Oral human brain natriuretic peptide activates cyclic guanosine 3′,5′-monophosphate and decreases mean arterial pressure

Alessandro Cataliotti, John A. Schirger, Fernando L. Martin, Horng Haur Chen, Paul McKie, Guido Boerrigter, Lisa C. Costello-Boerrigter, Gail Harty, Denise M. Heublein, Sharon M. Sandberg, Kenneth D. James, Mark A. Miller, Navdeep B. Malkar, Karen Polowy, John C Jr. Burnett

54 Scopus citations

Abstract

Background-The objective of this study was to address the feasibility and the biological activity of orally administered human brain natriuretic peptide (hBNP). Proprietary technology has been developed in which short, amphiphilic oligomers are covalently attached to peptides. The conjugated peptides are intended to have an improved pharmacokinetic profile and to enable oral administration. We hypothesized that novel oral conjugated hBNP (CONJ-hBNP) increases plasma hBNP, activates cGMP, and reduces mean arterial pressure (MAP). Methods and Results-This randomized crossover-designed study tested the biological activity of oral CONJ-hBNP compared with oral native hBNP in normal conscious dogs. Measurements of MAP, plasma hBNP, and cGMP were made at baseline (BL) and repeated at 10, 30, 60, 120, 180, and 240 minutes after oral administration. Plasma hBNP was not detectable in dogs at BL. Plasma hBNP was detected after native hBNP and CONJ-HBNP administration. However, plasma hBNP concentration was significantly higher after CONJ-hBNP than after native hBNP administration (P=0.0374 between groups). Plasma cGMP increased after CONJ-hBNP for 60 minutes (from 10.8±3 to 36.8±26 pmol/mL; P<0.05), whereas it did not change after native hBNP (P=0.001 between groups). MAP decreased at 10 minutes and remained decreased for 60 minutes after CONJ-hBNP (from 113±8 to 101±12 mm Hg after 10 minutes to 97.5±10 mm Hg after 30 minutes to 99±13 mm Hg after 60 minutes) while remaining unchanged after native hBNP (P=0.0387 between groups). Conclusions-This study reports for the first time that novel conjugated oral BlSfP activates cGMP and significantly reduces MAP, thus implying an efficacious coupling of CONJ-hBNP to the natriuretic receptor-A. These data advance a new concept of orally administered chronic BNP therapy for cardiovascular diseases.

Original languageEnglish (US)
Pages (from-to)836-840
Number of pages5
JournalCirculation
Volume112
Issue number6
DOIs
StatePublished - Aug 9 2005

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Keywords

  • Blood pressure
  • Cyclic GMP
  • Natriuretic peptides

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Oral human brain natriuretic peptide activates cyclic guanosine 3′,5′-monophosphate and decreases mean arterial pressure. / Cataliotti, Alessandro; Schirger, John A.; Martin, Fernando L.; Chen, Horng Haur; McKie, Paul; Boerrigter, Guido; Costello-Boerrigter, Lisa C.; Harty, Gail; Heublein, Denise M.; Sandberg, Sharon M.; James, Kenneth D.; Miller, Mark A.; Malkar, Navdeep B.; Polowy, Karen; Burnett, John C Jr.

In: Circulation, Vol. 112, No. 6, 09.08.2005, p. 836-840.

Research output: Contribution to journalArticle