Abstract 2495: Pharmacodynamic Profile of a Novel Chimeric Natriuretic Peptide, CD-NP, as Compared to C-Type Natriuretic Peptide

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Candace Y Lee ◽  
Guido Boerrigter ◽  
Gail J Harty ◽  
Ondrej Lisy ◽  
John C Burnett
Keyword(s):  
Natriuretic Peptide ◽  
Therapeutic Potential ◽  
Urine Flow ◽  
Peptide Receptor ◽  
Amino Acid Peptide ◽  
Chimeric Peptide ◽  
Equimolar Dose ◽  
C Terminus ◽  
Pharmacodynamic Profile ◽  
Anesthetized Dogs

Background: C-type natriuretic peptide (CNP), a 22-amino-acid peptide and a ligand of the natriuretic peptide receptor-B (NPR-B), exhibits venodilating, anti-fibrotic, and vascular-regenerating properties but limited renal actions. A Mayo-designed chimeric peptide, CD-NP, which consists of CNP and the C-terminus of Dendroaspis NP, was synthesized to test the hypothesis that CD-NP would possess CNP-like properties with an improved pharmacodynamic profile. Methods: Normal anesthetized dogs were given CD-NP 50 ng/kg/min (n = 10) or an equimolar dose of CNP 29.3 ng/kg/min (n = 9) i.v. for 75 min. Hemodynamic, renal, and hormonal data were obtained pre-infusion (pre-I), at 30 and 60 min I, and post-I, and were compared both within group vs pre-I (mean ± SE, P< 0.05*, < 0.01 † ) and between groups ( P < 0.05 ‡ , < 0.01 § , < 0.001 ¶ ). Plasma BNP was measured by radioimmunoassay. Results: CD-NP resulted in greater increases in plasma cGMP (7±.4 to 25±3 †¶ to 36±3 †¶ to 23±3 †¶ pmol/ml), urinary cGMP excretion (978±145, 3170±205 †¶ , 5919±616 †¶ , 3077±298 †¶ pmol/min) vs CNP (8±.8, 10±.6 † , 11±.7 † , 8±.5 pmol/ml; 976±110, 1104±115, 1317±103, 998±101 pmol/min, respectively). CD-NP also increased urine Na + excretion (19±4, 168±24 †§ , 237±26 †¶ , 96±12 † μEq/min), urine flow (0.2±.1, 1.3±.2 † , 1.8±.3 † , 0.8±.2 † ml/min), and GFR (37±2 ‡ , 48±3 † , 51±3 † , 53±4 † ml/min) vs CNP (36±12, 68±10, 85±26, 81±25 μEq/min; 0.4±.1, 0.9±.2, 1.2±.3*, 0.9±.3 ml/min; 52±5, 53±7, 50±4, 49±6 ml/min, respectively). CD-NP reduced PCWP (5.7±.7, 4.1±1*, 3.2±.7 † , 4.3±.8 mmHg), RAP (1.8±.4, 1.1±.4 † , 0.9±.5 †§ , 1.3±.5 § mmHg), PAP (12±.6, 10±.4*, 10±.6, 11±.7 mmHg) vs CNP (6±.6, 5±.8, 6±.8, 7±.9 † mmHg; 2.6±.3, 2.5±.3 to 2.9±.3 to 3.5±.5 † mmHg; 13±1, 12±1, 12±1, 13±1 mmHg, respectively). Mean blood pressure was unchanged in either group. CD-NP increased circulating BNP during infusion vs CNP (40±4 vs 18±2 pg/ml, P<0.001). Conclusion: This study demonstrates the successful transformation of CNP to a CNP-like peptide with enhanced natriuretic, diuretic, GFR-enhancing, and cardiac-unloading actions. CD-NP may also promote increases in plasma BNP which via the NPR-A receptor may contribute to its biological actions. The therapeutic potential of CD-NP in heart failure warrants further studies.

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

2007 ◽  
Vol 292 (2) ◽  
pp. R897-R901 ◽  
Author(s):  
Guido Boerrigter ◽  
Lisa C. Costello-Boerrigter ◽  
Gail J. Harty ◽  
Harald Lapp ◽  
John C. Burnett
Keyword(s):  
Amino Acids ◽  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Urinary Sodium Excretion ◽  
Urine Flow ◽  
Accelerated Degradation ◽  
Equimolar Dose ◽  
Terminal Amino ◽  
Physiologic Role

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. We hypothesized that BNP 3–32 has reduced vasodilating and natriuretic bioactivity compared with BNP 1–32 in vivo. Synthetic human BNP 3–32 and BNP 1–32 were administered to eight anesthetized normal canines. After baseline measurements, BNP 1–32 at 30 ng·kg−1·min−1 was administered, followed by a washout, a postinfusion clearance, and a clearance with an equimolar dose of BNP 3–32. In four studies, the sequence of BNP 1–32 and BNP 3–32 infusion was reversed. Peptides were compared by analyzing the changes from the respective preinfusion clearance to the respective infusion clearance. * P < 0.05 between peptides. BNP 3–32, unlike BNP 1–32, did not decrease mean arterial pressure (0 ± 1 vs. −7 ± 2* mmHg, respectively) and did not increase renal blood flow (+12 ± 10 vs. +52 ± 10* ml/min). Effects on heart rate and cardiac output were similar. Urinary sodium excretion increased 128 ± 18 μeq/min with BNP 3–32 and 338 ± 40* μeq/min with BNP 1–32. Urine flow increased 1.1 ± 0.2 ml/min with BNP 3–32 and 2.8 ± 0.4* ml/min with BNP 1–32. Plasma BNP immunoreactivity was lower with BNP 3–32, suggesting accelerated degradation. In this study, BNP 3–32 showed reduced natriuresis and diuresis and a lack of vasodilating actions compared with BNP 1–32.

CNP causes receptor-mediated positive dromotropic effects in anesthetized dog hearts

1998 ◽  
Vol 275 (2) ◽  
pp. H717-H720 ◽  
Author(s):  
Masamichi Hirose ◽  
Yasuyuki Furukawa ◽  
Yusuke Miyashita ◽  
Fumio Kurogouchi ◽  
Koichi Nakajima ◽  
...  
Keyword(s):  
Blood Flow ◽  
Coronary Artery ◽  
Natriuretic Peptide ◽  
Flow Rate ◽  
Blood Flow Rate ◽  
Natriuretic Peptide Receptor ◽  
Artery Blood Flow ◽  
Peptide Receptor ◽  
Av Conduction ◽  
Anesthetized Dogs

No data are available for the direct effect of C-type natriuretic peptide (CNP) on atrioventricular (AV) conduction in mammalian hearts. Thus we studied the dromotropic effects of CNP-22 injected into the AV node artery in autonomically decentralized hearts in open-chest, anesthetized dogs. CNP decreased AV interval (AV conduction time) in a dose-dependent manner with increase in coronary artery blood flow rate in six anesthetized dogs. Isosorbide dinitrate did not affect AV interval, but it increased coronary artery blood flow rate. A guanylyl cyclase-linked natriuretic peptide receptor antagonist, HS-142–1, inhibited the decreases in AV interval and the increases in coronary blood flow rate in response to CNP, whereas propranolol did not affect the positive dromotropic response to CNP. These results demonstrate that CNP decreases AV interval and increases coronary artery blood flow rate mediated by a guanylyl cyclase-linked natriuretic peptide receptor, but not β-adrenoceptor, in the dog heart.

Abstract 5432: Mutation of Three Amino Acids in the Disulfide-Ring of a CNP Based Chimeric Natriuretic Peptide Alters its Vascular Properties

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Horng H Chen ◽  
Brenda K Huntley ◽  
Candace Y Lee ◽  
Fernando L Martin ◽  
John A Schirger ◽  
...  
Keyword(s):  
Amino Acid ◽  
Natriuretic Peptide ◽  
Right Atrial ◽  
Bolus Administration ◽  
Amino Acid Peptide ◽  
Arterial Blood ◽  
C Terminus ◽  
Cardiac Unloading

BACKGROUND: C-type natriuretic peptide (CNP) is a 22-amino-acid peptide produced mainly in the endothelium with potent cardiac unloading and modest blood pressure lowering actions, but minimal renal actions. Based on our previous knowledge, we recently fused a 6 aa sequence from BNP to the C-terminus and a 5 aa sequence from ANP to the N-terminus of CNP. This novel hybrid peptide, CBA-NP, has cardiac unloading actions and mild hypotensive effects similar to CNP. Importantly however, the N and C terminus alterations resulted in potent renal excretory actions. here we test the hypothesis that the 3 aa GSM 15–17 in the disulfide-ring mediate the vascular and hypotensive actions. We therefore mutated GSM 15–17 to REA 15–17 , which we named ABC-NP and compared its in vivo and in vitro actions to CBA-NP. METHODS: We determined the cardiorenal and humoral actions of intravenous bolus administration of CBA-NP (n=5) and ABC-NP (n=5) at 25 microgram/Kg in 2 separate group of normal anesthetized dogs. We also assessed the cGMP response of both peptides in human aortic endothelial cells (HAEC), human cardiac fibroblast (HCF) and isolated canine glomeruli. * p<0.05 RESULTS: IV bolus administration of CBA-NP and ABC-NP resulted in diuresis* and natriuresis*. There was a significant decrease in mean arterial blood (MAP) pressure with CBA-NP (126±6 to113±7 mmHg*) but no change with ABC-NP(126±8 to126±8 mmHg) . In addition, the reduction in pulmonary capillary wedge pressure (PCWP) and right atrial pressure (RAP) was significantly greater with CBA-NP as compared to ABC-NP. cGMP generation in HAEC and HCF was minimal with ABC-NP and was significantly higher with CBA-NP*. In contrast, cGMP generation was similar in isolated glomeruli between the two peptides. CONCLUSION: Our studies demonstrates that mutation of three amino acid (aa) residues within the CNP ring of CBA-NP from GSM 15–17 to REA alters the vascular but not the renal excretory properties. Hence by this strategic mutation within the ring of CBA-NP, we have designed a renal specific peptide ABC-NP resulting in new sequence specific functional information which can be used to design organ specific therapeutic peptides with unique properties tailored for a specific disease state.

Abstract 414: Putative Role of MicroRNA-143 in Modulating Natriuretic Peptide Signaling via Down-regulation of the Expression of Natriuretic Peptide Receptor 3

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Juan Wang ◽  
Lee L Wong ◽  
Arthur M Richards ◽  
Yei-Tsung Chen
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Natriuretic Peptide ◽  
Therapeutic Potential ◽  
Cardiac Cells ◽  
Luciferase Reporter ◽  
Natriuretic Peptide Receptor ◽  
Down Regulation ◽  
Peptide Receptor

Cardiac natriuretic peptides (NPs) play important roles in the regulation of intravascular blood volume and vascular tone. Among other clearance mechanisms, bio-active circulating NPs are removed by the clearance receptor, Natriuretic Peptide Receptor 3 (NPR3). We hypothesized that the level of NPR3 could be modulated by microRNAs (miRNAs) resulting in changes in the bioactivity of NPs. We have previously reported a cluster of miRNAs potentially regulating NPR3 expression. To extend these findings, expression of the microRNAs concerned was examined in multiple platforms, including plasma from a clinical heart failure cohort, in the rat myocardial infarction model, and in a human cardiac derived cell line subjected to hypoxic challenge. Results: miR-143 was up-regulated in peripheral blood in heart failure patients compared with controls. The binding of miR-143 to the 3’UTR of NPR3 m RNA was verified by luciferase reporter assay. Antagomir-based silencing of miR-143 enhanced NPR3 expression in human derived cardiac cells. Elevation of miR-143 and down-regulation of NPR3 levels were observed in hypoxia treated cells and in the myocardium from the rat myocardial infarction model. Taken together, these findings suggest miR-143 may be involved in the down-regulation of NPR3 which in turn may provide more cardiac protective bioactivity from NPs in heart failure, myocardial hypoxic stress and in myocardial infarction. In summary, NPR3 is negatively regulated by miR-143, pointing to the therapeutic potential of miR-143 to beneficially enhance NP responses.

Neutral endopeptidase inhibition potentiates the natriuretic actions of adrenomedullin

1998 ◽  
Vol 275 (3) ◽  
pp. F410-F414 ◽  
Author(s):  
Ondrej Lisy ◽  
Michihisa Jougasaki ◽  
John A. Schirger ◽  
Horng H. Chen ◽  
Paul T. Barclay ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Filtration Rate ◽  
Urinary Sodium Excretion ◽  
Neutral Endopeptidase ◽  
Urine Flow ◽  
Sodium Reabsorption ◽  
Contralateral Kidney ◽  
Endogenous Peptides ◽  
Anesthetized Dogs ◽  
Nep Inhibition

Adrenomedullin (ADM) is a potent renal vasodilating and natriuretic peptide possessing a six amino acid disulfide ring. Neutral endopeptidase 24.11 (NEP) is localized in greatest abundance in the kidney and cleaves endogenous peptides like atrial natriuretic peptide, which also possesses a disulfide ring. We hypothesized that NEP inhibition potentiates the natriuretic actions of exogenous ADM in anesthetized dogs ( n = 6). We therefore investigated renal function in which one kidney received intrarenal infusion of ADM (1 ng ⋅ kg−1 ⋅ min−1) while the contralateral kidney served as control before and during the systemic infusion of a NEP inhibitor (Candoxatrilat, 8 μg ⋅ kg−1 ⋅ min−1; Pfizer). In response to ADM, glomerular filtration rate (GFR) in the ADM kidney did not change, whereas renal blood flow, urine flow (UV), and urinary sodium excretion (UNaV) increased from baseline. Proximal and distal fractional reabsorption of sodium decreased in the ADM-infused kidney. In response to systemic NEP inhibition, UNaV and UV increased further in the ADM kidney. Indeed, ΔUNaV and ΔUV were markedly greater in the ADM kidney compared with the control kidney. Plasma ADM was unchanged during ADM infusion but increased during NEP inhibition. In conclusion, the present investigation is the first to demonstrate that NEP inhibition potentiates the natriuretic and diuretic responses to intrarenal ADM. This potentiation occurs secondary to a decrease in tubular sodium reabsorption. Lastly, the increase in plasma ADM during systemic NEP inhibition supports the conclusion that ADM is a substrate for NEP.

scholarly journals Effects of Brain Natriuretic Peptide and C-Type Natriuretic Peptide Infusion on Urine Flow and Jejunal Absorption in Anesthetized Dogs.

1992 ◽  
Vol 42 (2) ◽  
pp. 349-353 ◽  
Author(s):  
Hironobu MORITA ◽  
Masanobu HAGIIKE ◽  
Takao HORIBA ◽  
Keisuke MIYAKE ◽  
Hideo OHYAMA ◽  
...  
Keyword(s):  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Urine Flow ◽  
Jejunal Absorption ◽  
Anesthetized Dogs

Immunoelectron microscope detection of C-type natriuretic peptide in normal human atrial tissue

1993 ◽  
Vol 51 ◽  
pp. 388-389
Author(s):  
Chi-Ming Wei ◽  
Margaret Hukee ◽  
Christopher G.A. McGregor ◽  
John C. Burnett
Keyword(s):  
Amino Acid ◽  
Natriuretic Peptide ◽  
Vascular Tone ◽  
Cardiac Tissue ◽  
Ring Structure ◽  
Terminal Amino Acid ◽  
Amino Acid Peptide ◽  
Normal Human ◽  
Terminal Amino ◽  
The Brain

C-type natriuretic peptide (CNP) is a newly identified peptide that is structurally related to atrial (ANP) and brain natriuretic peptide (BNP). CNP exists as a 22-amino acid peptide and like ANP and BNP has a 17-amino acid ring formed by a disulfide bond. Unlike these two previously identified cardiac peptides, CNP lacks the COOH-terminal amino acid extension from the ring structure. ANP, BNP and CNP decrease cardiac preload, but unlike ANP and BNP, CNP is not natriuretic. While ANP and BNP have been localized to the heart, recent investigations have failed to detect CNP mRNA in the myocardium although small concentrations of CNP are detectable in the porcine myocardium. While originally localized to the brain, recent investigations have localized CNP to endothelial cells consistent with a paracrine role for CNP in the control of vascular tone. While CNP has been detected in cardiac tissue by radioimmunoassay, no studies have demonstrated CNP localization in normal human heart by immunoelectron microscopy.

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