chymostatin and Heart-Failure

In the abdominal aortocaval (AV) fistula model of heart failure, we have shown that the acute doubling of cardiac mature mast cell (MC) density involved the maturation, but not proliferation, of a resident population of immature cardiac MCs. An increase in stem cell factor (SCF) may be responsible for this MC maturation process. Thus, the purpose of this study was to determine if: 1) myocardial SCF levels are increased following the initiation of cardiac volume overload; 2) the incubation of left ventricular (LV) tissue slices with SCF results in an increase in mature MC density; and 3) chemical degranulation of mature cardiac MCs in LV tissue slices results in an increase in SCF and mature MC density via MC chymase. Male rats with either sham or AV fistula surgery were studied at 6h and 1 and 3 days post-surgery. LV slices from normal male rat hearts were incubated for 16h with media alone or media containing one of the following: 1) recombinant rat SCF (20 ng/ml) to determine the effects of SCF on MC maturation; 2) the MC secretagogue compound 48/80 (20 μg/ml) to determine the effects of MC degranulation on SCF levels and mature MC density; 3) media containing compound 48/80 and anti-SCF (5 μg/ml) to block the effects of SCF; 4) chymase (100 nM) to determine the effects of chymase on SCF; and 5) compound 48/80 and chymostatin (chymase inhibitor, 10 μM) to block the effects of MC chymase. In AV fistula animals, myocardial SCF was significantly elevated above that in the sham group at 6h and 1 day post fistula by 2 and 1.8 fold, respectively, and then returned to normal by 3 days; this increase slightly preceded significant increases in MC density. Incubation of LV slices with SCF resulted in a doubling of mature MC density and this was concomitant with a significant decrease in the number of immature mast cells. Incubation of LV slices with compound 48/80 increased media SCF levels and mature MC density and with anti-SCF and chymostatin prevented these compound 48/80-induced increases. Incubation with chymase increased media SCF levels and mature MC density. These findings indicate that activated mature cardiac mast cells are responsible, in a paracrine fashion, for the increase in mature MC density post AV fistula by rapidly increasing SCF levels via the release of chymase.

Topics: Animals; Arterio-Arterial Fistula; Cardiac Surgical Procedures; Cell Count; Cell Degranulation; Cell Proliferation; Chymases; Heart; Heart Failure; Heart Ventricles; Male; Mast Cells; Myocardium; Oligopeptides; Rats; Rats, Sprague-Dawley; Stem Cell Factor; Ventricular Remodeling

We sought to demonstrate non-angiotensin converting enzyme (ACE) dependent angiotensin II (AII) generating pathways in resistance arteries from patients with chronic heart failure (CHF).. Non-ACE dependent AII generation occurs in resistance arteries from normal volunteers. Inhibition of non-ACE dependent AII generation may have therapeutic potential in CHF.. Resistance arteries were dissected from gluteal biopsies from patients with coronary heart disease (CHD) and preserved left ventricular function and from patients with CHF. Using wire myography, concentration response curves to angiotensin I (AI) and AII were constructed in the presence of 1) vehicle, 2) chymostatin [an inhibitor of chymase], 3) enalaprilat, and 4) the combination of chymostatin and enalaprilat.. In resistance arteries from patients with CHD, the vasoconstrictor response to AI was not inhibited by either inhibitor alone (chymostatin [p > or = 0.05] or enalaprilat [p > or = 0.05]) but was significantly inhibited by the combination (p < 0.001). In arteries from patients with CHF, AI responses were inhibited by enalaprilat (p < 0.05) but not by chymostatin alone (p > 0.05). The combination ofchymostatin and enalaprilat markedly inhibited the response to AI (p < 0.001) to a greater degree than enalaprilat alone (p < or = 0.01).. Non-ACE dependent AII generating pathways exist in resistance arteries from patients with both CHF and CHD. In resistance arteries from patients with CHD, inhibition of either the ACE or chymase pathway alone has no effect on AII generation, and both pathways must be blocked before the vasoconstrictor action of AI is inhibited. In CHF, blockade of ACE results in marked inhibition of responses to AI, but this is enhanced by coinhibition of chymase. These studies suggest that full suppression of the renin-angiotensin system cannot be achieved by ACE inhibition alone and provide a rationale for developing future therapeutic strategies.

Topics: Acetylcholine; Aged; Angina Pectoris; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Arteries; Bradykinin; Chymases; Enalaprilat; Female; Heart Failure; Humans; In Vitro Techniques; Losartan; Male; Middle Aged; Oligopeptides; Peptidyl-Dipeptidase A; Serine Endopeptidases; Vascular Resistance; Vasoconstriction