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Impact of chymase inhibitor on cardiac function and survival after myocardial infarction
Denan Jin1, Shinji Takai, Mayumi Yamada
1Department of Pharmacology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan. pha012@art.osaka-med.ac.jp
Insights
Inhibition of cardiac chymase activity with NK3201 improved cardiac function and survival after myocardial infarction (MI) in hamsters. This suggests chymase is a potential therapeutic target for post-MI treatment.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Biochemistry
Background:
- Hamsters, similar to humans, have both angiotensin converting enzyme (ACE) and chymase-dependent pathways for angiotensin II formation in the heart.
- Cardiac chymase activity was found to be significantly elevated following myocardial infarction (MI) in hamsters.
- Investigating novel therapeutic targets for post-MI recovery is crucial.
Purpose of the Study:
- To evaluate the therapeutic potential of NK3201, a specific chymase inhibitor, in improving cardiac function and survival post-MI.
- To determine if suppressing cardiac chymase activity offers prognostic benefits after myocardial infarction.
- To assess the impact of NK3201 on cardiac function and mortality in a hamster model of MI.
Main Methods:
- Myocardial infarction was induced in 210 male Syrian hamsters by ligating the left coronary artery.
- NK3201 (30 mg/kg/day) was administered orally, starting either 3 days before or 1 day after MI induction.
- Cardiac function and survival rates were monitored over 14 days post-MI.
Main Results:
- NK3201 treatment significantly inhibited the rise in cardiac chymase activity without affecting ACE activity post-MI.
- A notable improvement in cardiac function was observed at 3 and 14 days after MI in hamsters treated with NK3201.
- Mortality rates were significantly reduced in the NK3201 treatment groups compared to the vehicle control group.
Conclusions:
- Cardiac chymase plays a significant role in the pathological processes following myocardial infarction.
- Inhibition of cardiac chymase activity presents a promising novel therapeutic strategy for managing patients after MI.
- NK3201 demonstrated efficacy in improving cardiac outcomes and survival in a preclinical model of MI.
Objectives:
Recent studies have demonstrated that hamsters, like humans, possess both angiotensin converting enzyme (ACE)- and chymase-dependent angiotensin (Ang) II-forming pathways in cardiovascular tissues. We recently found that, after myocardial infarction (MI) in hamsters, cardiac chymase was significantly activated. In order to determine whether suppression of cardiac chymase activity could provide prognostic benefit after MI, we examined the effects of NK3201, a novel, orally active and specific chymase inhibitor, on cardiac function and survival during the acute phase of MI in hamsters.
Methods:
Two hundred and ten male Syrian hamsters were used in the present study. The left coronary artery of each hamster was ligated to induce MI. NK3201 at a dose of 30 mg/kg per day was administered orally by gastric gavage, starting either 3 days before or 1 day after MI.
Results:
ACE and chymase activities were significantly increased in the infarcted left ventricle 3 days after MI. NK3201 treatment starting 3 days before MI significantly inhibited the increase in cardiac chymase activity, while it did not affect ACE activity either in plasma or in heart 3 days after MI. A significant improvement in cardiac function was observed 3 and 14 days after MI in the group receiving NK3201. Compared with vehicle treatment, NK3201 treatment initiated either 3 days before or 1 day after MI significantly reduced the mortality rate during the 14 days of observation following MI.
Conclusions:
These findings indicate that cardiac chymase plays an important role after MI and this finding may provide a novel therapeutic target in post-MI treatment.
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