Ang I-converting enzyme (ACE) inhibitors are widely believed to suppress the deleterious cardiac effects of Ang II by inhibiting locally generated Ang II. However, the recent demonstration that chymase, an Ang IIforming enzyme stored in mast cell granules, is present in the heart has added uncertainty to this view. As discussed here, using microdialysis probes tethered to the heart of conscious mice, we have shown that chronic ACE inhibitor treatment did not suppress Ang II levels in the LV interstitial fluid (ISF) despite marked inhibition of ACE. However, chronic ACE inhibition caused a marked bradykinin/B2 receptor-mediated increase in LV ISF chymase activity that was not observed in mast cell-deficient Kit W /Kit W-v mice. In chronic ACE inhibitor-treated mast cell-sufficient littermates, chymase inhibition decreased LV ISF Ang II levels substantially, indicating the importance of mast cell chymase in regulating cardiac Ang II levels. Chymase-dependent processing of other regulatory peptides also promotes inflammation and tissue remodeling. We found that combined chymase and ACE inhibition, relative to ACE inhibition alone, improved LV function, decreased adverse cardiac remodeling, and improved survival after myocardial infarction in hamsters. These results suggest that chymase inhibitors could be a useful addition to ACE inhibitor therapy in the treatment of heart failure.
Exposure to chlorine (Cl2) gas during industrial accidents or chemical warfare leads to significant airway and distal lung epithelial injury that continues post exposure. While lung epithelial injury is prevalent, relatively little is known about whether Cl2 gas also promotes injury to the pulmonary vasculature. To determine this, rats were subjected to a sub-lethal Cl2 gas exposure (400ppm, 30min) and then brought back to room air. Pulmonary arteries (PA) were isolated from rats at various times post-exposure and contractile (phenylephrine) and nitric oxide (NO)-dependent vasodilation (acetylcholine and mahmanonoate) responses measured ex-vivo. PA contractility did not change, however significant inhibition of NO-dependent vasodilation was observed that was maximal at 24–48 hours post exposure. Superoxide dismutase restored NO-dependent vasodilation suggesting a role for increased superoxide formation. This was supported by ~2-fold increase in superoxide formation (measured using 2-hydroethidine oxidation to 2-OH-E+) from PA isolated from Cl2 exposed rats. We next measured PA pressures in anesthetized rats. Surprisingly, PA pressures were significantly (~4mmHg) lower in rats that had been exposed to Cl2 gas 24 hours earlier suggesting that deficit in NO-signaling observed in isolated PA experiments did not manifest as increased PA pressures in vivo. Administration of the iNOS selective inhibitor 1400W, restored PA pressures to normal in Cl2 exposed, but not control rats suggesting that any deficit in NO-signaling due to increased superoxide formation in the PA, is offset by increased NO-formation from iNOS. These data indicate that disruption of endogenous NO-signaling mechanisms that maintain PA tone is an important aspect of post-Cl2 gas exposure toxicity.
The serine protease chymase is stored in mast cell secretory granules and is released upon mast cell activation into the cardiac interstitium where it activates matrix metalloproteinases, causes cardiomyocyte apoptosis, and generates angiotensin (Ang) II. Miyazaki et. al. (Life Sci. 71:437, 2002) reported beneficial effects on cardiac function and survival of chymase inhibition during the acute phase of myocardial infarction in hamsters. Here we determined if mast cell‐chymase is released into the cardiac interstitium after acute myocardial ischemia (MI) and reperfusion in dogs. To measure in vivo left ventricle (LV) interstitial fluid (ISF) chymase activity, we combined cardiac microdialysis with direct ISF infusion of the chymase‐specific substrate [Pro11, DAla12]Ang I after MI. The ISF chymase activity in the ischemic region was 3.5‐fold (n=6, p<0.001) increased after 60 min MI followed 100 min reperfusion and it was significantly suppressed by TEI‐F00806 (100 mg/kg/BID, pretreated 5 days), a novel, orally active and specific chymase inhibitor (CI). Importantly, there was also 5‐fold (n=6, p<0.001) increased ISF chymase activity in the non‐ischemic region after reperfusion and this increase was completely blocked by CI treatment. The current investigation indicates that LV ISF chymase in vivo can be regulated by factors that affect mast cell activation, in particular, MI and reperfusion. These findings demonstrated for the first time that cardiac interstitial chymase participates directly in the pathophysiologic state after acute MI in dog. Supported by TEIJIN Pharma Limited and SCCOR in Cardiac Dysfunction P50HL077100 (LJD).
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