This Article Full Text Full Text (PDF) All Versions of this Article: 49/5/1128    most recent HYPERTENSIONAHA.106.083832v1 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 Boerrigter, G. Articles by Burnett, J. C. Search for Related Content PubMed PubMed Citation Articles by Boerrigter, G. Articles by Burnett, J. C., Jr Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Heart Failure Related Collections Cardio-renal physiology/pathophysiology Congestive Cardiovascular Pharmacology Animal models of human disease Endothelium/vascular type/nitric oxide Related Article

(Hypertension. 2007;49:1128.)
© 2007 American Heart Association, Inc.

Original Articles

Targeting Heme-Oxidized Soluble Guanylate Cyclase in Experimental Heart Failure

Guido Boerrigter; Lisa C. Costello-Boerrigter; Alessandro Cataliotti; Harald Lapp; Johannes-Peter Stasch; John C. Burnett, Jr

From the Cardiorenal Research Laboratory (G.B., L.C.C.-B., A.C., J.C.B.), Mayo Clinic and Foundation, Rochester, Minn; Pharma Research Center (J.-P.S.), Bayer HealthCare AG, Wuppertal, Germany; and the Department of Cardiology (H.L.), HELIOS-Klinikum, Erfurt, Germany.

Correspondence to Guido Boerrigter, Cardiorenal Research Laboratory, Guggenheim 915, Mayo Clinic and Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905. E-mail boerrigter.guido{at}mayo.edu

Soluble guanylate cyclase is a heterodimeric enzyme with a prosthetic heme group that, on binding of its main ligand, NO, generates the second messenger cGMP. Unlike conventional nitrovasodilators, the novel direct NO- and heme-independent soluble guanylate cyclase activator BAY 58-2667 is devoid of non-cGMP actions, lacks tolerance development, and preferentially activates NO-insensitive heme-free or oxidized soluble guanylate cyclase. BAY 58-2667, therefore, represents a novel therapeutic advance in mediating vasodilation. To date, its cardiorenal actions in congestive heart failure (CHF) are undefined. We, therefore, hypothesized that BAY 58-2667 would have beneficial preload- and afterload-reducing actions in experimental severe CHF together with renal vasodilating properties. We assessed the cardiorenal actions of intravenous administration of 2 doses of BAY 58-2667 (0.1 and 0.3 µg/kg per minute, respectively) in a model of tachypacing-induced severe CHF. In CHF, BAY 58-2667 dose-dependently reduced mean arterial, right atrial, pulmonary artery, and pulmonary capillary wedge pressure (from baseline 19±1 to 12±2 mm Hg). Cardiac output (2.4±0.3 to 3.2±0.4 L/min) and renal blood flow increased. Glomerular filtration rate and sodium and water excretion were maintained. Consistent with cardiac unloading, atrial and B-type natriuretic peptide decreased. Plasma renin activity (P=0.31) and aldosterone remained unchanged (P=0.19). In summary, BAY 58-2667 in experimental CHF potently unloaded the heart, increased cardiac output and renal blood flow, and preserved glomerular filtration rate and sodium and water excretion without further neurohumoral activation. These beneficial properties make direct soluble guanylate cyclase stimulation with BAY 58-2667 a promising new therapeutic strategy for cardiovascular diseases, such as heart failure.

Key Words: soluble guanylate cyclase • heart failure • drugs • oxidant stress • BAY 58-2667

Related Article:

Targeting Heme-Oxidized Soluble Guanylate Cyclase: Solution for All Cardiorenal Problems in Heart Failure?

Thomas Münzel, Sabine Genth-Zotz, and Ulrich Hink
Hypertension 2007 49: 974-976. [Full Text] [PDF]

This article has been cited by other articles:

				B. Kemp-Harper and R. Feil Meeting Report: cGMP Matters Sci. Signal., September 2, 2008; 1(35): pe12 - pe12. [Abstract] [Full Text] [PDF]

				T. Nagayama, M. Zhang, S. Hsu, E. Takimoto, and D. A. Kass Sustained Soluble Guanylate Cyclase Stimulation Offsets Nitric-Oxide Synthase Inhibition to Restore Acute Cardiac Modulation by Sildenafil J. Pharmacol. Exp. Ther., August 1, 2008; 326(2): 380 - 387. [Abstract] [Full Text] [PDF]

				B. Kemp-Harper and R. Feil Meeting Report: cGMP Matters Sci. Signal., March 4, 2008; 1200(1): pe12 - pe12. [Abstract] [Full Text] [PDF]

				B. Kemp-Harper and R. Feil Meeting Report: cGMP Matters Sci. Signal., March 4, 2008; 1(9): pe12 - pe12. [Abstract] [Full Text] [PDF]

				L. Paulis and F. Simko LA419, a Novel Nitric Oxide Donor, Prevents Cardiac Remodeling Via the Endothelial Nitric Oxide Synthase Pathway: NO Donors as a Means of Antiremodeling Hypertension, December 1, 2007; 50(6): 1009 - 1011. [Full Text] [PDF]

				F. L. Martin, T. Supaporn, H. H. Chen, S. M. Sandberg, Y. Matsuda, M. Jougasaki, and J. C. Burnett Jr. Distinct roles for renal particulate and soluble guanylyl cyclases in preserving renal function in experimental acute heart failure Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2007; 293(4): R1580 - R1585. [Abstract] [Full Text] [PDF]

				T. Munzel, S. Genth-Zotz, and U. Hink Targeting Heme-Oxidized Soluble Guanylate Cyclase: Solution for All Cardiorenal Problems in Heart Failure? Hypertension, May 1, 2007; 49(5): 974 - 976. [Full Text] [PDF]