Tissue renin-angiotensin systems and their modulation: the heart as a paradigm for new aspects of converting enzyme inhibition

Abstract

Local tissue-resident renin-angiotensin systems are increasingly recognized as important elements of neurohumoral mediation which may act in concert with, but also independently of, the circulating system. The presence of such a system within the heart is of particular interest; current evidence supporting its existence, functional integration, and physiopathological importance as well as the role which its pharmacological modulation may play are reviewed. The elements of the catalytic cascade, renin, angiotensinogen, and angiotensin-converting enzyme, have all been demonstrated in cardiac tissues; both at the protein level and (with the exception of converting enzyme) with regard to local expression of the respective genes. Modulation of gene expression in response to various perturbations has been demonstrated and may occur independently of the plasma or other tissue renin-angiotensin systems. In isolated hearts the generation of biologically active peptides, angiotensins I and II, has been documented, establishing the capability of this system to act as an independently regulated, functionally integrated catalytic pathway for the production of angiotensin II. Activation of either angiotensinogen to angiotensin I or of angiotensin I to angiotensin II is dose dependently inhibited by the administration of renin inhibitors and converting enzyme inhibitors, respectively. Through specific receptors, present in the heart as in other tissues, angiotensin mediates profound effects on cardiomyocyte function and, as we are beginning to learn, on structure and growth. We now have strong evidence that converting enzyme inhibition at a tissue level may profoundly influence and modulate these actions of the cardiac renin-angiotensin system, particularly in the setting of myocardial ischaemia. This may, in the future, open up new vistas for the application of converting enzyme inhibitors and their indications in a widening spectrum of cardiovascular disorders.