The DOCA-Salt Hypertensive Rat as a Model of Cardiovascular Oxidative and Inflammatory Stress

Iyer, Abishek; Chan, Vincent; Brown, Lindsay

doi:10.2174/157340310793566109

Cited by 77 publications

(57 citation statements)

References 84 publications

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“…22 This knowledge further reinforces the idea that Ang-(1-7) exerts beneficial effects even under conditions that involve complex activation of different signaling pathways.…”

Section: Discussionsupporting

confidence: 70%

Beneficial Effects of Angiotensin-(1–7) Against Deoxycorticosterone Acetate–Induced Diastolic Dysfunction Occur Independently of Changes in Blood Pressure

et al. 2015

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Abstract-Mineralocorticoids have been implicated in the pathogenesis of diastolic heart failure. On the contrary, angiotensin (Ang)-(1-7) has emerged as a potential strategy for treatment of cardiac dysfunction induced by excessive mineralocorticoid receptor activation. A critical question about the cardioprotective effect of Ang-(1-7) in hypertensive models is its dependence on blood pressure (BP) reduction. Here, we addressed this question by investigating the mechanisms involved in Ang-(1-7) cardioprotection against mineralocorticoid receptor activation. Sprague-Dawley (SD) and transgenic (TG) rats that overexpress an Ang-(1-7) producing fusion protein (TG(A1-7)3292) were treated with deoxycorticosterone acetate (DOCA) for 6 weeks. After treatment, SD rats became hypertensive and developed ventricular hypertrophy. These parameters were attenuated in TG-DOCA. SD-DOCA rats developed diastolic dysfunction which was associated at the cellular level with reduced Ca 2+ transient. Oppositely, TG-DOCA myocytes presented enhanced Ca 2+ transient. Moreover, higher extracellular signal-regulated kinase phosphorylation, type 1 phosphatase, and protein kinase Cα levels were found in SD-DOCA cells. In vivo, pressor effects of DOCA can contribute to the diastolic dysfunction, raising the question of whether protection in TG was a consequence of reduced BP. To address this issue, BP in SD-DOCA was kept at TG-DOCA level by giving hydralazine or by reducing the DOCA amount given to rats (Low-DOCA). Under similar BP, diastolic dysfunction and molecular changes were still evident in DOCA-hydralazine and SD-low-DOCA, but not in TG-DOCA. In conclusion, Ang-(1-7) protective signaling against DOCA-induced diastolic dysfunction occurs independently of BP attenuation and is mediated by the activation of pathways involved in Ca 2+ handling, hypertrophy, and survival.

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“…22 This knowledge further reinforces the idea that Ang-(1-7) exerts beneficial effects even under conditions that involve complex activation of different signaling pathways.…”

Section: Discussionsupporting

confidence: 70%

Beneficial Effects of Angiotensin-(1–7) Against Deoxycorticosterone Acetate–Induced Diastolic Dysfunction Occur Independently of Changes in Blood Pressure

et al. 2015

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“…The DOCA-salt hypertensive rat model is the model of cardiovascular oxidative and inflammatory stress. 49 The natural compounds that are able to lower the concentration of reactive free radical species can effectively restrain inflammation in the cardiovascular system in DOCA-salt hypertension model. The production of reactive oxygen species (oxidative stress) is the important etiological factor in the development of various diseases including hypertension.…”

Section: Discussionmentioning

confidence: 99%

Flax lignan concentrate reverses alterations in blood pressure, left ventricular functions, lipid profile and antioxidant status in DOCA-salt induced renal hypertension in rats

Sawant

Bodhankar

2016

Renal Failure

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Context Earlier we reported cardioprotective, antihyperlipidemic, and in vitro antioxidant activity of flax lignan concentrate (FLC) obtained from the seeds of Linum usitatissimum L. (Linaceae). Objective To investigate the effect of FLC in deoxycorticosterone acetate (DOCA)-salt induced experimental renal hypertension in rats. Materials and methods Hypertension was induced in uninephrectomized (UNTZD) male Wistar rats (230-280 g) by injecting DOCA (25 mg/kg, subcutaneously, twice weekly) and supplementing 1% NaCl in drinking water for 5 weeks. The rats were divided in six groups. Captopril (30 mg/kg, p.o.) and FLC (200, 400 and 800 mg/kg, p.o.) were administered daily to the rats of groups III-VI, respectively, for 5 weeks. Various hemodynamic and biochemical parameters were investigated as well as histology of kidney and heart were carried out. Results In this study, the FLC (400 and 800 mg/kg) significantly (p50.01, p50.001) decreased the systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure. It also significantly (p50.01, p50.001) decreased elevated end diastolic pressure (EDP), dP/dt max and dP/dt min, organs weights (kidney and heart) and activities of hepatic, renal and cardiac marker enzymes in the serum. Furthermore, FLC (400 and 800 mg/kg) significantly (p50.01, p50.001) restored altered antioxidant status, serum electrolyte level, lipid profile values, and histological abnormalities. Captopril (30 mg/kg) showed maximum antihypertensive effect but low dose of FLC (200 mg/kg) was not enough to show the antihypertensive activity. Conclusion FLC possessed antihypertensive effect via modulation of endogenous enzymes in DOCA-salt induced renal hypertension in rats.ARTICLE HISTORY

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“…In parallel, these models have developed to a point where they can provide a framework for simulating human physiology with a stronger link to clinical data (Ten Tusscher Iyer et al 2010;Niederer et al 2011;Smith et al 2011;O'Hara & Rudy, 2012). However, due to the inherent practical and ethical limitations on access to human tissue, the data for fitting the parameters for human models are routinely augmented using animal measurements.…”

Section: Discussionmentioning

confidence: 99%

Quantifying inter‐species differences in contractile function through biophysical modelling

Tøndel

Land

Niederer

et al. 2015

The Journal of Physiology

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Key pointsr To facilitate translation of data from animal models into clinical applications, it is important to analyse and quantify the differences and relevance of specific physiological mechanisms between species.r We propose a novel approach for the quantification of inter-species differences in terms of biophysical model parameters and apply this to elucidate the differences in cardiac contraction mechanisms between mouse, rat and human.r Our results indicate that the parameters related to the sensitivity and cooperativity of calcium binding to troponin C and the activation and relaxation rates of tropomyosin/crossbridge binding kinetics differ most significantly between mouse, rat and human.r Our results predict crossbridge binding to be slowest in human and fastest in mouse.Abstract Animal models and measurements are frequently used to guide and evaluate clinical interventions. In this context, knowledge of inter-species differences in physiology is crucial for understanding the limitations and relevance of animal experimental assays for informing clinical applications. Extensive effort has been put into studying the structure and function of cardiac contractile proteins and how differences in these translate into the functional properties of muscles. However, integrating this knowledge into a quantitative description, formalising and highlighting inter-species differences both in the kinetics and in the regulation of physiological mechanisms, remains challenging. In this study we propose and apply a novel approach for the quantification of inter-species differences between mouse, rat and human. Assuming conservation of the fundamental physiological mechanisms underpinning contraction, biophysically based computational models are fitted to simulate experimentally recorded phenotypes from multiple species. The phenotypic differences between species are then succinctly quantified as differences in the biophysical model parameter values. This provides the potential of quantitatively establishing the human relevance of both animal-based experimental and computational models for application in a clinical context. Our results indicate that the parameters related to the sensitivity and cooperativity of calcium binding to troponin C and the activation and relaxation rates of tropomyosin/crossbridge binding kinetics differ most significantly between mouse, rat and human, while for example the reference tension, as expected, shows only minor differences between the species. Hence, while confirming expected inter-species differences in calcium sensitivity due to large differences in the observed calcium transients, our results also indicate more unexpected differences in the cooperativity mechanism. Specifically, the decrease in the unbinding rate of calcium to troponin C with increasing active tension was much lower for mouse than for rat and human. Our results also predicted crossbridge binding to be slowest in human and fastest in mouse.

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The DOCA-Salt Hypertensive Rat as a Model of Cardiovascular Oxidative and Inflammatory Stress

Cited by 77 publications

References 84 publications

Beneficial Effects of Angiotensin-(1–7) Against Deoxycorticosterone Acetate–Induced Diastolic Dysfunction Occur Independently of Changes in Blood Pressure

Beneficial Effects of Angiotensin-(1–7) Against Deoxycorticosterone Acetate–Induced Diastolic Dysfunction Occur Independently of Changes in Blood Pressure

Flax lignan concentrate reverses alterations in blood pressure, left ventricular functions, lipid profile and antioxidant status in DOCA-salt induced renal hypertension in rats

Quantifying inter‐species differences in contractile function through biophysical modelling

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