Do engineered natriuretic peptides have greater therapeutic potential than do native peptides?

As is well known, intravenously infused nesiritide [a recombinant form of brain-type natriuretic peptide (BNP)] antagonizes renin– angiotensin–aldosterone system activation and induces natriuresis, diuresis, and venous and arterial dilation. When administered to patients with acutely decompensated heart failure, a rapid reduction of pulmonary capillary pressure and consequent relief of dyspnoea often results. However, BNP-induced dilation of resistance (arterioles) and capacitance (veins) vessels taken together with the diuresis-associated reduction of blood (plasma) volume causes clinically significant systemic hypotension in some patients. Unfortunately, this hypotension can be associated with decreased renal perfusion and worsening of renal function, and the latter has been associated with increased morbidity and mortality in some clinical trials. The hypotension and consequent complications can be attenuated by reducing the dose of nesiritide being administered. Recently, Burnett and colleagues speculated that they might be able to improve the therapeutic properties of natriuretic peptides by modifying their structures. Their goal was to generate a natriuretic peptide that retained the biological activities of BNP sans the capacity to dilate resistance vessels. Their first engineered chimeric natriuretic peptide (CD-NP) comprised the 15-amino acid C-terminus of the Dendroaspis peptide (a snake-derived natriuretic peptide) and the peptide ring component of the cardiac-type natriuretic peptide (CNP). CNP lacks renal actions but retains veno-dilator capacity and has only modest dilatory effects on resistance vessels. CD-NP had potent natriuretic and diuretic effects and retained veno-dilatory effects in normal dogs but did not cause significant systemic hypotension. Moreover, in in vitro studies, CD-NP was shown to inhibit proliferation of cardiac fibroblasts. In a preliminary pharmacological study performed in normal human volunteers, CD-NP was also found to have potent natriuretic and renin–angiotensin–aldosterone system antagonistic effects; notably, it did not induce significant systemic hypotension. CD-NP is now being evaluated in a Phase II clinical trial. In the current report, Kilić et al. examine the cellular effects of a newer chimeric molecule (designated CU-NP). In CU-NP, the ring structure of CNP is joined to the Nand C-termini of urodilatin. The latter is another natriuretic peptide with potent diuretic and natriuretic properties as well as arteriolar and venous dilatory effects. Preliminary studies of CU-NP in anaesthetized normal dogs had indicated that this agent increases the rates of glomerular filtration and renal sodium and water excretion. Further, although administration of CU-NP reduced pulmonary capillary wedge pressures, systemic hypotension did not occur. In this model, the natriuretic peptide urodilatin did induce significant arterial hypotension in addition to the aforementioned renal and veno-dilator effects (see cited references in Kilić et al.). That some natriuretic peptides antagonize hypertrophic signalling pathways in cardiomyocytes and fibrosis-associated signalling pathways in fibroblasts has been known for some time. To determine whether CU-NP retained these potentially beneficial properties, Kilić et al. tested the effects of CU-NP on selected hypertrophic signalling pathways following their activation (in neonatal rat cardiomyocytes) by classical Gqa-coupled receptor agonists. As expected, each agonist induced cardiomyocyte hypertrophy that was associated with significantly increased expression of the sarcolemmal sodium–hydrogen ion exchanger (NHE) mRNA, protein, and activity. A downstream consequence of increased NHE activity was increased calcineurin activity. This was presumably mediated by increased cytosolic entry of calcium (via the sodium–calcium exchanger) caused by the higher cytosolic sodium levels engendered by increased NHE activity. A significant consequence of calcineurin activation was greater nuclear localization of NFAT, a transcription factor known to activate many hypertrophy-associated genes. Notably, CU-NP abrogated this sequence of agonist-induced molecular responses with an efficacy comparable to that of native natriuretic peptides. These data are consistent with earlier reports that showed that direct inhibition of the NHE also antagonized the effects of pro-hypertrophic stimuli in conjunction with normalization of the calcineurin pathway. The precise mechanisms by