Newly developed renin and prorenin assays and the clinical evaluation of renin inhibitors
BACKGROUND: The last decade has seen the introduction of renin inhibitors and new plasma renin and prorenin assays, which has led to a better understanding of the tissue renin-angiotensin system. AIM OF THE STUDY: To clarify the consequences of these developments for the methodology and interpretation of measurements of renin and prorenin. METHODS: The principles and application of the newly developed immunosorbent assays (ISAs) are surveyed and the results are compared with those of enzyme-kinetic assays (EKAs). RESULTS AND CONCLUSIONS: Angiotensin (Ang) II in cardiac, renal and adrenal tissue is known to originate mainly from locally produced Ang I. Experimental evidence and theoretical considerations show that a simple relation between Ang II receptor occupancy, in tissue micromilieu, and the circulating levels of Ang II or renin may not exist. This supports the clinicians' view that the plasma level of renin tells more about the mechanisms regulating its release into the circulation than about the Ang II-dependency of hypertension. ISAs are a welcome addition to clinical studies of renin inhibitors. By comparing the results of ISAs with those of EKAs, the inhibitor-bound forms of renin and prorenin can be distinguished from the unbound forms. ISAs also provide important information on the molecular basis of prorenin activation. We propose a single kinetic model to incorporate the conformational changes of prorenin induced by cryo-activation and acid-activation, and by binding to renin inhibitors. It explains why renin ISAs can overestimate the rise of renin in response to these drugs, and shows how to deal with this artefact.