Drug Discovery Opinion

Angiotensin converting enzyme (ACE) inhibitors are widely used for the treatment of hypertension and heart failure. The beneficial effects of ACE inhibitors in heart failure are believed to be linked to reduced local production of the potent vasopressor, angiotensin II (AII), but the realisation that another enzyme, chymase, can also produce AII suggests that chronic ACE inhibitor treatment may not completely suppress production of AII.

Chymase is a serine protease found mainly in mast cells but also in the cardiac interstitial space and in some cardiac endothelial cells. Scientists at Emory University, the University of Alabama, Birmingham, and Fukuoka University have now shown that adding a chymase inhibitor to ACE inhibitor treatment can significantly improve recovery of heart function in animals following a heart attack.

The team showed that chronic ACE inhibition produced a bradykinin-dependent release of a chymase (mouse mast cell protease-4, mMCP4) from mast cells in conscious mice, which maintains levels of AII in the interstitial fluid. ACE inhibition also decreases bradykinin degradation and the release of chymase into the left ventricular interstitial fluid may be the result of activation of bradykinin B2 receptors on mast cells. In hamsters, chronic ACE inhibition was found to improve left ventricular function and reduce the amount of dead tissue and scarring after myocardial infarction (MI) and the beneficial effects of chymase inhibition were greater when combined with ACE inhibition. Chymase inhibition may also affect maturation of proteases involved in tissue remodelling, independently of increases in AII levels.

Although recognising that clinical validation is still needed – and that there are no chymase inhibitors available for use in the clinic – the authors propose that addition of a chymase inhibitor to ACE inhibitor therapy may improve outcomes for patients with cardiac diseases including hypertensive heart disease, viral myocarditis, and atherosclerotic coronary artery disease, the prelude to MI.

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