Vasopeptidase Inhibitors: Just Another Blood Pressure Lowering Agent or Something More?

Experts gathered on May 15, 2002, at a symposium held during the ASH Annual Meeting, to discuss the role of vasopeptidase inhibitors—a new class of antihypertensive agents that combine the qualities of ACE inhibitors and neutral endopeptidase inhibitors—in the treatment of hypertension. They described the mechanism of action of the drugs and their future clinical implications.

This program was supported by an educational grant from Aventis Pharmaceuticals.

Antihypertensive Therapy: The Place for Vasopeptidase Inhibitors

Nancy J. Brown, MD, Associate Professor of Medicine and Pharmacology, Vanderbilt University Medical Center, Nashville, provided an overview of the role of vasopeptidase inhibitors in antihypertensive therapy.

Despite major advances in the treatment of hypertension, including the development of ACE inhibitors and ARBs, there are some groups of patients in whom these drugs do not work, for example populations with low renin levels such as the elderly and African Americans. “There has been a need to develop new strategies to reduce blood pressure in these populations,” she said. One such strategy involves drugs that combine angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitors.

ACE and NEP are membrane-bound zinc-dependent metalloproteinases. While ACE activity can be measured in the blood, because small amounts are cleaved from the membrane, this does not occur with NEP, so its activity can’t be measured easily in plasma. NEP is found in endothelial cells, vascular smooth muscle cells, myocytes, and renal epithelial cells. “The relative importance of ACE versus NEP varies from tissue bed to tissue bed,” she noted.
ACE cleaves the conversion of angiotensin I to angiotensin II and blocks the degradation of bradykinin, while NEP plays a role in the breakdown of several vasoactive peptides, including ones that cause both vasodilation and vasoconstriction. It is involved in the degradation of bradykinin, the natriuretic peptides, and substance P, all of which cause vasodilation. NEP is also involved in the formation of endothelin and the degradation of angiotensin II.
“Many of the effects of natriuretic peptides oppose the effects of the renin-angiotensin system,” said Dr. Brown. “Whereas angiotensin II decreases natriuresis and diuresis and causes vasoconstriction, the natriuretic peptides increase natriuresis and diuresis and cause vasodilation and, interestingly, decrease renin and aldosterone secretion.”

Bradykinin is a target of interest because of the role it plays in the potential side effects of these drugs. “Bradykinin is cleaved sequentially by ACE to yield bradykinin 1 to 5,” Dr. Brown explained. “It is also cleaved by NEP and kininase I at the carboxy end and by aminopeptidase P and DPP IV at the amino end.”

While ACE is the main enzyme responsible for degrading bradykinin, when it is inhibited several other enzymes may step in to break down the protein. ACE inhibitors also increase bradykinin sensitivity at a receptor level. While cells can lose their response to bradykinin, this can be overcome when both the receptor and the enzyme are present in the membrane. “Importantly, NEP inhibitors also potentiate the effects of bradykinin on the B2 receptor,” said Dr. Brown.

The primary difference among the ACE NEP inhibitors under development, she added, is their relative potency in inhibiting ACE versus NEP. Dr. Brown said she would speak primarily about omapatrilat, for which the most data is available. Omapatrilat is equipotent as an ACE and NEP inhibitor. It is not clear, she said, whether this has an impact on outcome or favorable events and the incidence of angioedema.

Clinical data so far has shown that combined ACE-NEP inhibition reduces blood pressure in both renin-dependent and volume-dependent hypertension. “In humans, NEP inhibitors have been shown to decrease blood pressure and to increase urinary NO and urinary cyclic GNP with variable effects on plasma ANP and variable effects on natriuresis depending on the study,” Dr. Brown explained.

She focused her remarks on the Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril (OCTAVE) trial, which included more than 25,000 patients with untreated or poorly controlled hypertension. The trial compared forced titration of up to 10 to 20 mg of omapatrilat, with optional titration up to 80 mg by 8 weeks, compared to enalapril with titration up to 40 mg. Endpoints were blood pressure at 8 weeks, and up to 24 weeks with the option of adding adjunctive therapy, along with safety.

There were three groups in the study: those with previously untreated hypertension, those who had stopped their original drug and replaced it with a study drug, and those for whom the study drug was used as an additional drug. For all groups, reduction in systolic and diastolic blood pressure at 8 weeks was greater with omapatrilat than with ACE inhibitor. However, the rate of angioedema was higher with omapatrilat. Blacks had a higher risk of angioedema with this drug, and smoking exacerbated this risk.

In the omapatrilat group, about half of the cases of angioedema happened during the first day on the drug. Bradykinin and substance P, both of which can increase vascular permeability, are potential candidates for causing angioedema. “The definitive data as to mechanism will not come until we can give either a bradykinin receptor antagonist or substance P antagonist to people with angioedema in a randomized trial,” said Dr. Brown.

But there are clues to this mechanism, she noted. There is evidence that patients who develop angioedema have a defect in the bradykinin degradation pathway. Dr. Brown’s research also found a decrease in DPP IV activity during acute angioedema. This finding has brought substance P into more serious consideration as a potential culprit.

She concluded by noting that ACE NEP inhibitors might have benefits beyond lowering blood pressure, including reducing MI risk through their bradykinin potentiation.

Improving Vascular Compliance: Components of Antihypertensive Therapy

Joseph L. Izzo, Jr., MD, Professor of Medicine and Pharmacology and Chief of the Clinical Pharmacology Division, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, discussed the potential of ACE NEP inhibitors to bring down systolic blood pressure further than is possible with ACE inhibitors.

Dr. Izzo began by noting that systolic pressure is now known to be the central public health concern in terms of hypertension. And people with lower diastolic pressures actually have higher risk. “This is something that is certainly counterintuitive to some and definitely opposite to what medical school teaching has been for the last many decades in this country,” he said.

There are clinical data to confirm the benefit of lowering systolic blood pressure. “I think the best study is SHEP, in which thiazide was compared with placebo,” he said. This study showed that a 10 mm difference in systolic pressure cut stroke risk 36%, reduced risk of coronary disease by 27%, and brought down heart failure risk by 55%, with all-cause morbidity and mortality cut by roughly one-third.

He noted that the SYST-EUR trial, comparing a calcium antagonist to placebo, also reported a 30% to 35% reduction in overall morbidity and mortality when systolic pressure was brought down. But, he noted, controlling systolic blood pressure becomes more difficult in people older than 75.

“What drives this whole system?” he asked. “I think there’s increasing recognition that we need to split out the stiffening or hardening of arteries, arteriosclerosis, from the inflammatory process, which we’ve lumped together as atherosclerosis.” The stiffening is responsible for the wide pulse pressure of old age, while elastin is lost in the major arteries and conduit vessels and collagen increases, leading to fibrosis.

“The other process I want to bring to your attention is the augmentation of central systolic pressure, increased pulse wave reflection, with the pathogenesis being dependent on increased pulse wave velocity and also to a degree increased distal vasoconstriction,” Dr. Izzo said.

The increased pulse pressure is caused by no elastic recoil to the systolic pulse, and therefore no diastolic flow, he explained. “So we really have a disruption of the flow parameters that are most physiologically effective and this is all directly the result of stiffening of the aorta in principle and some of the proximal branches of the aorta,” he added. This is exacerbated by an increased pulse wave reflection, which puts an additional load on the heart. And hypertensive vessels get stiffer faster.

There are two major features related to the development of systolic hypertension. “One is the stiffness of the conduit arteries, principally the aorta leading to the wide pulse pressure, and the second is that arterial constriction sets up even higher amplitude of reflected waves causing distal vasoconstriction and the progression of systolic pressure,” he said.

Meanwhile, this process has the opposite effect on the diastolic pressure, pushing it down rather than bringing it up. “We can’t totally ignore diastolic,” said Dr. Izzo, “because it may be an early marker for patients who go on to develop premature arterial stiffness.”

Also, the effect of antihypertensive drugs will depend on the patient’s original pattern of blood pressure, meaning a person with elevated systolic pressure would have a greater reduction in systolic pressure. “Unfortunately these changes in pulse pressure during therapy are now being interpreted as evidence that there are improved elements of vascular compliance and it is not right to do so,” he warned.

There’s also evidence that the renin angiotensin system somehow participates in the development of vascular fibrosis and stiffness. ACE inhibitors appear to prevent or slow the development of this stiffness, or perhaps even reverse it. “The renin angiotensin system appears to play a role in the stiffening process,” he said.

ACE NEP inhibitors have many more mechanisms of action than ACE inhibitors, including improvement in natriuretic peptides. “It should come as no surprise that we can do better at turning back the clock and restoring normal arterial function,” Dr. Izzo concluded.

Preservation of Kidney Function: Can We Do Better Than ACE Inhibitors or ARBs?

Norman K. Hollenberg, MD, PhD, Professor of Medicine, Harvard Medical School, and Director of Physiologic Research, Brigham & Women’s Hospital, spoke about whether vasopeptidase inhibitors might have benefits beyond ACE inhibitors in preserving kidney function.

“Azotemia, with or without hypotension, is still one of the major problems leading to discontinuation of ACE inhibitor use in patients with heart failure,” said Dr. Hollenberg. The IMPRESS study found that there was more azotemia with lisinopril than with omapatrilat, even though omapatrilat was more effective in lowering blood pressure. This finding remained the case whether BUN or serum creatinine was used to gauge azotemia. “So omapatrilat is a kidney-friendly drug,” he said.

Two studies of ACE NEP inhibitors in a rat model of hypertension, in which the animal is prone to develop proteinuria, also found that the new drugs did a better job of preventing proteinuria than ACE inhibitors.

In terms of clinical evidence, in a study of 89 patients with azotemia and creatinine clearance of under 60 ml per minute and an average blood pressure of 162/101, doses of omapatrilat brought their systolic blood pressure down to 135. Only two had to stop treatment due to increasing azotemia. Also, early studies have found aggressive dosing with omapatrilat produces no natriuretic response, Dr. Hollenberg noted.

Studies have found that omapatrilat is equally effective in salt-sensitive and salt-resistant patients. The drug is also effective in “young and old, black and white, obese and lean, diabetic and essential hypertensive,” Dr. Hollenberg said.

“The likelihood that the metabolic pathways involved are the same in all these patients is essentially zero, so we’re going to have to work very hard to work out precisely how blood pressure is being lowered in these patients, but one bonus will be that we’ll actually come to understand hypertension a little better,” he concluded.

Optimizing Heart Failure Management in the Hypertensive Patient: Role of Vasopeptidase Inhibitors

John C. Burnett, Jr., MD, Director for Research and Head of the Cardiorenal Research Laboratory, Mayo Clinic, and Professor of Medicine and Physiology, Mayo Medical School, Rochester, Minnesota, spoke about the effect of vasopeptidase inhibitors on patients with heart failure.

The prevalence of heart failure is increasing among the elderly, Dr. Burnett pointed out, and poor control of blood pressure probably plays a role. Treating hypertension clearly lowers the risk of heart failure.

In treating heart disease, kidney disease or heart failure, treatments attempt to target angiotensin II and endothelin, which are vasoconstricting, fibrosing, and sodium retaining. Another goal is to augment the actions of the vasodilating, growth-inhibiting, and natriuretic peptides ANP, BNP, CNP, bradykinin, and adrenomedullin.

ACE inhibitors remain flagships in the treatment of cardiovascular and renal disease. “One might think of this as sort of an inexpensive vasopeptidase inhibitor because in many ways it does inhibit the breakdown of bradykinin,” Dr. Burnett said.

While ACE inhibits the generation of angiotensin II and modulates its downstream actions, NEP inhibits the breakdown of the natriuretic peptides and bradykinin. “Both of these systems function through this second messenger cyclic GMP and very importantly mediate a number of actions, principally the natriuretic peptide actions,” he said.

He went on to discuss omapatrilat and its effect in heart failure. The Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril (OCTAVE) study found that omapatrilat was more effective for reducing systolic pressure, suggesting the drug could help prevent heart failure.

The Omapatrilat Versus Enalapril Trial of Utility in Reducing Events (OVERTURE) trial compared omapatrilat to enalapril and didn’t find a difference. However, a smaller study—the Inhibition of Metallo Protease by BMS-186716 in a Randomized Exercise and Symptoms Study in Subjects With Heart Failure (IMPRESS)—that compared omapatrilat to lisinopril found the newer drug was better in terms of preventing death, hospitalization, or worsening heart failure.

He noted that the SOLVD trial found that kidney function was more important than ejection fraction or New York Heart Association Class in predicting progression of heart failure. “The kidney, in some way, plays a very important role in the outcome of an intervention,” he said.

“If we look at the neurohumoral activation in heart failure, we can target asymptomatic left ventricular dysfunction with VPIs,” he said. This is ventricular dilation with preserved sodium balance and selective activation of the natriuretic peptides and nitric oxide. This is a “very important” subset of patients. In fact, Dr. Burnett said, the NIH plans to target these patients as a top research priority.

Next, he asked, can VPI go beyond ACE inhibitors in terms of models of asymptomatic left ventricular dysfunction, and is there a role for natriuretic peptides? He pointed to a study by a member of his group, Horng H. Chen (Circulation 2002;105:999-1003), which found in an animal model of heart failure that omapatrilat had a natriuretic effect not seen with an ACE inhibitor.

Another study found that the greatest unloading of the heart came with omapatrilat and a diuretic. “Pulmonary artery pressure and wedge pressure dropped the greatest with a vasopeptidase inhibitor,” he said. “I think these are very important.”

Questions remain to be answered about the most effective ratio of NEP versus ACE for treating heart failure and how other drugs might modify the efficacy of VPIs, he concluded.

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