabetes in male Wistar rats, with a particular focus on the pressure-flow-volume relationship. METHODS: Diabetes was induced by a single tail vein injection of 55 mg kg(-1) streptozotocin. The diabetic animals were treated on a daily basis with either acetyl-L-carnitine (1 g L(-1) in drinking water) or oxfenicine (150 mg kg(-1) by oral gavage) for 8 wk. They were also compared with untreated age-matched diabetic controls. LV pressure and ascending aortic flow signals were recorded to calculate the maximal systolic elastance (E max) and the theoretical maximum flow (Q max). 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. RESULTS: When comparing the diabetic rats with their age-matched controls, the cardiodynamic condition was characterized by a decline in E max associated with the unaltered Q max. Acetyl-l-carnitine (but not oxfenicine) had reduced cardiac levels of malondialdehyde in these insulin-deficient animals. However, treating with acetyl-l-carnitine or oxfenicine resulted in an increase in E max, which suggests that these 2 drugs may protect the contractile status from deteriorating in the diabetic heart. By contrast, Q max showed a significant fall after administration of oxfenicine, but not with acetyl-L-carnitine. The decrease in Q max corresponded to an increase in total vascular resistance when treated with oxfenicine. CONCLUSIONS: Acetyl-l-carnitine, but not oxfencine, optimizes the integrative nature of cardiac pumping mechanics by preventing the diabetes-induced deterioration in myocardial intrinsic contractility associated with unaltered LV internal resistance.

Early return of augmented wave reflection impairs left ventricular relaxation in aged Fisher 344 rats.

Left ventricular (LV) relaxation is influenced by vascular loads imposed on the heart. The current study investigated the influence of the timing and magnitude of arterial wave reflection on LV isovolumic pressure relaxation, with a specific focus on the aging process. Fisher 344 rats aged 6, 18, and 24 months were anesthetized and thoracotomized. Arterial wave reflection was characterized by wave transit time (τ(w)) and wave reflection factor (R(f)) using the impulse response of the filtered aortic input impedance spectra. Indices of LV pressure relaxation included peak -dP(LV)/dt and the isovolumic relaxation time constant (τ(e)). The vascular dynamic condition in the rats was characterized by (1) a progressive increase in R(f) and decrease in τ(w) associated with age, especially at 24 months; and (2) a decline in aortic compliance (C(m)). Changes in LV relaxation consisted of a fall in peak -dP(LV)/dt and a rise in LV τ(e) with age. Taking LV τ(e) as the dependent variable and arterial R(f) and τ(w) as the two independent variables, multiple linear regression was employed to fit the data. The correlation among the three parameters reached significance (τ(e) =11.885+5.350×R(f)-0.213×τ(w); r=0.5823, p<0.05). This finding indicated that as arterial τ(w) shortened and arterial R(f) was augmented with age, LV τ(e) became more prolonged and late pressure relaxation slowed. Thus, the heavy reflection intensity with early return of the pulse wave reflection might account for the age-related deterioration in LV isovolumic pressure decay.

Development of in situ thermosensitive drug vehicles for glaucoma therapy.

The goal of this research was to design thermosensitive drug vehicles for glaucoma therapy. Thermosensitive ophthalmic drop was prepared by mixing linear poly(N-isopropylacrylamide-g-2-hydroxyethyl methacrylate) (PNIPAAm-g-PHEMA), PNIPAAm-g-PHEMA gel particles and antiglaucoma drug. This produced polymeric eyedrop containing the drug epinephrine was a clear solution at room temperature which became a soft film after contacting the surface of cornea. The drug entrapped within the tangled polymer chains was therefore released progressively after topical application. Evaluation of the drug release responded as a function of crosslinking density and PHEMA macromer contents. The in vivo studies indicated that the intraocular pressure (IOP)-lowering effect for a polymeric eyedrop lasted for 26 h, which is significantly better than the effect of traditional eyedrop (8 h). Hence our investigations successfully prove that the thermosensitive polymeric eyedrop with ability of controlled drug release exhibits a greater potential for glaucoma therapy.