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 Jr. Burnett

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1128-1133
Number of pages6
JournalHypertension
Volume49
Issue number5
DOIs
StatePublished - May 2007

Fingerprint

Heme
Heart Failure
Renal Circulation
Glomerular Filtration Rate
Cardiac Output
Sodium
Pulmonary Wedge Pressure
Water
Brain Natriuretic Peptide
Atrial Natriuretic Factor
Second Messenger Systems
BAY 58-2667
Soluble Guanylyl Cyclase
Aldosterone
Renin
Vasodilation
Intravenous Administration
Pulmonary Artery
Cardiovascular Diseases
Ligands

Keywords

  • BAY 58-2667
  • Drugs
  • Heart failure
  • Oxidant stress
  • Soluble guanylate cyclase

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Boerrigter, G., Costello-Boerrigter, L. C., Cataliotti, A., Lapp, H., Stasch, J. P., & Burnett, J. C. J. (2007). Targeting heme-oxidized soluble guanylate cyclase in experimental heart failure. Hypertension, 49(5), 1128-1133. https://doi.org/10.1161/HYPERTENSIONAHA.106.083832

Targeting heme-oxidized soluble guanylate cyclase in experimental heart failure. / Boerrigter, Guido; Costello-Boerrigter, Lisa C.; Cataliotti, Alessandro; Lapp, Harald; Stasch, Johannes Peter; Burnett, John C Jr.

In: Hypertension, Vol. 49, No. 5, 05.2007, p. 1128-1133.

Research output: Contribution to journalArticle

Boerrigter, G, Costello-Boerrigter, LC, Cataliotti, A, Lapp, H, Stasch, JP & Burnett, JCJ 2007, 'Targeting heme-oxidized soluble guanylate cyclase in experimental heart failure', Hypertension, vol. 49, no. 5, pp. 1128-1133. https://doi.org/10.1161/HYPERTENSIONAHA.106.083832
Boerrigter, Guido ; Costello-Boerrigter, Lisa C. ; Cataliotti, Alessandro ; Lapp, Harald ; Stasch, Johannes Peter ; Burnett, John C Jr. / Targeting heme-oxidized soluble guanylate cyclase in experimental heart failure. In: Hypertension. 2007 ; Vol. 49, No. 5. pp. 1128-1133.
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