Guido Boerrigter

John C Burnett

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BMC Pharmacology
Open AccessOral presentation
cGMP enhancing strategies for acute and chronic heart failure
John C Burnett Jr* and Guido Boerrigter
Address: Mayo Medical School, Rochester, Minnesota 55905, USA
Email: John C Burnett* - burnett.john@mayo.edu
* Corresponding author    
Acute and chronic heart failure (HF) are multi-organ and
-cell syndromes characterized by myocardial structural
and functional abnormalities, excessive vascular dysfunc-
tion and vasoconstriction, avid sodium retention, and
neurohumoral maladaptations. In this syndrome, the
cGMP pathway may be disrupted, either with impaired
production of nitric oxide or its excessive degradation,
thus impairing the soluble guanylate cyclase (sGC) signal-
ing pathway or inadequate release of particulate guanylate
cyclase (PGC) ligands such as the natriuretic peptide ANP
or BNP or the release of abnormal forms, therefore
impairing the PGC pathway.
We have explored in human and experimental HF novel
therapeutic strategies targeting both acute and chronic HF
in order to delay disease progression, improve myocardial
and renal function and structure, and enhance clinical
wellbeing.
In acute HF we have targeted SGC with a novel heme-
independent and NO-independent molecule, BAY 58-
2667. In acute congestive HF with marked decompensa-
tion, BAY 58-2667 improved myocardial function with a
decrease in filling pressures both pre-load and after-load,
with a preservation of renal function, consistent with
enhancement of sGC/cGMP signaling. In contrast, we
have designed and synthesized a novel PGC activator,
which is CD-NP. This novel peptide possesses the 17-
amino acid ring structure of CNP so as to target the NPR-
B receptor but with the 15-amino acid C-terminus derived
from DNP. This novel peptide, by targeting NPR-B, lacks
hypotensive actions but decreases cardiac filling pressure
through CNP/NPR-B venodilation, together with marked
improvement in renal function, presumably due to the
15-amino acid C-terminus from DNP. Thus, these two
cGMP activating molecules (BAY 58-2667 and CD-NP)
have promise for the treatment of acute decompensated
HF by targeting this important second messenger system.
So as to chronically enhance myocardial and renal func-
tion and structure in HF, we have recently completed stud-
ies employing a novel orally available conjugate of
human BNP. By novel technology that makes this peptide
orally available but preserves intrinsic cGMP activating
properties, it emerges as a new generation of orally active
peptitic molecules targeting cardiovascular disease.
Recently published studies by our group demonstrate the
ability in the conscious dog to absorb this novel conjugate
to increase circulating levels of BNP, activate cGMP, and
reduce arterial pressures. Studies are underway targeting
both systolic and diastolic dysfunction in experimental
chronic HF to improve myocardial and renal function and
to reduce cardiac fibrosis, a hallmark of HF.
from 2nd International Conference of cGMP Generators, Effectors and Therapeutic Implications
Potsdam, Germany, 10–12 June, 2005
Published: 16 June 2005
BMC Pharmacology 2005, 5(Suppl 1):S22 doi:10.1186/1471-2210-5-S1-S22
<supplement> <title> <p>2nd International Conference of cGMP Generators, Effectors and Therapeutic Implications</p> </title> <note>Meeting abstracts</note> </supplement>


cGMP enhancing strategies for acute and chronic heart failure

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cGMP enhancing strategies for acute and chronic heart failure

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