Chymase inhibitor improves survival in hamsters with myocardial infarction.
The purpose of the present study was to assess the effects of chronic treatment with an orally active chymase inhibitor, 4-[1-(naphthylmethyl)benzimidazol-2-ylthio]butanoic acid (TEI-E548), in a hamster myocardial infarction model. In the first experiment, after confirming the biochemical inhibitory action of TEI-E548 on human and hamster chymases (Ki = 6.2 and 30.6 nM, respectively), the biological action of TEI-E548 in vivo was assessed by the inhibition of hamster chymase-induced microvascular leakage. In the second experiment, myocardial infarction was produced by coronary artery ligation in male Syrian hamsters. TEI-E548 (0.1% containing chow) was given 24 h after surgery and continued for 3 or 5 weeks, while the control and sham-operated groups were fed a standard chow. The survival rate was assessed in each group. At the end of each study period, blood pressure was measured at the left hind-limb, the heart rate and cardiac function were measured by echocardiography, the end-diastolic pressure by a direct catheterization, and organ weights and biochemical parameters, including plasma renin and angiotensin-converting enzyme activities and plasma angiotensin I and angiotensin II concentrations, were measured. In the first experiment, a standard chow containing 0.1% TEI-E548 completely inhibited the hamster chymase-induced microvascular leakage. In the second experiment, TEI-E548 treatment significantly increased the survival rate (37% versus control), and attenuated cardiac hypertrophy (13% versus control) and end-diastolic left ventricular pressure (34% versus control), but it did not decrease the infarction size nor improve the ejection fraction. The plasma angiotensin II concentration post-myocardial infarction was significantly suppressed by TEI-E548 throughout the study period. We conclude that TEI-E548 is an orally active useful chymase inhibitor and improves survival and cardiac hypertrophy of the post-myocardial infarction hamster.
Hoshino
Fumihiro
F
Department of Internal Medicine, Fukuoka University, School of Medicine, Fukuoka, Japan.
Urata
Hidenori
H
Inoue
Yukiko
Y
Saito
Yuri
Y
Yahiro
Eiji
E
Ideishi
Munehito
M
Arakawa
Kikuo
K
Saku
Keijiro
K
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D002087:Butyrates / Q000494:pharmacology / Q000627:therapeutic use*; D053818:Chymases; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008647:Mesocricetus; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015996:Survival Rate
C554849:4-(1-(naphthylmethyl)benzimidazol-2-ylthio)butanoic acid; D001562:Benzimidazoles; D002087:Butyrates; D004791:Enzyme Inhibitors; D012697:Serine Endopeptidases; D053818:Chymases