ET_Aselective receptor antagonism prevents ventricular remodeling in volume-overloaded rats

Abstract

Murray DB, McMillan R, Brower GL, Janicki JS. ETA selective receptor antagonism prevents ventricular remodeling in volume-overloaded rats. Am J Physiol Heart Circ Physiol 297: H109 -H116, 2009. First published May 8, 2009 doi:10.1152/ajpheart.00968.2008.-The objective of this study was to investigate the ability of selective endothelin receptor subtype A (ET A) endothelin receptor antagonism (ETA) to prevent the acute myocardial remodeling process secondary to volume overload. Left ventricular tissue from sham-operated (Sham) and untreated (Fist), and TBC-3214 (Fist ϩ ETA, 25 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 )-treated fistula animals was analyzed for mast cell density, matrix metalloproteinase (MMP) activity, and extracellular collagen volume fraction (CVF) 1 and 5 days following the initiation of volume overload. Compared with Fist, ETA treatment prevented the increase in left ventricular mast cell density at 1 day and 5 days. Additionally, at 1 day postfistula, a substantial decrease in MMP-2 activity below Sham levels was observed following endothelin receptor antagonism (1.7 Ϯ 0.7 vs. 0.3 Ϯ 0.3 vs. 0.9 Ϯ 0.2 arbitrary activity units, Fist vs. Fist ϩ ETA vs. Sham, P Յ 0.05). This same effect was also seen at 5 days postfistula (1.9 Ϯ 0.3 vs. 0.5 Ϯ 0.1 arbitrary activity units, Fist vs. Fist ϩ ETA, P Յ 0.05). The marked decrease in myocardial CVF seen in Fist hearts (0.7 Ϯ 0.1 vs. 1.6 Ϯ 0.1% myocardial area, Fist vs. Sham, P Յ 0.05) was prevented by ETA (1.7 Ϯ 0.1% Fist ϩ ETA, P Ͻ 0.05 vs. Fist). This preservation of the collagen matrix was also present on day 5 in the TBC-treated group vs. the Fist group (1.0 Ϯ 0.1 vs. 1.4 Ϯ 0.1%, Fist vs. Fist ϩ ETA, P Յ 0.01). Furthermore, an 8-wk preventative treatment with ETA significantly attenuated the increase in left ventricular end systolic and diastolic volumes compared with untreated fistula hearts. In conclusion, the novel findings of this study indicate that the activation of cardiac mast cells and subsequent MMP activation/collagen degradation during the acute stages of volume overload are prevented by blockade of the ET A receptor subtype. Furthermore, by preventing these events, ET-1 antagonism was efficacious in attenuating ventricular dilatation and limiting the development of structural and functional deficits.endothelin-1; mast cell; matrix metalloproteinase; TBC-3214 ENDOTHELIN (ET)-1 is a potent neurohormone produced throughout the cardiovascular system, and the observation that plasma ET-1 is elevated in patients with heart failure is suggestive of a role in the pathophysiology of heart failure (16,19,34,40,47). The cardiovascular effects of ET-1 (a 21-amino-acid peptide) are dictated by binding to one of two G protein-linked receptor subtypes [endothelin receptor subtypes A (ET A ) or B (ET B )] (23). In the heart and vasculature, binding and activation of ET A is known to mediate powerful vasoconstrictor and pressor affects, in addition to chronotropic and ionotropic effects (12,25). The ET B receptor subtype is responsible for systemic clearance of circulating ...

TNF-α inhibition attenuates adverse myocardial remodeling in a rat model of volume overload

“…However, most studies, exemplified by Levine et al (22), have focused on the positive correlation between end-stage heart failure and elevated circulating levels of TNF-␣. We recently established that myocardial levels of TNF-␣ initially become elevated in the 1st wk after creation of an AV fistula (21,25,26). Accordingly, this study sought to elucidate the contribution of endogenous TNF-␣ at different stages of the remodeling process, using TNF-␣ inhibition with etanercept.…”

“…However, a similar pattern of myocardial remodeling consisting of LV wall thinning, dilatation, and collagen degradation was reported by Bozkurt et al (3) following infusion of pathophysiological levels of TNF-␣ in normal rats. The possibility that mast cells initiate collagen degradation and subsequent long-term remodeling by regulating the release of TNF-␣ was raised based upon our recent observation that TNF-␣ is elevated within 24 h after creation of an AV fistula (25,26). That cardiac mast cells contribute to increases in myocardial levels of TNF-␣ is not a novel observation.…”

“…Presumably, any intervention that attenuates ventricular dilatation, preserving a normal mass-to-volume ratio as seen herein at 8 wk, would impart significant functional improvement and limit the extent of hypertrophy. Indeed, in our experience, this has been the outcome using a variety of interventions that attenuate ventricular dilatation (8,10,13,21,26).…”

“…However, the majority of studies to date have focused on the causal association between TNF-␣ activation and the transition to congestive heart failure (12,35). In contrast, we have recently shown that myocardial levels of TNF-␣ are acutely elevated in the aortocaval (AV) fistula model of heart failure (21,25,26). Based on these observations, we hypothesized that treatment of AV fistula rats with the TNF-␣ inhibitor, etanercept, would prevent the adverse myocardial remodeling known to occur in this model (6 -8).…”

Assessing the validity of a novel model of vertebral artery type of cervical syndrome induced by injecting sclerosing agent next to transverse process of cervical vertebra

“…Norepinephrine and endothelin can up-regulate the activity and expression of MMP-2 [22][23][24][25] . This study found that the expression of MMP-2 was increased in model group as compared with normal group.…”