Zinc metallopeptidase inhibitors. A novel antihypertensive treatment.

Abstract

Inhibitors of two zinc metallopeptidases, angiotensin I converting enzyme (ACE) and neutral metalloendopeptidase-24.11 (EP-24.11), are antihypertensive agents. In this issue of Hypertension, Genden and Molineaux report that yet another peptidase inhibitor, metalloendopeptidase-24.15, EC 3.4.24.15 (EP-24.15), lowers blood pressure in normotensive rats. In this editorial we discuss the possible role of kinins as common mediators of part of the vasodepressor action of these peptidase inhibitors. Genden and Molineaux report that the marked fall in blood pressure caused by the EP-24.15 inhibitor is almost abolished by a kinin receptor antagonist, supporting the hypothesis that kinins play a role in the regulation of normal blood pressure. We have confirmed that the EP-24.15 inhibitor used by these investigators lowers blood pressure. Up to now, EP-24.15 has not been implicated in in vivo metabolism of kinins. Although a number of kininases have been identified, our own previous work indicated that the metabolic pathway responsible for clearing kinins from the circulation involves the action of kininase II (angiotensin I converting enzyme) and renal peptidases. Nevertheless, the main metabolic pathway involved some other unidentified enzyme, since in these experiments disappearance of kinins from the circulation was only marginally reduced by a "cocktail" of inhibitors of ACE, EP-24.11, and carboxypeptidase N. It could be that EP-24.15 is involved in kinin metabolism. However, a number of questions need to be answered with regard to the mechanism by which the EP-24.15 inhibitor lowers blood pressure. The data obtained with the EP-24.15, NE-24.11, and ACE inhibitors suggest that potentiation of vasodilator peptides is yet another possible relevant therapeutic approach to hypertension and perhaps heart failure. (Hypertension 1991;68:366-371)

Environmental Lead Exposure and Progressive Renal Insufficiency

“…The effect of improving renal function after chelation therapy might theoretically relate to removal of essential trace elements, such as zinc and copper, which act as cofactors for enzymes that affect synthesis of vasoactive hormones. 18,19 For example, zinc is a cofactor for neutral metalloendopeptidase, a kidney enzyme of degrading atrial natriuretic peptide, 26 and for angiotensin-converting enzyme. 27 A depletion of zinc might cause an elevation in atrial natriuretic peptide and a reduction in angiotensin II formation together with a decline in blood pressure and an increase in renal blood flow.…”

Role of angiotensin converting enzyme in the vascular effects of an endopeptidase 24.15 inhibitor

“…Recently there has been renewed interest in the role that metalloendopeptidases play in blood pressure control, and thus their potential as therapeutic agents (Carretero & Scicli, 1991). Much of this interest has focussed on endopeptidase E.C.3.4.24:15 (EP 24.15), first identified in soluble fractions of brain homogenates by Orlowski et al (1983).…”

Effects of a metalloendopeptidase-24.15. Inhibitor on renal hemodynamics and function in rats.

“…cFP-AAF-pAB also potentiated the bradykinin-induced vasodepressor response. In preliminary studies, 6 - 7 we found that cFP-AAF-pAB lowers MBP and increases cardiac output, renal blood flow (RBF), and plasma kinins. A recent report 8 states that in vitro cFP-AAF-pAB competitively inhibits purified angiotensin converting enzyme (ACE) with a K, of 0.2 fimo\[L and also inhibits serum ACE activity.…”