Burnett, John C

BMC Pharmacology

English

PubMed

John C Burnett

Crossref

Modulating cGMP in heart failure by novel natriuretic peptides

Springer - Publisher Connector

BioMed Central
Page 1 of 1
(page number not for citation purposes)
BMC Pharmacology
Open AccessOral presentation
Modulating cGMP in heart failure by novel natriuretic peptides
John C Burnett Jr
Address: Cardiovascular Diseases, Cardiorenal Research Laboratory, Mayo Clinic, Rochester, MN, USA
Email: John C Burnett - burnett.john@mayo.edu
An emerging concept in cardiorenal therapeutics is the
design and synthesis of chimeric drugs that are single-
chemical entities that combine structural and biological
components of different molecules resulting in novel
agents possessing highly desirable properties. Such a strat-
egy optimizes favorable actions of a least two different
molecules and often reduces unwanted adverse effects.
We recently reported the design, synthesis and biological
actions of a novel chimeric natriuretic peptide (NP) fusing
the 22-amino acid (AA) sequence of mature C-type natri-
uretic peptide (CNP), a member of the NP family that is
highly conserved among species, with the 15-AA C-termi-
nus of Dendroaspis natriuretic peptide (DNP) that was
isolated from the venom of the eastern green mamba
snake (Dendroaspis angusticeps).
The rationale of the design of this novel chimeric NP was
based upon our knowledge that CNP, principally an
endothelial cell derived peptide, has favorable venorelax-
ing properties that would unload the heart in states of vol-
ume overload but when compared to atrial NP (ANP), B-
type NP (BNP) or urodilatin (URO), which are marked
arterial vasodilators, would be less hypotensive thus bet-
ter preserving renal perfusion pressure. Such hemody-
namic properties are a consequence of CNP activation of
the NP receptor-B (NPR-B) that is highly expressed in
veins as compared to arteries. In contrast, ANP and BNP
which function via the NP receptor-A (NPR-A) principally
vasorelax arteries where NPR-A is highly expressed. A ther-
apeutic limitation of the use of CNP in volume overload
states is that in contrast to ANP and BNP, CNP lacks renal
actions limiting its utility in states of sodium and water
retention or altered glomerular function.
The second principle in the design of CD-NP was based
upon our understanding of DNP. Indeed, previous studies
from our laboratory have demonstrated that DNP is
potently natriuretic and diuretic but also markedly hypo-
tensive. More recently, studies have established that DNP
like ANP and BNP is a ligand for NPR-A. Further, Lisy et al
have reported that the 15-AA C-terminus of DNP pos-
sessed mild natriuretic and diuretic actions, which pro-
vided the rationale for the hypothesis that the C-terminus
of DNP in a chimeric design would provide CNP with the
ability to activate NPR-A and transform CNP into a natri-
uretic and diuretic peptide lacking significant hypotensive
actions. Indeed, in recent studies in cells overexpressing
either NPR-A or NPR-B, CD-NP activated both NPR-B and
NPR-A with predominate stimulation being NPR-B. Spe-
cifically, CD-NP was able to activate in cells expressing
either NPR-A or NPR-B the generation of cyclic guanosine
monophosphate (cGMP) that is the second messenger for
both NP receptors.
Here we will review both preclinical development and the
first clinical studies including first in humans and studies
in human heart failure.
from 4th International Conference of cGMP Generators, Effectors and Therapeutic Implications
Regensburg, Germany. 19–21 June 2009
Published: 11 August 2009
BMC Pharmacology 2009, 9(Suppl 1):S8 doi:10.1186/1471-2210-9-S1-S8
<supplement> <title> <p>4th International Conference of cGMP Generators, Effectors and Therapeutic Implications</p> </title> <note>Meeting abstracts – A single PDF containing all abstracts in this Supplement is available <a href="http://www.biomedcentral.com/content/files/pdf/1471-2210-9-S1-full.pdf">here</a>.</note> <url>http://www.biomedcentral.com/content/pdf/1471-2210-9-S1-info.pdf</url> </supplement>
This abstract is available from: http://www.biomedcentral.com/1471-2210/9/S1/S8
© 2009 Burnett; licensee BioMed Central Ltd. 


file:///data/core-remote/dit/data/Springer-OA/pdf/e0b/aHR0cDovL2xpbmsuc3ByaW5nZXIuY29tLzEwLjExODYvMTQ3MS0yMjEwLTktUzEtUzgucGRm.pdf

Modulating cGMP in heart failure by novel natriuretic peptides

Abstract

Similar works

Full text

Available Versions

Crossref

Springer - Publisher Connector