Structural and Functional Considerations

The renin-angiotensin system (RAS) profoundly influences cardiovascular function. The system likely evolved to meet the need to preserve cardiovascular function in response to stressors such as hemorrhage, dehydration and dietary sodium deficiency. However, the RAS can also induce pathological changes, either in response to renal dysfunction or relatively uncharacterized alterations in organs containing local renin-angiotensin systems. From a medical viewpoint, hypertension is the pathological alteration induced by the RAS of greatest interest. Sustained high blood pressure takes a toll on the cardiovascular system and secondarily on the organ systems it perfuses, e.g., high fluid pressure leads to cardiac hypertrophy and valvular insufficiency, damage to vascular endothelium, generation of thrombi, and rupture of vessel walls leading to hemorrhagic and ischaemic damage within various organs of the body. Because of this morbidity considerable research has been directed to understanding the mechanisms of actions of the RAS and finding means to prevent or reverse them. From a pharmacological viewpoint, therapeutic agents designed to oppose the actions of an endogenous system such as the RAS can either target the steps involved in the synthesis or release of the active agent(s), or block the receptors that mediate the effects of the active agent. Presently the only drugs available are those that inhibit angiotensin converting enzyme (ACE), also known as kininase II, and dipeptidyl carboxypeptidase (EC 3.4.15.1). These drugs, whose names share a common suffix, -pril, e.g., captopril, enalapril, ramipril, etc., competitively inhibit ACE, blocking the formation of the active octapeptide angiotensin II