Franz Volhard Lecture. Renin-angiotensin system: a dual tissue and hormonal system for cardiovascular control.

BACKGROUND: The renin-angiotensin system is both a circulating and a local tissue hormonal system. All components of the renin-angiotensin system have been found in important cardiovascular structures, including the heart, vessels, brain, kidney and adrenal gland. The angiotensin converting enzyme (ACE) is the final step in the enzymatic cascade of the renin-angiotensin system, which converts angiotensin in both the circulation and the tissues. IMPORTANCE OF ACE CATALYTIC SITES: ACE is predominantly an ectoenzyme with a bilobed homodimer extracellular portion, a short transmembrane span and a small intracellular extension. ACE contains two catalytic sites, one on each lobe. There is evidence that these catalytic sites may differ in several properties and may have different conformational requirements. This raises the possibility that there may be different endogenous substrates for each site and it may be feasible to design more specific ACE inhibitors that inhibit only one catalytic site. CARDIOVASCULAR ROLE OF LOCAL RENIN-ANGIOTENSIN SYSTEM: The physiological cardiovascular functions of the tissue renin-angiotensin system may include regulation of regional blood flow, modulation of local sympathetic activity and interaction with the endothelium. There is increasing evidence that the local renin-angiotensin system may be involved in the maintenance of cardiovascular structure and repair. ACE is increased in many forms of vascular and cardiac hypertrophy and the administration of ACE inhibitors has led to regression of hypertrophy. Many of the beneficial effects of ACE inhibitors may be due to inhibition of the local renin-angiotensin system. ACE INHIBITION FOLLOWING MYOCARDIAL INJURY: The local renin-angiotensin system may also be involved in the response to injury and in the inflammatory response. ACE is known to be increased in granulomas, it is expressed on monocytic macrophages and fibroblasts and many of the peptides involved in the inflammatory response (bradykinin, substance P, enkephalins) can act as ACE substrates. Following an acute myocardial infarct, ACE is increased in the myocardial scar and in the hypertrophying cardiac muscle. This provides a possible mechanism for the beneficial effect of ACE inhibitors in postmyocardial infarction trials. NON-CARDIOVASCULAR SYSTEM: Neither the function of the renin-angiotensin system in the brain and non-cardiovascular tissues nor its role in the pathophysiology of hypertension are known as yet.