Clinical and physiologic significance of local tissue renin-angiotensin systems

Increasing and compelling evidence continues to amass that favors the existence of local tissue renin-angiotensin systems. All renin-angiotensin system components have been demonstrated in kidney, brain, arteries, adrenals, and other organs. Favoring its clinical importance are direct demonstration of its components in tissues; dissociation between hemodynamic and structural effects of renin-angiotensin system inhibition; evidence for local modulating roles with other humoral, autocrine/paracrine, and growth factors; and the effects of renin-angiotensin system inhibitors in patients who are anephric or have low plasma renin activity. Evidence will be presented demonstrating the hemodynamic/structural dissociation of pharmacologic agents that reduce cardiac mass in spontaneously hypertensive rats with left ventricular hypertrophy. Although centrally active adrenolytic agents, angiotensin-converting enzyme inhibitors, and calcium antagonists all reduce cardiac mass, their structural and cardiac functional effects differ greatly. Even within the angiotensin-converting enzyme inhibitor group their effects vary: improving, impairing, or not changing the Frank-Starling relationships. It is postulated that there is great variability of cardiac intramyocytic penetration of the pharmacologic agents and of their local intracellular effects on mitogenesis. The implications for cardiac function and therapy are vast.