Nesiritide in Resistant Hypertension

Hypertension remains a global burden in cardiovascular disease leading to stroke, myocardial
infarction, and heart failure. Its myocardial complications result from increased mechanical
load on the heart. Under physiological conditions of increased myocardial load and resulting
myocardial stretch, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP)
synthesis and secretion occur contributing to maintenance of optimal cardiorenal and blood
pressure homeostasis. However, studies indicate that in subjects with cardiovascular diseases
the biological structure of these hormones may be altered, thus reducing their favorable
protective activities. New studies indicate that early and moderate hypertension is
associated with a derangement of the natriuretic peptide system which is characterized by the
lack of activation of biologically active ANP and BNP, while severe hypertension is
characterized by cardiac release of altered molecular forms of ANP and BNP that have reduced
biological properties and/or enhanced degradation.

The broad objective of proposal is to advance the biology and therapeutics of the natriuretic
peptides (NPs) with a special focus on the cardiac peptide BNP in human hypertension. The
investigators' proposal is based upon the biological properties of BNP (i.e., natriuretic,
renin-angiotensin-aldosterone suppressing, vasodilating, anti-fibrotic, anti-hypertrophic and
positive lusitropic), its mechanistic role in human hypertension, and thus its potential as
an innovative chronic protein therapeutic to enhance the treatment of patients with
uncontrolled and or resistant hypertension. Importantly, BNP is an endocrine hormone normally
produced by the human heart, and its use as therapeutic agent has been approved in USA for
more than a decade and has been proven to be safe.

Inclusion criteria:

Subjects with resistant hypertension as defined by the Seventh Report of the Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC
7) guidelines, systolic blood pressure and/or diastolic blood pressure > 140/90 mm Hg. For
patients with hypertension and diabetes or renal disease, blood pressure > 130/80 mm Hg
despite treatment with diuretic, sympathetic depressant and vasodilators.

Medications may include a three drug regimen including:

- diuretic at therapeutic dose

- a second line agent such as sympatholytic (e.g. beta-blockade, central agent such as
clonidine) or angiotensin converting enzyme inhibitor (ACEi) / angiotensin receptor
blocker (ARB) or calcium channel blocker (CCB).

- third line agent including one of the above and/or direct vasodilator, such as
hydralazine or minoxidil.

Exclusion criteria:

- Congestive Heart Failure (any New York Heart Association (NYHA) class)

- Ejection Fraction < 50%

- Known renal artery stenosis

- Myocardial infarction within 3 months of screening

- Unstable angina within 14 days of screening, or any evidence of myocardial ischemia

- Moderate to severe pulmonary hypertension

- Valvular stenosis, hypertrophic, restrictive or obstructive cardiomyopathy,
constrictive pericarditis, primary pulmonary hypertension, or biopsy proven active
myocarditis

- Sustained ventricular tachycardia or ventricular fibrillation within 14 days of
screening

- Sustained Atrial Fibrillation

- Second or third degree atrioventricular (AV) block without a permanent cardiac
pacemaker

- Cerebral vascular accident within 3 months of screening, or other evidence of
significantly compromised central nervous system perfusion

- Total bilirubin of > 1.5 mg/dL or aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) 1.5 times the upper limit of normal range

- Renal insufficiency assessed by calculated Glomerular Filtration Rate (GFR) < 30
ml/min (Cockcroft-Gault equation)

- Serum sodium of < 125 milliequivalent (mEq)/dL or > 160 mEq/dL

- Serum potassium of < 3.0 mEq/dL or > 5.5 mEq/dL

- Women taking hormonal contraceptives

- Pregnancy

- Body mass index (BMI) > 35