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Kidney International, Vol. 63, Supplement 84 (2003), pp. S54–S57

Vasopeptidase inhibition: A new treatment approach for endothelial dysfunction

THOMAS QUASCHNING,JAN GALLE, and CHRISTOPH WANNER

Department of Medicine, Division of Nephrology, University Clinic Wu¨rzburg, Wu¨rzburg, Germany

Vasopeptidase inhibition: A new treatment approach for endo- of potent paracrine mediators such as nitric oxide (NO), thelial dysfunction. -converting enzyme (ACE) in- angiotensin II, and endothelin-1 (Fig. 1). The different hibition is a well-established principle in the treatment of endo- circulating and local systems show important synergisms thelial dysfunction. Numerous preclinical and clinical studies have clearly demonstrated the beneficial effects of inhibiting and interactions. They may either have synergistic effects the -angiotensin-aldosterone system (RAS) in states of im- or may be the functional counterpart of another system paired endothelial function. The successful use of ACE inhibi- in a subtle multivariate balance. As such, atrial natriuretic tors encouraged attempts to inhibit other key enzymes in the peptides (ANP) counteract the effects of angiotensin II. regulation of vascular tone, such as the neutral endopeptidase (NEP). Similar to ACE, NEP is an endothelial cell surface metal- Since effects of endothelium-derived substances are not loproteinase that is involved in the degradation of several regu- limited to vasoconstriction or vasodilatation, but may also latory peptides, including the natriuretic peptides, and, thus, include regulation of mitogenesis, endothelial dysfunc- NEP inhibition augments vasodilatation and natriuresis through tion not only affects the function of the cardiovascular increased levels of atrial natriuretic peptide (ANP). By inhib- system, but also its structure. In fact, some endothelial iting the RAS and potentiating the natriuretic peptide system at the same time, combined NEP/ACE inhibitors, the so-called substances stimulate the production of cytokines and vasopeptidase inhibitors, reduce vasoconstriction and enhance growth factors, leading to vascular smooth muscle cell vasodilatation, thereby decreasing peripheral vascular resis- proliferation. Thus, the balance of vasoactive peptides tance and blood pressure. Within the vessel wall this may lead to warrants an appropriate adaptation of vascular tone and a reduction of vasoconstrictor and proliferative mediators, such as angiotensin II and endothelin-1, and may increase local regulates oxidative, proliferative, and inflammatory pro- levels of as well as natriuretic peptides. Even though cesses (Fig. 1). Therefore, the maintenance of the subtle first results of both preclinical and clinical studies indicate endothelial balance is crucial for the prevention and that combined inhibition of ACE and NEP by vasopeptidase treatment of cardiovascular disease. inhibitors represents a promising strategy in the treatment of hypertension and , occurs more fre- quently on vasopeptidase inhibition as compared to ACE inhi- ACE INHIBITION AND NEP INHIBITION: bition. To establish vasopeptidase inhibition as a novel option in the treatment of cardiovascular disease, further validation THE COMPONENTS OF of efficacy and safety of this promising therapeutic principle VASOPEPTIDASE INHIBITION is mandatory. The beneficial effect of ACE inhibition has been docu- mented in many large randomized trials for the treatment of hypertension [2], after myocardial infarction, and in The importance of the renin-angiotensin-aldosterone heart failure. The Heart Outcomes Prevention Evalua- system (RAS) in the pathophysiology of endothelial dys- tion (HOPE) study confirmed that ACE inhibitors are function, which represents an early stage of cardiovascu- vasoprotective, independent of their effects on blood lar damage, is illustrated by numerous trials which dem- pressure and remodeling [3]. In addition, in patients with onstrate improvement of endothelial function [1], and coronary artery disease, improvement of endothelial even reduction of clinical end points, using agents that function by ACE inhibition could be demonstrated angi- interrupt this system. The RAS plays a crucial role in ographically in the Trial on Reversing Endothelial Dys- cardiovascular regulation both as a circulating and para- function (TREND), particularly in patients with high crine local vascular system. The endothelium is a source serum cholesterol who are prone to severe endothelial dysfunction [1]. The mechanisms involved may be re- Key words: vasopeptidase, endothelial dysfunction, ACE inhibition, lated to inhibitory effects on angiotensin formation hypertension. and/or on activation of bradykinin-related effects. ACE  2003 by the International Society of Nephrology inhibitors not only prevent the formation of a potent

S-54 Quaschning et al: Vasopeptidase inhibition in endothelial dysfunction S-55

Fig. 1. Balance of endothelial function: in- fluence of simultaneous inhibition of angio- tensin-converting enzyme (ACE) and neutral endopeptidase (NEP) by vasopeptidase inhib- itors (VPI) on production and degradation of vasoactive peptides. Abbreviations are: ET-1, endothelin-1; ECE, endothelin converting en- zyme, ANP, atrial natriuretic peptide; CNP, C-type natriuretic peptide; NOS, nitric oxide synthase; Arg, arginine; PLC, phospholipase C; GC, guanylate cyclase; EC, endothelial cell; VSMC, vascular smooth muscle cell. vasoconstrictor with proliferative properties, but also in- including renovascular hypertension, spontaneous hy- crease the local concentration of bradykinin. In turn, the pertension [4, 5], deoxycorticosterone acetate-induced production of NO and prostacyclin, which may contrib- hypertension [5], as well as salt-sensitive hypertension ute to the vascular protective effects of ACE inhibitors [6, 7]. In spontaneously hypertensive rats, vasopeptidase by vasopeptidase inhibition, by improving local blood inhibition significantly lowered blood pressure, even flow, and preventing platelet activation. As a principle when combined with experimental diabetes [4]. Since of vasopeptidase inhibition, beneficial effects of ACE antihypertensive effects of combined ACE/NEP inhibi- inhibition are combined with the additional inhibition tion exceeded those of ACE inhibition alone, and re- of the neutral endopeptidase (NEP). sulted in additional improvement of endothelial function Selective NEP inhibition prevents the degradation of to a greater extent than attributable to lowering of blood vasoactive peptides such as ANP, BNP, CNP, substance pressure [6, 8], vasopeptidase inhibition may advance as P, and bradykinin, and increases their biologic activity. a promising novel option for the treatment of various This implicates that simultaneous inhibition of ACE and forms of hypertension. NEP may exceed the effects of inhibiting either system In salt-sensitive Dahl rats omapatrilat, as compared alone. Therefore, compounds with the capability of in- with equipotent doses of the ACE inhibitor , hibiting ACE and NEP at the same time may offer the restored the impaired NO system by increasing protein possibility to inhibit the RAS and to potentiate the natri- levels of endothelial NO synthase and vascular nitrate uretic peptide system by the use of one single molecule, levels, and normalized endothelium-dependent relax- and, thus, may simultaneously reduce vasoconstriction ations [6]. Since endothelial dysfunction is not only the and enhance vasodilatation. Correspondingly, a number of substances with affinities for both ACE and NEP are result, but also initiator as well as promoter of cardiovas- currently under development. Among those so-called cular disease, vasopeptidase inhibition may be beneficial “vasopeptidase inhibitors,” omapatrilat is the compound in interrupting the vicious cycle of altered endothelial for which most preclinical and clinical data are presently function. available. VASOPEPTIDASE INHIBITORS IN THE VASOPEPTIDASE INHIBITORS IN TREATMENT OF HYPERTENSION EXPERIMENTAL HYPERTENSION Vasopeptidase inhibitors have been shown to be well- Vasopeptidase inhibition has been shown to lower tolerated and effective in clinical trials on hypertensive blood pressure under various experimental conditions, patients under several conditions. In 63 patients with S-56 Quaschning et al: Vasopeptidase inhibition in endothelial dysfunction salt-sensitive hypertension, 40 mg/day of omapatrilat re- The plasma concentrations of omapatrilat administered vealed a greater reduction in systolic, diastolic, and in to 29 patients with moderate to severe renal impairment, mean arterial pressure as compared to 20 mg/day of and even in patients on hemodialysis treatment, did not [9]. In a study on 690 patients with mild to differ between the control and those patients with nor- moderate hypertension, omapatrilat (5 to 40 mg/day) mal renal function [13]. Therefore, no dose adjustment lowered systolic blood pressure (sBP) a much greater of omapatrilat is required in patients with renal impair- extent than lisinopril (20 to 40 mg/day). However, com- ment, independent of its severity. In addition, even in pared with studies of other antihypertensive drugs, such patients with impaired renal function, omapatrilat in- as ACE inhibitors, the number of patients treated with creased urinary ANP excretion [14, 15], indicating the vasopeptidase inhibitors at present is rather small. presence of its beneficial properties irrespective of the Therefore, a large-scale clinical trial with 12,600 pa- degree of renal impairment. tients, Omapatrilat in Persons with Enhanced Risk of Atherosclerosis (OPERA), was initiated to evaluate the impact of vasopeptidase inhibition in isolated systolic SAFETY OF VASOPEPTIDASE INHIBITORS hypertension [10]. Patients older than 65 years with sBP Vasopeptidase inhibitors have been used over a broad between 140 and 160 mm Hg will be randomized in 900 range of dosages, but the number of patients treated centers to receive either 40 mg/day of omapatrilat or and documented at present is still rather low. In clinical placebo, and cardiovascular morbidity and mortality will studies, side effects were comparable to those of ACE be followed up for 3 to 5 years. Another clinical trial with inhibitors. Cough and flush in 573 patients in the Inhibi- 25,267 hypertensive patients, the Omapatrilat Cardiovas- tion of Metalloproteinase in a Randomized Exercise and cular Treatment Assessment Versus (OCTAVE) Symptoms Study in Heart Failure (IMPRESS) trial were trial, to assess the efficacy and safety of low doses (10 reported to occur equally often with ACE inhibitor treat- mg/day) of omapatrilat versus 5 mg/day of enalapril has ment [16]. Similarity of adverse effects of ACE inhibition recently been completed and preliminary results were and vasopeptidase inhibition were recently confirmed in presented in March 2002. These data indicate that in all 5770 patients in the Omapatrilat Versus Enalapril Ran- subgroups, omapatrilat was capable of lowering sBP and domized Trial of Utility in Reducing Events (OVER- dBP after 8 and 24 weeks of treatment, respectively, to TURE) trial [17]. Nevertheless, in data submitted for a greater extent when compared to enalapril. the new drug application of omapatrilat to the US Food and Drug Administration (FDA), 44 instances of angi- VASOPEPTIDASE INHIBITORS AND oedema were reported among more than 6600 patients THE KIDNEY [18]. Therefore, the incidence of angioedema reported Because inhibition of ANP degradation seems to be in the Heart Outcomes Prevention Evaluation (HOPE) one of the most important features of vasopeptidase study [3] was about twice as high (0.7%) as on treatment inhibitors, and elevation of plasma ANP levels by vaso- with . Since patients in the IMPRESS and peptidase inhibition has been demonstrated in several OVERTURE trial were pretreated with ACE inhibitors, preclinical [6] and clinical studies, there is a strong link elevated incidence of angioedema after the onset of vaso- to renal involvement in the regulatory processes induced peptidase inhibition requires even more careful evalua- by vasopeptidase inhibition. tion in large scale, randomized, double-blind clinical tri- Since renal protection, such as in diabetic nephropa- als. The OCTAVE study was especially designed to thy, is one of the favorable effects of ACE inhibitors, the evaluate the risk of adverse effects on omapatrilat treat- influence of vasopeptidase inhibitors on renal function is ment in low doses. Preliminary data of the OCTAVE of major interest. In experimental diabetes, vasopepti- study released in March 2002 indicate that in the treat- dase inhibition reduced albuminuria and led to improve- ment of hypertension, omapatrilat is indeed efficient and ment of renal function [4]. In 89 patients with impaired safe. Although all other adverse effects occurred with renal function (creatinine clearance Ͻ60 mL/min), 12 comparable frequency, angioedema presented with a weeks treatment with omapatrilat reduced proteinuria threefold higher incidence in patients treated with a va- by about 20% and increased serum creatinine by about sopeptidase inhibitior as compared to patients on ACE 15%, thus indicating improvement of renal function by inhibitors (2.17% vs. 0.68%, respectively). Thus, an in- vasopeptidase inhibition. Meanwhile, vasopeptidase in- creased incidence of angioedema appears to be associ- hibition has been proven to slow the progression of renal ated with simultaneous inhibition of NEP and ACE, and injury in subtotally nephrectomized rats [11, 12]. it may be speculated that its occurrence is linked to Since renal impairment is a frequent condition among the decreased degradation of bradykinin. Since patients patients with advanced cardiovascular disease, safety of were treated for 24 weeks only in the OCTAVE study, pharmacotherapy in these patients is an important issue. safety of vasopeptidase inhibitors remains a matter of Quaschning et al: Vasopeptidase inhibition in endothelial dysfunction S-57 debate until extensive data about adverse effects on long- 3. Yusuf S, Sleight P, Pogue J, et al: Effects of an angiotensin- converting-enzyme inhibitor, ramipril, on cardiovascular events in term treatment are available. high-risk patients. The Heart Outcomes Prev Eval Study Investiga- tors. N Engl J Med 342:145–153, 2000 4. Tikkanen T, Tikkanen I, Rockell MD, et al: Dual inhibition of CONCLUSION neutral endopeptidase and angiotensin-converting enzyme in rats with hypertension and diabetes mellitus. Hypertens 32:778–785, In all preclinical and clinical trials completed so far, 1998 vasopeptidase inhibition has proven highly effective in 5. Trippodo NC, Robl JA, Asaad MM, et al: Effects of omapatrilat treatment of endothelial dysfunction, hypertension, and in low, normal, and high renin experimental hypertension. Am J Hypertens 11:363–372, 1998 heart failure. To replace or extend traditional treatment 6. Quaschning T, d’Uscio LV, Shaw S, Lu¨ scher TF: Vasopeptidase concepts, novel cardiovascular drugs will have to provide inhibition exhibits endothelial protection in salt-induced hyperten- an excellent profile of beneficial effects and/or minimized sion. Hypertens 37:1108–1113, 2001 7. Ferrario CM, Smith RD, Brosnihan B, et al: Effects of omapatrilat side effects. Vasopeptidase inhibition has been demon- on the renin-angiotensin system in salt-sensitive hypertension. Am strated to be beneficial in diabetes and renal failure, J Hypertens 15:557–564, 2002 which are common conditions among cardiovascular pa- 8. Quaschning T, d’Uscio LV, Shaw S, et al: Vasopeptidase inhibi- tion restores renovascular endothelial dysfunction in salt-induced tients. The encouraging experimental and clinical results hypertension. J Am Soc Nephrol 12:2280–2287, 2001 obtained with this broad spectrum and potent cardiovas- 9. Campese VM, Lasseter KC, Ferrario CM, et al: Omapatrilat ver- cular active agent warrant further clinical investigation. sus lisinopril: Efficacy and neurohormonal profile in salt-sensitive hypertensive patients. Hypertens 38:1342–1348, 2001 Since clinical trials on vasopeptidase inhibition in hyper- 10. Kostis JB, Cobbe S, Johnston C, et al: Design of the Omapatrilat in tension have demonstrated efficient blood pressure low- Persons with Enhanced Risk of Atherosclerotic events (OPERA) ering by this novel therapeutic principle, but suggested trial. Am J Hypertens 15:193–198, 2002 11. Cao Z, Burrell LM, Tikkanen I, et al: Vasopeptidase inhibition a higher incidence of angioedema as compared to ACE attenuates the progression of renal injury in subtotal nephrecto- inhibitor treatment, the relation of efficacy and safety mized rats. Kidney Int 60:715–721, 2001 will have to be evaluated carefully in large-scale clinical 12. Taal MW, Nenov VD, Wong W, et al: Vasopeptidase inhibition affords greater renoprotection than angiotensin-converting en- studies. Their future results will help to better assess the zyme inhibition alone. J Am Soc Nephrol 12:2051–2059, 2001 place of vasopeptidase inhibition in the treatment of 13. 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