Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cell-mediated ventricular remodeling in rats

Abstract

Murray DB, Gardner JD, Brower GL, Janicki JS. Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cellmediated ventricular remodeling in rats. Am J Physiol Heart Circ Physiol 294: H1251-H1257, 2008. First published January 4, 2008 doi:10.1152/ajpheart.00622.2007.-The objective of this study was to investigate the effect a nonselective endothelin-1 (ET-1) receptor antagonist (bosentan) had on the acute myocardial remodeling process including left ventricular (LV) mast cells and matrix metalloproteinase (MMP) activity secondary to volume overload. Additionally, we investigated the overall functional outcome of preventative endothelin receptor antagonism during 14 days of chronic volume overload. LV tissue from sham-operated (Sham), untreated-fistula (Fist), and bosentan (100 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 )-treated animals (Fist ϩ Bos) was analyzed for mast cell density, MMP activity, and myocardial collagen volume fraction at 1 and 5 days after the creation of an aortocaval fistula. When compared with untreated fistulas, bosentan treatment prevented the marked increase in LV mast cell density at 1 day postfistula (3.1 Ϯ 0.3 vs. 1.3 Ϯ 0.3 LV mast cells/mm 2 , Fist vs. Fist ϩ Bos, P Յ 0.01). Additionally, the substantial increase in MMP-2 activation in the untreated fistula at 1 day was prevented following bosentan treatment (1.6 Ϯ 0.3 vs. 0.9 Ϯ 0.1 arbitrary activity units, Fist vs. Fist ϩ Bos, P Յ 0.01). The marked decrease in collagen volume fraction seen in the Fist group (1.4 Ϯ 0.1 vs. 0.8 Ϯ 0.1% myocardial tissue, Sham vs. Fist, P Յ 0.01) was significantly attenuated following bosentan treatment at both the 1-and 5-day time points. Lastly, a 2-wk preventative treatment with bosentan resulted in significant attenuation of the increase in LV end-systolic and -diastolic volumes compared with those in untreated fistula hearts. In summary, nonselective ET-1 antagonism prevents the acute increases in cardiac mast cell density and MMP activation induced secondary to chronic volume overload. By preventing these events, ET-1 antagonism was efficacious in attenuating ventricular dilatation and limiting the development of structural and functional deficits in the first 2 wk of chronic volume overload. Accordingly, these results are the first to demonstrate that cardiac mast cells are responsive to the endogenous endothelin system in vivo. Another novel finding from this study is that chronic nonspecific endothelin antagonism may inadvertently potentiate ET-1-mediated signaling.bosentan; heart; extracellular matrix; cardiac function DISCOVERED ONLY 16 years ago, the neurohormone endothelin-1 (ET-1) has been intensely investigated due to its potent cardiovascular effects and strong association with the pathophysiological worsening of cardiac function in congestive heart failure (7,13,16,29,35). ET-1 is a 21 amino acid peptide predominantly synthesized and secreted by endothelial cells. The effects of ET-1 are dictated by binding to one of two G protein-linked receptor subtypes A or B (ET A or ET B ) (16). In th...

ETAselective receptor antagonism prevents ventricular remodeling in volume-overloaded rats

“…Initially investigated for potent vasoactive properties, evidence for ET-1 involvement in extracellular matrix turnover in disease states has been mounting (1,2,21,38,46). Clinical trials using ET A receptor antagonist in congestive heart failure patients reported lower systemic vascular resistance that resulted in higher cardiac index (6,31).…”

“…An infrarenal AV fistula was created in rats as described previously (38,39). Briefly, a ventral abdominal laparotomy was performed to expose the aorta and caudal vena cava.…”

“…In vivo LV volume and function was assessed in anesthetized rats using a high-fidelity Millar (SPR-838; Millar Instruments, Houston, TX) conductance catheter inserted in the LV via the right carotid artery at 8 wk postsurgery as previously described (38,51). This measurement technique requires that a small amount (0.1 ml) of 15% saline be introduced in the external jugular vein of the anesthetized animal at the end of the experimental protocol as a correction factor for the blood-tissue interface.…”

“…Previously, we established that ET-1 was capable of activating cardiac mast cells (37). Recently, we were able to demonstrate in the aortocaval fistula model that combined ET A /ET B receptor antagonism prevented the acute increase in MMP activity by limiting LV mast cell activation (38). Therefore, the aim of the present study was to determine the ability of a highly selective ET A antagonist to attenuate the maladaptive changes occurring in the initial phase of ventricular remodeling in the aortocaval fistula model of volume overload.…”

Prevention of Inflammation-Associated Preterm Birth by Knockdown of the Endothelin-1-Matrix Metalloproteinase-1 Pathway

“…lin receptor antagonist (25). Deschamps et al (26) showed that the increase in MMP-1 levels in porcine hearts associated with ischemia and reperfusion injury did not occur if the animals were treated with the ET-1-receptor A antagonist BQ-123.…”