Vasopeptidase Inhibitors, Neutral Endopeptidase Inhibitors, and Dual Inhibitors of Angiotensin-Converting Enzyme and Neutral Endopeptidase

Abstract

Vasopeptidase inhibitors represent a new class of cardiovascular drugs. They function as a combined angiotensin-converting enzyme (ACE) inhibitor and neutral endopeptidase (NEP) inhibitor, the latter of which potentiates the actions of atrial natriuretic peptide (ANP) by minimizing its degradation in the circulation. The consequence of such dual inhibition is a synergistic reduction of vasoconstriction and enhancement of vasodilation, thereby serving to more effectively reduce blood pressure. Furthermore, inhibition of the renin-angiotensin-aldosterone system (RAAS) prevents physiologic compensatory responses in vivo seen with NEP inhibition alone. Vasopeptidase inhibitors have also shown to potentiate bradykinin and adrenomedullin, which additionally contribute to cardiovascular regulation. The most extensively researched and promising agents within the class of VP inhibitors is omapatrilat, a mercaptoacyl derivative of a bicyclic thiazepinone dipeptide. It is a single molecule with equal potency and affinity for ACE and NEP inhibition. Although ACE inhibition tends to more selectively benefit high-renin models of hypertension, vasopeptidase inhibition has been shown to be equally efficacious in low-, normal-, and high-renin models. Contrary to NEP inhibition alone, omapatrilat has also demonstrated the ability to significantly reduce blood pressure in spontaneously hypertensive rats, the equivalent of essential hypertension in humans. Studies also suggest that omapatrilat has cardioprotective properties, especially in the setting of congestive heart failure. More specifically, animal models have demonstrated omapatrilat to be more effective than ACE inhibition alone in remodeling the heart and improving its contractile function. Human studies have documented the efficacy of omapatrilat in the treatment of both hypertension and, to a lesser extent, heart failure. Safety concerns (specifically angioedema) are currently being addressed before the widespread utilization of this promising new agent.