This Article Full Text Full Text (PDF) All Versions of this Article: 112/6/836    most recent CIRCULATIONAHA.105.538520v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cataliotti, A. Articles by Burnett, J. C. Search for Related Content PubMed PubMed Citation Articles by Cataliotti, A. Articles by Burnett, J. C., Jr Related Collections Cardiovascular Pharmacology Animal models of human disease

(Circulation. 2005;112:836-840.)
© 2005 American Heart Association, Inc.

Heart Failure

Oral Human Brain Natriuretic Peptide Activates Cyclic Guanosine 3',5'-Monophosphate and Decreases Mean Arterial Pressure

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

From the Cardiorenal Research Laboratory, Department of Physiology and Internal Medicine, Mayo Clinic and Foundation, Rochester Minn (A.C., J.A.S., F.L.M., H.H.C., P.M.M., G.B., L.C.C.-B., G.H., D.M.H., S.M.S., J.C.B.), and Nobex Corporation, Research Triangle Park, NC (K.D.J., M.A.M., N.B.M., K.P.).

Correspondence to Alessandro Cataliotti, MD, PhD, Cardiorenal Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905. E-mail cataliotti.alessandro{at}mayo.edu

Received January 26, 2005; revision received April 11, 2005; accepted April 14, 2005.

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 BNP 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.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				G. W Yip B-type natriuretic peptide: a treatment, not a diagnostic marker Heart, May 1, 2008; 94(5): 542 - 544. [Full Text] [PDF]

				A. K. Green, R. C. Stratton, P. E. Squires, and A. W. M. Simpson Atrial Natriuretic Peptide Attenuates Elevations in Ca2+ and Protects Hepatocytes by Stimulating Net Plasma Membrane Ca2+ Efflux J. Biol. Chem., November 23, 2007; 282(47): 34542 - 34554. [Abstract] [Full Text] [PDF]

				J. C. Burnett Jr and T. M. Olson Natriuretic Peptides and Myocardial Structure: Insights From Population Genetics Hypertension, April 1, 2007; 49(4): 765 - 766. [Full Text] [PDF]

				H. H. Chen, B. K. Huntley, J. A. Schirger, A. Cataliotti, and J. C. Burnett Jr Maximizing the Renal Cyclic 3'-5'-Guanosine Monophosphate System with Type V Phosphodiesterase Inhibition and Exogenous Natriuretic Peptide: A Novel Strategy to Improve Renal Function in Experimental Overt Heart Failure J. Am. Soc. Nephrol., October 1, 2006; 17(10): 2742 - 2747. [Abstract] [Full Text] [PDF]

				P. Belluardo, A. Cataliotti, L. Bonaiuto, E. Giuffre, E. Maugeri, P. Noto, G. Orlando, G. Raspa, B. Piazza, L. Babuin, et al. Lack of activation of molecular forms of the BNP system in human grade 1 hypertension and relationship to cardiac hypertrophy Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1529 - H1535. [Abstract] [Full Text] [PDF]

				H. H. Chen and J. C. Burnett Jr Clinical application of the natriuretic peptides in heart failure Eur. Heart J. Suppl., September 1, 2006; 8(suppl_E): E18 - E25. [Abstract] [Full Text] [PDF]

				J. C. Burnett Jr Urocortin: Advancing the Neurohumoral Hypothesis of Heart Failure Circulation, December 6, 2005; 112(23): 3544 - 3546. [Full Text] [PDF]