CRRL269.

Rationale: Acute kidney injury (AKI) has a high prevalence and mortality in critically ill patients. It is also a powerful risk factor for heart failure incidence driven by hemodynamic changes and neurohormonal activation. However, no drugs have been approved by the Food and Drug Administration.

Design, Synthesis, and Actions of an Innovative Bispecific Designer Peptide.

Despite optimal current therapies, cardiovascular disease remains the leading cause for death worldwide. Importantly, advances in peptide engineering have accelerated the development of innovative therapeutics for diverse human disease states. Additionally, the advancement of bispecific therapeutics targeting >1 signaling pathway represents a highly innovative strategy for the treatment of cardiovascular disease.

CRRL269: a novel designer and renal-enhancing pGC-A peptide activator.

The natriuretic peptides (NPs) B-type NP (BNP) and urodilatin (URO) exert renal protective properties via the particulate guanylyl cyclase A receptor (pGC-A). As a potential renal-enhancing strategy, we engineered a novel designer peptide that we call CRRL269. CRRL269 was investigated in human cell lines and in normal canines to define potential cardiorenal enhancing actions.

Early activation of deleterious molecular pathways in the kidney in experimental heart failure with atrial remodeling.

Heart failure (HF) is a major health problem with worsening outcomes when renal impairment is present. Therapeutics for early phase HF may be effective for cardiorenal protection, however the detailed characteristics of the kidney in early-stage HF (ES-HF), and therefore treatment for potential renal protection, are poorly defined. We sought to determine the gene and protein expression profiles of specific maladaptive pathways of ES-HF in the kidney and heart.

Differential expression of the pro-natriuretic peptide convertases corin and furin in experimental heart failure and atrial fibrosis.

In heart failure (HF), the cardiac hormone natriuretic peptides (NPs) atrial (ANP), B-type (BNP), and C-type (CNP) play a key role to protect cardiac remodeling. The proprotein convertases corin and furin process their respective pro-NPs into active NPs. Here we define in a canine model of HF furin and corin gene and protein expression in normal and failing left atrium (LA) or ventricle (LV) testing the hypothesis that the NP proproteins convertases production is altered in experimental HF.

Renal and anti-aldosterone actions of vasopressin-2 receptor antagonism and B-type natriuretic peptide in experimental heart failure.

Background: Hemodynamic and neurohumoral function can affect the efficacy of diuretic therapy in congestive heart failure. Arginine vasopressin increases water reabsorption through the V(2) receptor in the collecting duct, whereas B-type natriuretic peptide (BNP) decreases sodium reabsorption in the collecting duct. We hypothesized that combining BNP to the V(2)-receptor antagonist tolvaptan (TLV) would enhance renal excretory function by augmenting sodium excretion together with aquaresis without adversely affecting renal hemodynamics in experimental congestive heart failure.

B-type natriuretic peptide 8-32, which is produced from mature BNP 1-32 by the metalloprotease meprin A, has reduced bioactivity.

32-amino acid B-type natriuretic peptide (BNP 1-32) plays an important role in cardiovascular homeostasis. Recently, it was reported that BNP 1-32 is cleaved by the metalloprotease meprin A to BNP 8-32, the bioactivity of which is undefined. We hypothesized that BNP 8-32 has reduced vasodilating and natriuretic bioactivity compared with BNP 1-32 in vivo.

Mineralocorticoid escape by the kidney but not the heart in experimental asymptomatic left ventricular dysfunction.

Unlike healthy subjects, overt congestive heart failure cannot "escape" the sodium- and water-retaining actions of mineralocorticoid excess. It is undefined whether escape occurs in asymptomatic left ventricular dysfunction (ALVD), which is characterized by preserved sodium homeostasis, natriuretic peptide activation, and normal circulating aldosterone. We hypothesized that, in ALVD, mineralocorticoid excess with exogenous deoxycorticosterone acetate (DOCA) would overwhelm renal compensatory mechanisms, resulting in sodium and water retention, and promote renal and cardiac collagen deposition.

Des-serine-proline brain natriuretic peptide 3-32 in cardiorenal regulation.

Brain natriuretic peptide (BNP 1-32) plays an important physiologic role in cardiorenal homeostasis. Recently, it has been reported that BNP 1-32 is rapidly cleaved by the ubiquitous enzyme dipeptidyl peptidase IV to BNP 3-32, which lacks the two NH2-terminal amino acids of BNP 1-32. The bioactivity of BNP 3-32 in cardiorenal regulation is unknown.

Oral human brain natriuretic peptide activates cyclic guanosine 3',5'-monophosphate and decreases mean arterial pressure.

Background: The objective of this study was to address the feasibility and the biological activity of orally administered human brain natriuretic peptide (hBNP). Proprietary technology has been developed in which short, amphiphilic oligomers are covalently attached to peptides. The conjugated peptides are intended to have an improved pharmacokinetic profile and to enable oral administration.

Cardiorenal and humoral properties of a novel direct soluble guanylate cyclase stimulator BAY 41-2272 in experimental congestive heart failure.

Background: BAY 41-2272 is a recently introduced novel orally available agent that directly stimulates soluble guanylate cyclase (sGC) and sensitizes it to its physiological stimulator, nitric oxide. To date, its therapeutic actions in congestive heart failure (CHF) remain undefined. We characterized the cardiorenal actions of intravenous BAY 41-2272 in a canine model of CHF and compared it to nitroglycerin (NTG).

Maximizing the natriuretic peptide system in experimental heart failure: subcutaneous brain natriuretic peptide and acute vasopeptidase inhibition.

Background: A hallmark of congestive heart failure (CHF) is the elevation of the cardiac natriuretic peptides (NPs), which have natriuretic, renin-inhibiting, vasodilating, and lusitropic properties. We have reported that chronic subcutaneous (SQ) administration of brain natriuretic peptide (BNP) in experimental CHF improves cardiorenal function. Vasopeptidase inhibitors (VPIs) are single molecules that simultaneously inhibit both neutral endopeptidase 24.