VASOPEPTIDASE INHIBITION - SOLVING THE CARDIOVASCULAR PUZZLE?

摘要

The therapeutic blockade of the renin-angiotensin-aldosterone system (RAAS) using angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, aldosterone receptor antagonists and, more recently, renin inhibitors has been a mainstay for the treatment of hypertension, the main risk factor for cardiovascular disease. Blood pressure and fluid homeostasis are regulated by the interconnected pathways of the RAAS, the endothelin system, the natriuretic peptide system and the kallikrein-kinin system. The simultaneous modulation of several neurohumoral mediators has been an attractive approach that has received much attention. The dual ACEeu-tral endopeptidase (NEP) and triple ACE/NEP/endothelin-converting enzyme (ECE) inhibitors are the most celebrated vasopeptidase inhibitors, but their progress to the clinic has been stalled by kinin-mediated adverse effects. NEP/ECE and ACE/ECE inhibitors and compounds targeting the angiotensin receptor and NEP are other attractive options that have been investigated. In this review, we discuss the systems that regulate the concentrations ofvasoactive pep-tides, the current therapies and the molecular basis for the design and action of vasopeptidase inhibition.