Dysfunction In Rat Model Research Articles

Evidence of endothelial dysfunction in a rat model of PCOS: increased constrictor prostaglandin activity, reversible through cox inhibition

To characterize endothelial function in resistance arteries in a novel model of PCOS. Animal model, in vitro studies Female rats were randomized at 3-4 weeks to implantation of a 7.5 mg, 90-day dihydrotestosterone (DHT) pellet (n = 24) or a matched placebo (n = 24) as previously described by Manneras et al, 2007 (a rat model exhibiting both metabolic and ovarian aspects of PCOS). At 15-16 weeks, experiments were performed on isolated mesenteric arteries using a pressurized arteriograph. Endothelial function was assessed by the response (efficacy) of pre-constricted arteries to acetylcholine (ACh) in the absence and presence of inhibitors for COX (indomethacin) and the thromboxane prostanoid receptor antagonist(SQ29,548). Distensibility was assessed by measuring vessel diameter from 3-100mmHg. Serum steroid levels were analyzed by sensitive RIA. Differences between groups were determined by ANOVA. DHT rats cycled irregularly and had significantly reduced efficacy to ACh and reduced distensibility compared to controls. Within DHT animals, maximal dilation correlated negatively to DHT levels (r2 = 0.58), but not to weight. Pre-incubation with either indomethacin or SC29,548 abrogated the dysfunction and restored full efficacy to ACh(p<0.05).Tabled 1ControlPCOSP valueWeight (g)232 ± 6299 ± 7<0.001Blood pressure (mmHg)122/85137/98<0.001Estradiol (pg/ml)4.6 ± 0.53.6 ± 0.60.218DHT (pg/ml)31 ± 3253 ± 17<0.001Mesenteric artery diameter at 50mmHg (μm)227 ± 8212 ± 40.07Efficacy (%maximal dilation)100 ± 0.178 ± 6.0<0.05Distensibility (%)235 ± 33137 ± 10<0.05Values expressed as mean ± SE. Open table in a new tab Values expressed as mean ± SE. Clinically, PCOS is associated with endothelial dysfunction, a pathologic state widely believed to be a hallmark of vascular disease. This is the first report to demonstrate endothelial dysfunction in a hyperandrogenic rat model of PCOS, and to identify the role of vasoconstrictor prostanoids, allowing for more targeted research regarding the development of disease and potential therapeutic interventions.

Protection of cholinergic and antioxidant system contributes to the effect of berberine ameliorating memory dysfunction in rat model of streptozotocin-induced diabetes

Memory impairment induced by streptozotocin in rats is a consequence of changes in CNS that are secondary to chronic hyperglycemia, impaired oxidative stress, cholinergic dysfunction, and changes in glucagon-like peptide (GLP). Treatment with antihyperglycemics, antioxidants, and cholinergic agonists are reported to produce beneficial effect in this model. Berberine, an isoquinoline alkaloid is reported to exhibit anti-diabetic and antioxidant effect, acetylcholinesterase (AChE) inhibitor, and increases GLP release. However, no report is available on influence of berberine on streptozotocin-induced memory impairment. Therefore, we tested its influence against cognitive dysfunction in streptozotocin-induced diabetic rats using Morris water maze paradigm. Lipid peroxidation and glutathione levels as parameters of oxidative stress and choline esterase (ChE) activity as marker of cholinergic function were assessed in the cerebral cortex and hippocampus. Thirty days after diabetes induction rats showed a severe deficit in learning and memory associated with increased lipid peroxidation, decreased reduced glutathione, and elevated ChE activity. In contrast, chronic treatment with berberine (25–100 mg/kg, p.o., twice daily, 30 days) improved cognitive performance, lowered hyperglycemia, oxidative stress, and ChE activity in diabetic rats. In another set of experiment, berberine (100 mg/kg) treatment during training trials also improved learning and memory, lowered hyperglycemia, oxidative stress, and ChE activity. Chronic treatment (30 days) with vitamin C or metformin, and donepezil during training trials also improved diabetes-induced memory impairment and reduced oxidative stress and/or choline esterase activity. In conclusion, the present study demonstrates treatment with berberine prevents the changes in oxidative stress and ChE activity, and consequently memory impairment in diabetic rats.

Hypotensive, Hypolipidemic, and Vascular Protective Effects of Morus alba L. in Rats Fed an Atherogenic Diet

Morus alba L. has been used in traditional Chinese medicine and almost all parts of this plant are useful in cardiovascular, liver and spleen disorders. The present study was designed to investigate the inhibitory effect of a water extract from Morus alba L. (WMA) on vascular dysfunction in rat models fed a high fat and high cholesterol diet. Male rats were fed an atherogenic diet consisting of food with 7.5% cocoa butter and 1.25% cholesterol, with or without 100 or 200 mg/day/kg WMA, for 14 weeks. Chronic treatment with low (100 mg/kg/day) or high (200 mg/day/kg) doses of WMA markedly attenuated hypertension and the impairments of acetylcholine-induced relaxation of aortic rings in rats fed an atherogenic diet. WMA reduced intima/media thickness in rats fed an atherogenic diet. WMA improved plasma levels of triglyceride (TG) and augmented plasma levels of high-density lipoprotein (HDL) and plasma low-density lipoprotein (LDL), but did not affect blood glucose levels. Interestingly, WMA suppressed increased cell adhesion molecules such as E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intracellular adhesion molecule-1 (ICAM-1) expression in the aorta. Taken together, these results suggested that Morus alba L. could improve an atherogenic diet-induced hypertension, hyperlipidemia, and vascular dysfunction through inhibition of cell adhesion molecules expression and induction of vascular relaxation.

Hypotensive, hypolipidemic, and vascular protective effect of Morus alba L. in rats fed a high‐fat diet

Morus alba L. has been used in traditional Chinese medicine and almost all parts of this plant is useful in cardiovascular, liver and spleen disorders. Present study was designed to investigate the inhibitory effect of a water extract from Morus alba L. (WMA) on vascular dysfunction in rat models fed a high‐fat diet. Male rats were fed a high‐fat diet consisting of 60 kcal% fat, with or without 100, 200 mg/day/kg WMA of diet, for 9 weeks. Chronic treatment with low (100 mg/kg/day) or high (200 mg/day/kg) doses of WMA markedly significantly attenuated hypertension and the impairments of acetylcholine‐ and SNP‐induced relaxation of aortic rings in rats fed a high‐fat diet. WMA attenuated plasma levels of triglyceride (TG) and augmented plasma level of high‐density lipoprotein (HDL), whereas, no effects in blood glucose levels and plasma low‐density lipoprotein (LDL) levels in rats fed a high‐fat diet. Interestingly, WMA suppressed increased cell adhesion molecules such as intracellular adhesion molecule‐1 (ICAM‐1), vascular cell adhesion molecule‐1 (VCAM‐1), and E‐selectin expression in aorta. Taken together, these results suggested that Morus alba L. could improve high‐fat diet‐induced hypertension, hyperlipidemia, and vascular dysfunction through inhibition of cell adhesion molecules expression and induction of vascular relaxation.relaxation.

Targeted inhibition of activin receptor-like kinase 5 signaling attenuates cardiac dysfunction following myocardial infarction

Following myocardial infarction (MI), the heart undergoes a pathological process known as remodeling, which in many instances results in cardiac dysfunction and ultimately heart failure and death. Transforming growth factor-beta (TGF-beta) is a key mediator in the pathogenesis of cardiac remodeling following MI. We thus aimed to inhibit TGF-beta signaling using a novel orally active TGF-beta type I receptor [activin receptor-like kinase 5 (ALK5)] inhibitor (GW788388) to attenuate left ventricular remodeling and cardiac dysfunction in a rat model of MI. Sprague-Dawley rats underwent left anterior descending coronary artery ligation to induce experimental MI and then were randomized to receive GW788388 at a dosage of 50 mg.kg(-1).day(-1) or vehicle 1 wk after surgery. After 4 wk of treatment, echocardiography was performed before the rats were euthanized. Animals that received left anterior descending coronary artery ligation demonstrated systolic dysfunction, Smad2 activation, myofibroblasts accumulation, collagen deposition, and myocyte hypertrophy (all P < 0.05). Treatment with GW788388 significantly attenuated systolic dysfunction in the MI animals, together with the attenuation of the activated (phosphorylated) Smad2 (P < 0.01), alpha-smooth muscle actin (P < 0.001), and collagen I (P < 0.05) in the noninfarct zone of MI rats. Cardiomyocyte hypertrophy in MI hearts was also attenuated by ALK5 inhibition (P < 0.05). In brief, treatment with a novel TGF-beta type I receptor inhibitor, GW788388, significantly reduced TGF-beta activity, leading to the attenuation of systolic dysfunction and left ventricular remodeling in an experimental rat model of MI.

Usefulness of Mitral Annulus Velocity for the Early Detection of Left Ventricular Dysfunction in a Rat Model of Diabetic Cardiomyopathy

Diabetic cardiomyopathy (DMCMP) is characterized by myocardial dysfunction regardless of coronary artery disease in diabetic patients. The features of LV dysfunction in rat model of type 1 DM induced by streptozocin, are variable and controversial. Thus, we tested the usefulness of tissue Doppler imaging in the early detection of ventricular dysfunction in a rat model of DMCMP. Diabetes was induced by intra-peritoneal injection of streptozocin (70 mg/kg) in 8 weeks of Sprague-Dawley rat. Diagnosis of diabetes was defined as venous glucose level over 350 mg/dL 48 hrs after streptozocin injection. Echocardiography was done at baseline and 10 weeks after diabetes induction both in diabetes group (n=15) and normal control (n=10). After echocardiography at 10 weeks, invasive hemodynamic measurement using miniaturized conductance catheter was done in both groups. Ten weeks after diabetes induction, heart and lung mass indexes of diabetes were larger than those of normal control (3.2+/-0.3 vs. 2.4+/-0.2 mg/g, p<0.001, 5.5+/-1.1 vs. 3.6+/-0.6 mg/g, p<0.001, respectively). In echocardiographic data, s' (2.4+/-0.4 vs. 3.1+/-0.5 cm/s, p<0.001), e' velocity of mitral annulus (2.9+/-0.6 vs. 3.8+/-1.1 cm/s, p<0.001), and E/e' ratio (27.1+/-5.6 vs. 19.7+/-2.6, p<0.001) were impaired in diabetes group. In hemodynamic measurement, there were no differences in ejection fraction, peak dP/dt between the diabetic group and normal control. However, load independent indexes of contractility, the slope of the end-systolic pressure volume relation (0.18+/-0.07 vs. 0.62+/-0.18 mmHg/microL, p<0.001) and preload recruitable stroke work (51.8+/-22.0 vs. 90.9+/-22.5 mmHg, p<0.001) were impaired in diabetic group compared to normal control. In a rat model of diabetic cardiomyopathy, tissue Doppler imaging of mitral annulus can be a good modality for early detection of myocardial dysfunction.

Zebrafish provide a sensitive model of persisting neurobehavioral effects of developmental chlorpyrifos exposure: Comparison with nicotine and pilocarpine effects and relationship to dopamine deficits

Chlorpyrifos (CPF) an organophosphate pesticide causes persisting behavioral dysfunction in rat models when exposure is during early development. In earlier work zebrafish were used as a complementary model to study mechanisms of CPF-induced neurotoxicity induced during early development. We found that developmental (first five days after fertilization) chlorpyrifos exposure significantly impaired learning in zebrafish. However, this testing was time and labor intensive. In the current study we tested the hypothesis that persisting effects of developmental chlorpyrifos could be detected with a brief automated assessment of startle response and that this behavioral index could be used to help determine the neurobehavioral mechanisms for persisting CPF effects. The swimming activity of adult zebrafish was assessed by a computerized video-tracking device after a sudden tap to the test arena. Ten consecutive trials (1/min) were run to determine startle response and its habituation. Additionally, habituation recovery trials were run at 8, 32 and 128 min after the end of the initial trial set. CPF-exposed fish showed a significantly ( p < 0.025) greater overall startle response during the 10-trial session compared to controls (group sizes: Control N = 40, CPF N = 24). During the initial recovery period (8 min) CPF-exposed fish showed a significantly ( p < 0.01) greater startle response compared to controls. To elucidate the contributions of nicotinic and muscarinic acetylcholine receptors to developmental CPF-mediated effects, the effects of developmental nicotine and pilocarpine exposure throughout the first five days after fertilization were determined. Developmental nicotine and pilocarpine exposure significantly increased startle response, though nicotine (group sizes: Control N = 32, 15 mM N = 12, 25 mM N = 20) was much more potent than pilocarpine (group sizes: Control N = 20, 100 µM N = 16, 1000 µM N = 12). Neither was as potent as CPF for developmental exposure increasing startle response in adulthood. Lastly, developmental CPF exposure decreased dopamine and serotonin levels and increased transmitter turnover in developing zebrafish larvae ( N = 4 batches of 50 embryos/treatment). Only the decline in dopamine concentrations persisted into adulthood (group sizes: Control N = 14, CPF N = 13). This study shows that a quick automated test of startle can detect persisting neurobehavioral impairments caused by developmental exposure to CPF. This may be helpful in screening for persisting neurobehavioral defects from a variety of toxicants.

Prevention of Vasculogenic Erectile Dysfunction in Rat Model by the Chronic Administration of Oral Rho Kinase Inhibitor

Purpose: Since Rho-Rho kinase calcium sensitizing pathway is being regarded as a potential target not only for the treatment of erectile dysfunction but also atherosclerosis, we designed a study to prevent vasculogenic erectile dysfunction in an atherosclerotic rat model by chronic administration of fasudil, oral Rho kinase inhibitor. Materials and Methods: Rats (3 months old) were divided into 3 groups (n=10 in each group): control (group 1), atherosclerosis (group 2), and fasudiltreated (group 3). The group 2, 3 received atherosclerosis-prone treatment but group 3 was concurrently treated by fasudil (30mg/kg/day) for 6 weeks. Following the treatment, the erectile function and the amount of pelvic atherosclerosis amount were determined. Cavernosal tissues were prepared for Western blot and malondialdehyde (MDA) assay. Results: Compared to group 2, the progression of atherosclerosis in iliac and pudendal arteries was significantly suppressed by the chronic administration of fasudil. Also the treatment lowered the level of malondialdehyde in the cavernosal tissue. The results of Western blot revealed that systemically administered fasudil could ameliorate cavernosal molecular environment characterized by the decreased expression of Rho A, transforming growth factor-beta 1 and overexpression of endothelial nitric oxide synthase. As a result, erectile function was maintained by the treatment. Conclusions: These results indicate that Rho/Rho kinase pathway is substantially involved in the development of penile erection and pelvic atherosclerosis, both of which could be prevented by chronic treatment of fasudil. Thus, Rho-kinase might be considered as a novel target for prevention of vasculogenic erectile dysfunction. (Korean J Urol 2006;47:322-330) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ

FK962, a novel enhancer of somatostatin release, exerts cognitive-enhancing actions in rats

FK962 ( N-(1-acetylpiperidin-4-yl)-4-fluorobenzamide) is a derivative of FK960 ( N-(4-acetyl-1-piperazinyl)- p-fluorobenzamide monohydrate), with putative anti-dementia properties. Here, we wanted to determine whether FK962 retained the ability of the parent compound to both facilitate somatostatinergic nerve activity in hippocampal neurons and to ameliorate cognitive dysfunction in rat models. FK962 (10 −9–10 − 6 M) significantly enhanced high K +-evoked somatostatin release from rat hippocampal slices. FK962 also significantly reduced somatostatin-induced inhibition of Ca 2+ channels at 10 − 9 –10 − 7 M in single rat hippocampal neurons using whole-cell patch-clamp. Furthermore, administration of FK962 (0.032–3.2 mg/kg, i.p.) significantly ameliorated memory deficits in passive avoidance task in animal models: scopolamine-treated rats, nucleus basalis magnocellularis-lesioned rats and aged rats. FK962 (0.01–1 mg/kg, i.p.) significantly improved spatial memory deficits induced by nucleus basalis magnocellularis-lesion in water maze task. These results suggest that FK962 ameliorates cognitive impairment in rats via activation of the somatostatinergic nervous system in the hippocampus, indicating that FK962 could be a potent cognitive enhancer and therefore might be of therapeutic value for cognitive disorders such as Alzheimer's disease.