Targeting Carbonic Anhydrases in Cardiovascular and Pulmonary Disease

Abstract

Carbonic anhydrase (CA) is present within many cells of the heart, lungs, and the vasculature. An understanding of its roles in cardiac muscle and vascular smooth muscle, the vascular endothelium and lungs, was not fully appreciated until the 1980s and even presently more functions are being discovered. Despite its presence and roles in the physiological functioning of the cardiovascular and respiratory systems, its inhibition in some clinical circumstances may be therapeutic. In this chapter, we will review the expression and functions of the enzyme in the heart, lungs, and vasculature as background to a comprehensive discussion of how the enzyme may be targeted and its function altered in various disease afflicting these organs. While activators of CA exist, to date no studies of these compounds have been undertaken beyond a few neurological conditions. Targeting CA has largely involved the use of inhibitors, particularly acetazolamide, the first clinically approved inhibitor and still most widely used in its class. Interestingly, acetazolamide once thought to only bind to CAs at relevant clinical concentrations has many actions independent of CA with relevance to the heart, lungs, and vasculature. These include aquaporin blockade, activation of several membrane ion channels, and oxygen radical scavenging to name a few. Inhibition of carbonic anhydrase and actions of acetazolamide unrelated to enzyme inhibition have possible benefits in heart failure, myocardial infarction, acute lung injury, and systemic and pulmonary hypertension.