Ram Gupta

TRC4186, a novel AGE-breaker, improves diabetic cardiomyopathy and nephropathy in Ob-ZSF1 model of type 2 diabetes.

Advanced glycation end products (AGEs) contribute significantly to diabetic complications, both macro- and microvascular. TRC4186 is an AGE-breaker that has been evaluated in vitro and in vivo and shown to reduce AGE burden. The aim of this study was to determine the effect of TRC4186 on diabetic cardiomyopathy and nephropathy in obese Zucker spontaneously hypertensive fatty rats (Ob-ZSF1), an animal model of diabetes with progressive cardiac and renal dysfunction. Ob-ZSF1 rats loaded with 0.5% salt were treated with TRC4186, 9 or 27 mg/kg twice daily intraperitoneally or vehicle control and monitored telemetrically throughout the study. Cardiac function was assessed terminally by Millar catheter. Markers of cardiac and renal dysfunction were measured and changes evaluated histopathologically. TRC4186 at 27 mg/kg prevented rise in blood pressure (BP) and also improved cardiac output (CO) secondary to better diastolic relaxation as well as systolic emptying in association with the reduction in afterload. At 9 mg/kg, CO was improved by compensatory increase in pre-load however afterload reduction was not adequate to allow efficient systolic emptying. Brain natriuretic peptide (BNP) and interleukin-6 (IL-6) expression was reduced with treatment. Deterioration in renal function was retarded as evident from albumin to creatinine ratio and renal histopathology. TRC4186, an AGE-breaker, clearly preserved cardiac function and reduced the severity of renal dysfunction in Ob-ZSF1, an animal model with persistent severe hyperglycemia leading to diabetic heart failure and renal failure.

Therapeutic treatment with a novel hypoxia-inducible factor hydroxylase inhibitor (TrC160334) ameliorates murine colitis

Background and aim Mucosal healing in inflammatory bowel disease (IBD) can be achieved by improvement of intestinal barrier protection. Activation of hypoxia-inducible factor (HIF) has been identified as a critical factor for barrier protection during mucosal insult and is linked with improvement in symptoms of colitis. Although prophylactic efficacy of HIF hydroxylase inhibitors in murine colitis have been established, its therapeutic efficacy in clinically relevant therapeutic settings have not been established. In the present study we aim to establish therapeutic efficacy of TRC160334, a novel HIF hydroxylase inhibitor, in animal models of colitis. Methods The efficacy of TRC160334 was evaluated in two different mouse models of colitis by oral route. A prophylactic efficacy study was performed in a 2,4,6-trinitrobenzene sulfonic acid-induced mouse model of colitis representing human Crohn’s disease pathology. Additionally, a therapeutic efficacy study was performed in a dextran sulfate sodium-induced mouse model of colitis, a model simulating human ulcerative colitis. Results TRC160334 treatment resulted in significant improvement in disease end points in both models of colitis. TRC160334 treatment resulted into cytoprotective heatshock protein 70 induction in inflamed colon. TRC160334 successfully attenuated the rate of fall in body weight, disease activity index, and macroscopic and microscopic scores of colonic damage leading to overall improvement in study outcome. Conclusion Our findings are the first to demonstrate that therapeutic intervention with a HIF hydroxylase inhibitor ameliorates IBD in disease models. These findings highlight the potential of TRC160334 for its clinical application in the treatment of IBD.

TRC120038, a Novel Dual AT1/ETA Receptor Blocker for Control of Hypertension, Diabetic Nephropathy, and Cardiomyopathy in ob-ZSF1 Rats

In hypertensive subjects, angiotensin II and endothelin participate in a manner involving closely interwoven pathways in increasing blood pressure (BP) and inducing end organ damage. The primary objective of this study was to determine the effect of TRC120038, a novel dual AT1/ETA receptor blocker on BP, in obese Zucker spontaneously hypertensive fatty rats (ob-ZSF1), an animal model of moderate hypertension, diabetes with progressive renal and cardiac dysfunction. Ob-ZSF1 rats loaded with 0.5% salt were treated with TRC120038 (11.8 mg/kg bid.) or candesartan cilexetil (0.3 mg/kg od.) or vehicle control. Blood pressure (by radio-telemetry) and renal functional markers were monitored throughout the study. Cardiac function was assessed terminally by pressure volume catheter. Markers for renal dysfunction were measured and changes were evaluated histopathologically. TRC120038 showed greater fall in both systolic and diastolic BP in comparison to candesartan at its maximum antihypertensive dose. TRC120038 also reduced the severity of renal dysfunction and preserved cardiac function in ob-ZSF1 rat.

TRC150094 attenuates progression of nontraditional cardiovascular risk factors associated with obesity and type 2 diabetes in obese ZSF1 rats.

Chronic overnutrition and consequential visceral obesity is associated with a cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus. Moreover, individuals who have a triad of hypertension, dysglycemia, and elevated triglycerides along with reduced high-density lipoprotein cholesterol have a greater residual cardiovascular risk even after factoring for the traditional risk factors such as age, smoking, diabetes, and elevated low-density lipoprotein cholesterol. In our previous study we demonstrated that TRC150094, when administered to rats receiving a high-fat diet, stimulated mitochondrial fatty acid oxidation (FAO) and reduced visceral adiposity, opening an interesting perspective for a possible clinical application. In the present study, oral administration of TRC150094 to obese Zucker spontaneously hypertensive fatty rats (obese ZSF1) improved glucose tolerance and glycemic profile as well as attenuated a rise in blood pressure. Obese ZSF1 rats treated with TRC150094 also showed reduced hepatic steatosis, reduced progression of nephropathy, and improved skeletal muscle function. At the cellular level, TRC150094 induced a significant increase in mitochondrial respiration as well as an increased FAO in liver and skeletal muscle, ultimately resulting in reduced hepatic as well as total body fat accumulation, as evaluated by magnetic resonance spectroscopy and magnetic resonance imaging, respectively. If reproduced in humans, these results could confirm that TRC150094 may represent an attractive therapeutic agent to counteract multiple residual cardiovascular risk components.

The Evolving Face of Heart Failure Associated with Elevated Cardio-Metabolic Risk Factors

1.1 Evolving profile of heart failure There have been many definitions of Heart Failure and yet the most recent definitions rely heavily on clinical manifestations: dyspnoea or undue fatigue on exertion, along with the evidence of fluid retention, supported by objective evidence of structural or functional abnormalities of the heart at rest. A more recent classification also recognizes and emphasizes the need for the above signs and symptoms for both the development and progression of heart failure (Dickstein et al., 2008). The 2009 update of the AHA guideline identifies patients at higher risk of developing or progressing more rapidly to heart failure as traditionally defined. Table 1. The presence of cardio-metabolic risk factors (hypertension, diabetes, obesity and metabolic syndrome) in addition to atherosclerotic disease puts the patient at twice greater risk of developing and/or progressing to heart failure as currently defined i.e. with structural or functional heart disease at rest. Studies across the world, particularly in India, China and Latin America suggest that overweight, metabolically challenged individuals are at greater risk of heart failure at a younger age and are also twice as likely to have heart failure linked events such as hospitalization or mortality (Clarke et al., 2010). Echocardiography and Doppler imaging of the heart are the current gold standards for identification of structural and to extent also functional abnormalities. Advances in Echocardiography and Doppler imaging have enabled the identification of an underdiagnosed entity described as diastolic dysfunction, an additional handicap for a failing heart. Prognosis of patients with predominant diastolic dysfunction (Heart Failure with Preserved Ejection Fraction: HFPEF) has been reported to be similar to those who have predominant systolic dysfunction. In some population surveys, up to 50% of patients fall in this category (Paulus, 1998). Many have co-morbidities identified as risk factors in Stage A of the AHA classification. It is therefore pertinent to understand why and how these additional risk factors influence the development and progression of heart failure as different from and often in addition to Atherosclerotic Coronary Artery Disease. Diabetes, hypertension, dyslipidemia and thyroid dysfunction affecting heart are often considered as factors contributing to coronary artery disease. However, there is evidence to

Development and Validation of a Rat Model for Examining the AT1 and ETA Receptor-Blocking Activity of Dual AT1 and ETA Receptor Blockers

AbstractBackground: Hypertension is a multifactorial disease, with angiotensin II (Ang II) as the established target of pharmacological intervention. However, there has been increasing interest in the biological effects of other vasoactive peptides such as endothelin (ET). A separate estimation of activity for the dual angiotensin type-1 (AT1) and endothelin type-A (ETA) receptor blocker mediated through individual AT1 and ETA receptors is important as there is evidence demonstrating an interaction between the renin-angiotensin and ET systems. Objective: An appropriate animal model to separate out and individually measure the AT1 and ETA receptor-blocking activity of the dual-action molecules is required for the screening of therapeutic agents that would target the renin-angiotensin and ET systems together. The objective of this study is to validate such an animal model. Methods: In anesthetized male Sprague Dawley rats, isolation of AT1 receptor-blocking activity was validated with losartan (a selective AT1 receptor blocker) by measuring reversal of the pressor effect of exogenously administered Ang II in the presence of maximal blockade of endogenous ETA receptors. Similarly, measurement of isolated ETA receptor-blocking activity was validated with ZD1611 (selective ETA receptor blocker), by measuring the reversal of exogenously administered big ET-1 pressor response in the presence of maximal blockade of endogenous AT1 receptors. The model was validated finally with BMS346567, a dual AT1 and ETA receptor blocker. Results: A dose-dependent fall in mean blood pressure upon losartan or ZD1611 infusion was observed when endogenous ETA or AT1 receptors were blocked. Similar results were obtained using BMS346567 in both models. Conclusions: A model was developed and validated for screening pharmacological activity of dual AT1 and ETA receptor blockers on each target in isolation without the influence of an interacting pathway.