Chronic actions of a novel oral B-type natriuretic peptide conjugate in normal dogs and acute actions in angiotensin II-mediated hypertension

Alessandro Cataliotti, Horng Haur Chen, John A. Schirger, Fernando L. Martin, Guido Boerrigter, Lisa C. Costello-Boerrigter, Kenneth D. James, Karen Polowy, Mark A. Miller, Navdeep B. Malkar, Kent R Bailey, John C Jr. Burnett

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Background - We previously reported the feasibility of an acute, orally delivered, newly developed, conjugated form of human B-type natriuretic peptide (hBNP) in normal animals. The objective of the present study was to extend our findings and to define the chronic actions of an advanced oral conjugated hBNP (hBNP-054) administered for 6 days on sodium excretion and blood pressure. We also sought to establish the ability of this new conjugate to acutely activate cGMP and to reduce blood pressure in an experimental model of angiotensin II (ANG II) -mediated hypertension. Methods and Results - First, we developed additional novel conjugated forms of oral hBNP that were superior to our previously reported hBNP-021 in reducing blood pressure in 6 normal dogs. We then tested the new conjugate, hBNP-054, chronically in 2 normal dogs to assess its biological actions as a blood pressure-lowering agent and as a natriuretic factor. Second, we investigated the effects of acute oral hBNP-054 or vehicle in 6 dogs that received continuous infusion of ANG II to induce hypertension. After baseline determination of mean blood pressure (MAP) and blood collection for plasma hBNP and cGMP, all dogs received continuous ANG II infusion (20 ng·kg-1·min-1, 1 mL/min) for 4 hours. After 30 minutes of ANG II, dogs received oral hBNP-054 (400 μg/kg) or vehicle in a random crossover fashion with a 1-week interval between dosing. Blood sampling and MAP measurements were repeated 30 minutes after ANG II administration and 10, 30, 60, 120, 180, and 240 minutes after oral administration of hBNP-054 or vehicle. In the chronic study in normal dogs, oral hBNP-054 effectively reduced MAP for 6 days and induced a significant increase in 24-hour sodium excretion. hBNP was not present in the plasma at baseline in any dogs, and it was not detected at any time in the vehicle group. However, hBNP was detected throughout the duration of the study after oral hBNP-054, with a peak concentration at 30 minutes of 1060±818 pg/mL. In the acute study, after ANG II administration, plasma cGMP was not activated after vehicle, whereas it was significantly increased after oral hBNP-054 (P=0-01 between the 2 groups). Importantly, MAP was significantly increased after ANG II throughout the acute study protocol. However, although no changes occurred in MAP after vehicle administration, oral hBNP-054 reduced MAP for >2 hours (from 138±1 mm Hg after ANG II to 124±2 mmHg at 30 minutes, 124±2mmHgat 1 hour, and 130±5 mmHg at 2 hours after oral hBNP-054; P<0.001). Conclusions - This study reports for the first time that a novel conjugated oral hBNP possesses blood pressure-lowering and natriuretic actions over a 6-day period in normal dogs. Furthermore, hBNP-054 activates cGMP and reduces MAP in a model of acute hypertension. These findings advance the concept that orally administered chronic BNP is a potential therapeutic strategy for cardiovascular diseases such as hypertension.

Original languageEnglish (US)
Pages (from-to)1729-1736
Number of pages8
JournalCirculation
Volume118
Issue number17
DOIs
StatePublished - Oct 21 2008

Fingerprint

Brain Natriuretic Peptide
Angiotensin II
Dogs
Hypertension
Blood Pressure
Oral Administration
Sodium
Blood Pressure Determination
Natriuretic Agents

Keywords

  • Blood pressure
  • Cyclic GMP
  • Natriuretic peptides

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Chronic actions of a novel oral B-type natriuretic peptide conjugate in normal dogs and acute actions in angiotensin II-mediated hypertension. / Cataliotti, Alessandro; Chen, Horng Haur; Schirger, John A.; Martin, Fernando L.; Boerrigter, Guido; Costello-Boerrigter, Lisa C.; James, Kenneth D.; Polowy, Karen; Miller, Mark A.; Malkar, Navdeep B.; Bailey, Kent R; Burnett, John C Jr.

In: Circulation, Vol. 118, No. 17, 21.10.2008, p. 1729-1736.

Research output: Contribution to journalArticle

Cataliotti, A, Chen, HH, Schirger, JA, Martin, FL, Boerrigter, G, Costello-Boerrigter, LC, James, KD, Polowy, K, Miller, MA, Malkar, NB, Bailey, KR & Burnett, JCJ 2008, 'Chronic actions of a novel oral B-type natriuretic peptide conjugate in normal dogs and acute actions in angiotensin II-mediated hypertension', Circulation, vol. 118, no. 17, pp. 1729-1736. https://doi.org/10.1161/CIRCULATIONAHA.107.759241
Cataliotti, Alessandro ; Chen, Horng Haur ; Schirger, John A. ; Martin, Fernando L. ; Boerrigter, Guido ; Costello-Boerrigter, Lisa C. ; James, Kenneth D. ; Polowy, Karen ; Miller, Mark A. ; Malkar, Navdeep B. ; Bailey, Kent R ; Burnett, John C Jr. / Chronic actions of a novel oral B-type natriuretic peptide conjugate in normal dogs and acute actions in angiotensin II-mediated hypertension. In: Circulation. 2008 ; Vol. 118, No. 17. pp. 1729-1736.
@article{11e966d23df9482b9c4745dfec9eb4d3,
title = "Chronic actions of a novel oral B-type natriuretic peptide conjugate in normal dogs and acute actions in angiotensin II-mediated hypertension",
abstract = "Background - We previously reported the feasibility of an acute, orally delivered, newly developed, conjugated form of human B-type natriuretic peptide (hBNP) in normal animals. The objective of the present study was to extend our findings and to define the chronic actions of an advanced oral conjugated hBNP (hBNP-054) administered for 6 days on sodium excretion and blood pressure. We also sought to establish the ability of this new conjugate to acutely activate cGMP and to reduce blood pressure in an experimental model of angiotensin II (ANG II) -mediated hypertension. Methods and Results - First, we developed additional novel conjugated forms of oral hBNP that were superior to our previously reported hBNP-021 in reducing blood pressure in 6 normal dogs. We then tested the new conjugate, hBNP-054, chronically in 2 normal dogs to assess its biological actions as a blood pressure-lowering agent and as a natriuretic factor. Second, we investigated the effects of acute oral hBNP-054 or vehicle in 6 dogs that received continuous infusion of ANG II to induce hypertension. After baseline determination of mean blood pressure (MAP) and blood collection for plasma hBNP and cGMP, all dogs received continuous ANG II infusion (20 ng·kg-1·min-1, 1 mL/min) for 4 hours. After 30 minutes of ANG II, dogs received oral hBNP-054 (400 μg/kg) or vehicle in a random crossover fashion with a 1-week interval between dosing. Blood sampling and MAP measurements were repeated 30 minutes after ANG II administration and 10, 30, 60, 120, 180, and 240 minutes after oral administration of hBNP-054 or vehicle. In the chronic study in normal dogs, oral hBNP-054 effectively reduced MAP for 6 days and induced a significant increase in 24-hour sodium excretion. hBNP was not present in the plasma at baseline in any dogs, and it was not detected at any time in the vehicle group. However, hBNP was detected throughout the duration of the study after oral hBNP-054, with a peak concentration at 30 minutes of 1060±818 pg/mL. In the acute study, after ANG II administration, plasma cGMP was not activated after vehicle, whereas it was significantly increased after oral hBNP-054 (P=0-01 between the 2 groups). Importantly, MAP was significantly increased after ANG II throughout the acute study protocol. However, although no changes occurred in MAP after vehicle administration, oral hBNP-054 reduced MAP for >2 hours (from 138±1 mm Hg after ANG II to 124±2 mmHg at 30 minutes, 124±2mmHgat 1 hour, and 130±5 mmHg at 2 hours after oral hBNP-054; P<0.001). Conclusions - This study reports for the first time that a novel conjugated oral hBNP possesses blood pressure-lowering and natriuretic actions over a 6-day period in normal dogs. Furthermore, hBNP-054 activates cGMP and reduces MAP in a model of acute hypertension. These findings advance the concept that orally administered chronic BNP is a potential therapeutic strategy for cardiovascular diseases such as hypertension.",
keywords = "Blood pressure, Cyclic GMP, Natriuretic peptides",
author = "Alessandro Cataliotti and Chen, {Horng Haur} and Schirger, {John A.} and Martin, {Fernando L.} and Guido Boerrigter and Costello-Boerrigter, {Lisa C.} and James, {Kenneth D.} and Karen Polowy and Miller, {Mark A.} and Malkar, {Navdeep B.} and Bailey, {Kent R} and Burnett, {John C Jr.}",
year = "2008",
month = "10",
day = "21",
doi = "10.1161/CIRCULATIONAHA.107.759241",
language = "English (US)",
volume = "118",
pages = "1729--1736",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "17",

}

TY - JOUR

T1 - Chronic actions of a novel oral B-type natriuretic peptide conjugate in normal dogs and acute actions in angiotensin II-mediated hypertension

AU - Cataliotti, Alessandro

AU - Chen, Horng Haur

AU - Schirger, John A.

AU - Martin, Fernando L.

AU - Boerrigter, Guido

AU - Costello-Boerrigter, Lisa C.

AU - James, Kenneth D.

AU - Polowy, Karen

AU - Miller, Mark A.

AU - Malkar, Navdeep B.

AU - Bailey, Kent R

AU - Burnett, John C Jr.

PY - 2008/10/21

Y1 - 2008/10/21

N2 - Background - We previously reported the feasibility of an acute, orally delivered, newly developed, conjugated form of human B-type natriuretic peptide (hBNP) in normal animals. The objective of the present study was to extend our findings and to define the chronic actions of an advanced oral conjugated hBNP (hBNP-054) administered for 6 days on sodium excretion and blood pressure. We also sought to establish the ability of this new conjugate to acutely activate cGMP and to reduce blood pressure in an experimental model of angiotensin II (ANG II) -mediated hypertension. Methods and Results - First, we developed additional novel conjugated forms of oral hBNP that were superior to our previously reported hBNP-021 in reducing blood pressure in 6 normal dogs. We then tested the new conjugate, hBNP-054, chronically in 2 normal dogs to assess its biological actions as a blood pressure-lowering agent and as a natriuretic factor. Second, we investigated the effects of acute oral hBNP-054 or vehicle in 6 dogs that received continuous infusion of ANG II to induce hypertension. After baseline determination of mean blood pressure (MAP) and blood collection for plasma hBNP and cGMP, all dogs received continuous ANG II infusion (20 ng·kg-1·min-1, 1 mL/min) for 4 hours. After 30 minutes of ANG II, dogs received oral hBNP-054 (400 μg/kg) or vehicle in a random crossover fashion with a 1-week interval between dosing. Blood sampling and MAP measurements were repeated 30 minutes after ANG II administration and 10, 30, 60, 120, 180, and 240 minutes after oral administration of hBNP-054 or vehicle. In the chronic study in normal dogs, oral hBNP-054 effectively reduced MAP for 6 days and induced a significant increase in 24-hour sodium excretion. hBNP was not present in the plasma at baseline in any dogs, and it was not detected at any time in the vehicle group. However, hBNP was detected throughout the duration of the study after oral hBNP-054, with a peak concentration at 30 minutes of 1060±818 pg/mL. In the acute study, after ANG II administration, plasma cGMP was not activated after vehicle, whereas it was significantly increased after oral hBNP-054 (P=0-01 between the 2 groups). Importantly, MAP was significantly increased after ANG II throughout the acute study protocol. However, although no changes occurred in MAP after vehicle administration, oral hBNP-054 reduced MAP for >2 hours (from 138±1 mm Hg after ANG II to 124±2 mmHg at 30 minutes, 124±2mmHgat 1 hour, and 130±5 mmHg at 2 hours after oral hBNP-054; P<0.001). Conclusions - This study reports for the first time that a novel conjugated oral hBNP possesses blood pressure-lowering and natriuretic actions over a 6-day period in normal dogs. Furthermore, hBNP-054 activates cGMP and reduces MAP in a model of acute hypertension. These findings advance the concept that orally administered chronic BNP is a potential therapeutic strategy for cardiovascular diseases such as hypertension.

AB - Background - We previously reported the feasibility of an acute, orally delivered, newly developed, conjugated form of human B-type natriuretic peptide (hBNP) in normal animals. The objective of the present study was to extend our findings and to define the chronic actions of an advanced oral conjugated hBNP (hBNP-054) administered for 6 days on sodium excretion and blood pressure. We also sought to establish the ability of this new conjugate to acutely activate cGMP and to reduce blood pressure in an experimental model of angiotensin II (ANG II) -mediated hypertension. Methods and Results - First, we developed additional novel conjugated forms of oral hBNP that were superior to our previously reported hBNP-021 in reducing blood pressure in 6 normal dogs. We then tested the new conjugate, hBNP-054, chronically in 2 normal dogs to assess its biological actions as a blood pressure-lowering agent and as a natriuretic factor. Second, we investigated the effects of acute oral hBNP-054 or vehicle in 6 dogs that received continuous infusion of ANG II to induce hypertension. After baseline determination of mean blood pressure (MAP) and blood collection for plasma hBNP and cGMP, all dogs received continuous ANG II infusion (20 ng·kg-1·min-1, 1 mL/min) for 4 hours. After 30 minutes of ANG II, dogs received oral hBNP-054 (400 μg/kg) or vehicle in a random crossover fashion with a 1-week interval between dosing. Blood sampling and MAP measurements were repeated 30 minutes after ANG II administration and 10, 30, 60, 120, 180, and 240 minutes after oral administration of hBNP-054 or vehicle. In the chronic study in normal dogs, oral hBNP-054 effectively reduced MAP for 6 days and induced a significant increase in 24-hour sodium excretion. hBNP was not present in the plasma at baseline in any dogs, and it was not detected at any time in the vehicle group. However, hBNP was detected throughout the duration of the study after oral hBNP-054, with a peak concentration at 30 minutes of 1060±818 pg/mL. In the acute study, after ANG II administration, plasma cGMP was not activated after vehicle, whereas it was significantly increased after oral hBNP-054 (P=0-01 between the 2 groups). Importantly, MAP was significantly increased after ANG II throughout the acute study protocol. However, although no changes occurred in MAP after vehicle administration, oral hBNP-054 reduced MAP for >2 hours (from 138±1 mm Hg after ANG II to 124±2 mmHg at 30 minutes, 124±2mmHgat 1 hour, and 130±5 mmHg at 2 hours after oral hBNP-054; P<0.001). Conclusions - This study reports for the first time that a novel conjugated oral hBNP possesses blood pressure-lowering and natriuretic actions over a 6-day period in normal dogs. Furthermore, hBNP-054 activates cGMP and reduces MAP in a model of acute hypertension. These findings advance the concept that orally administered chronic BNP is a potential therapeutic strategy for cardiovascular diseases such as hypertension.

KW - Blood pressure

KW - Cyclic GMP

KW - Natriuretic peptides

UR - http://www.scopus.com/inward/record.url?scp=55449094132&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=55449094132&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.107.759241

DO - 10.1161/CIRCULATIONAHA.107.759241

M3 - Article

C2 - 18838565

AN - SCOPUS:55449094132

VL - 118

SP - 1729

EP - 1736

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 17

ER -