A New Animal Model to Study Endogenous Cardiotonic Steroids and the Progression of Cardiovascular Events in Salt-Sensitive Hypertension

Abstract

The Dahl salt-sensitive rat is a well-established model to study essential hypertension. We first described a subgroup of these rats based on the unique response pattern in systolic blood pressure during the first weeks of exposure to a high salt diet that included cataract formation. We classified this group as cataract-prone Dahl salt-sensitive rat. We also were able to predict and prevent cataract formation in these rats. Further studies showed an inhibition of lens Na, KATPase activity which may be in part responsible for the cataract formation. Other studies in Dahl salt-sensitive rats maintained on a high salt diet have also shown decreased Na, K-ATPase activity in several tissues and increased levels of endogenous circulating Na, K pump inhibitors. For over 20 years, endogenous cardiotonic steroids have been postulated to inhibit Na, K-ATPase in both humans as well as in experimental animal models of hypertension. Recent findings have shown results suggesting that there are several forms of cardiotonic steroids with minor differences in structural functionalities, site of production, and specific pump selectivity. We present original data that supports a role for cardiotonic steroids in disease progression related to increased saltsensitivity. We found increased levels of free endogenous cardiotonic steroids in those rats that were classified as cataract-prone according to their initial systolic blood pressure response to a high salt intake when compared to non-cataract prone Dahl salt-sensitive rats and their control Dahl salt-resistant rats. The cataract-prone Dahl salt-sensitive rat is an animal model that can help and contribute to open a new door to possibly elucidate the role of endogenous cardiotonic steroids in the pathogenesis and progression of diseases related to salt-sensitive hypertension.This is an open

Plasma Levels of the Cardiotonic Steroid Marinobufagenin in Ischemic Stroke Survivors and Treated Hypertensives: A Pilot Study

“…Salt-sensitive blood pressure has been shown to be a risk factor for cardiovascular morbidity and mortality with a similar or higher impact on health than increased BP alone [4–6]. Using the Dahl salt-sensitive (DS) rat as a model of essential hypertension, we previously reported that total CTS (digoxin-like immunoreactive factor, DLIF) was the same independent of the blood pressure response to high salt and only the free, unbound circulating DLIF increased in those DS rats that had a higher sensitivity to salt intake [7]. This variability in blood pressure response to high salt diet and unevenness in circulating of unbound MBG levels is also found in salt-sensitive subjects with sex-specific [23] and race-related associations [24].…”

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“…Salt-sensitive blood pressure has been shown to be a risk factor for cardiovascular morbidity and mortality with a similar or higher impact on health than increased BP alone [4][5][6]. Using the Dahl salt-sensitive (DS) rat as a model of essential hypertension, we previously reported that total CTS (digoxin-like immunoreactive factor, DLIF) was the same independent of the blood pressure response to high salt and only the free, unbound circulating DLIF increased in those DS rats that had a higher sensitivity to salt intake [7]. This variability in blood pressure response to high salt diet and unevenness in circulating of unbound MBG levels is also found in salt-sensitive subjects with sex-specific [23] and race-related associations [24].…”

“…An increase in salt intake increases the circulating level of cardiotonic steroids (CTS) in both experimental animal and human subjects [7,8]. Endogenous cardiotonic steroids are a group of hormones that have in common a steroid structure and their ability to inhibit or modulate the activity of the Na, K ATPase [9].…”

Protein Interaction and Na/K-ATPase-Mediated Signal Transduction

“…A series of studies from our laboratory published in the late 1990s and early 2000s revealed that CTS could stimulate protein tyrosine phosphorylation and a number of growth-related pathways in cell type- and tissue type-dependent manner [ 53 , 54 , 55 , 56 , 57 ], which has now been largely confirmed by studies from other laboratories around the world [ 49 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 ]. These new findings suggest NKA as an important signal transducer, and the involvement of protein kinase cascades in the cell growth regulation by CTS rather than the inhibition of ATPase activity.…”