Cardiorenal and humoral properties of a novel direct soluble guanylate cyclase stimulator BAY 41-2272 in experimental congestive heart failure

Guido Boerrigter, Lisa C. Costello-Boerrigter, Alessandro Cataliotti, Toshihiro Tsuruda, Gail J. Harty, Harald Lapp, Johannes Peter Stasch, John C Jr. Burnett

Research output: Contribution to journalArticle

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Abstract

Background - BAY 41-2272 is a recently introduced novel orally available agent that directly stimulates soluble guanylate cyclase (sGC) and sensitizes it to its physiological stimulator, nitric oxide. To date, its therapeutic actions in congestive heart failure (CHF) remain undefined. We characterized the cardiorenal actions of intravenous BAY 41-2272 in a canine model of CHF and compared it to nitroglycerin (NTG). Methods and Results - CHF was induced by rapid ventricular pacing for 10 days. Cardiorenal and humoral function were assessed at baseline and with administration of 2 doses of BAY 41-2272 (2 and 10 μg · kg-1 · min-1; n=8) or NTG (1 and 5 μg · kg-1 · min-1; n=6). Administration of 10 μg · kg-1 · min-1 BAY 41-2272 reduced mean arterial pressure (113±8 to 94±6 mm Hg; P<0.05), pulmonary artery pressure (29±2 to 25±2 mm Hg; P<0.05), and pulmonary capillary wedge pressure (25±2 to 20±2 mm Hg; P<0.05). Cardiac output (2.1±0.2 to 2.3±0.2 L/min; P<0.05) and renal blood flow (131±17 to 162±18 mL/min; P<0.05) increased. Glomerular filtration rate was maintained. There were no changes in plasma renin activity, angiotensin II, or aldosterone. NTG mediated similar hemodynamic changes and additionally decreased right atrial pressure and pulmonary vascular resistance. Conclusion - The new sGC stimulator BAY 41-2272 potently unloaded the heart, increased cardiac output, and preserved glomerular filtration rate without activation of the renin-angiotensin-aldosterone system in experimental CHF. These beneficial properties make direct sGC stimulation with BAY 41-2272 a promising new strategy for the treatment of cardiovascular diseases such as CHF.

Original languageEnglish (US)
Pages (from-to)686-689
Number of pages4
JournalCirculation
Volume107
Issue number5
DOIs
StatePublished - Feb 11 2003

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Heart Failure
Nitroglycerin
Glomerular Filtration Rate
Cardiac Output
Pulmonary Wedge Pressure
Atrial Pressure
Renal Circulation
Renin-Angiotensin System
Aldosterone
Renin
Angiotensin II
Vascular Resistance
Pulmonary Artery
Soluble Guanylyl Cyclase
3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
Canidae
Arterial Pressure
Nitric Oxide
Cardiovascular Diseases
Hemodynamics

Keywords

  • Enzymes
  • Heart failure
  • Nitric oxide
  • Pharmacology

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Cardiorenal and humoral properties of a novel direct soluble guanylate cyclase stimulator BAY 41-2272 in experimental congestive heart failure. / Boerrigter, Guido; Costello-Boerrigter, Lisa C.; Cataliotti, Alessandro; Tsuruda, Toshihiro; Harty, Gail J.; Lapp, Harald; Stasch, Johannes Peter; Burnett, John C Jr.

In: Circulation, Vol. 107, No. 5, 11.02.2003, p. 686-689.

Research output: Contribution to journalArticle

Boerrigter, Guido ; Costello-Boerrigter, Lisa C. ; Cataliotti, Alessandro ; Tsuruda, Toshihiro ; Harty, Gail J. ; Lapp, Harald ; Stasch, Johannes Peter ; Burnett, John C Jr. / Cardiorenal and humoral properties of a novel direct soluble guanylate cyclase stimulator BAY 41-2272 in experimental congestive heart failure. In: Circulation. 2003 ; Vol. 107, No. 5. pp. 686-689.
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AU - Costello-Boerrigter, Lisa C.

AU - Cataliotti, Alessandro

AU - Tsuruda, Toshihiro

AU - Harty, Gail J.

AU - Lapp, Harald

AU - Stasch, Johannes Peter

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N2 - Background - BAY 41-2272 is a recently introduced novel orally available agent that directly stimulates soluble guanylate cyclase (sGC) and sensitizes it to its physiological stimulator, nitric oxide. To date, its therapeutic actions in congestive heart failure (CHF) remain undefined. We characterized the cardiorenal actions of intravenous BAY 41-2272 in a canine model of CHF and compared it to nitroglycerin (NTG). Methods and Results - CHF was induced by rapid ventricular pacing for 10 days. Cardiorenal and humoral function were assessed at baseline and with administration of 2 doses of BAY 41-2272 (2 and 10 μg · kg-1 · min-1; n=8) or NTG (1 and 5 μg · kg-1 · min-1; n=6). Administration of 10 μg · kg-1 · min-1 BAY 41-2272 reduced mean arterial pressure (113±8 to 94±6 mm Hg; P<0.05), pulmonary artery pressure (29±2 to 25±2 mm Hg; P<0.05), and pulmonary capillary wedge pressure (25±2 to 20±2 mm Hg; P<0.05). Cardiac output (2.1±0.2 to 2.3±0.2 L/min; P<0.05) and renal blood flow (131±17 to 162±18 mL/min; P<0.05) increased. Glomerular filtration rate was maintained. There were no changes in plasma renin activity, angiotensin II, or aldosterone. NTG mediated similar hemodynamic changes and additionally decreased right atrial pressure and pulmonary vascular resistance. Conclusion - The new sGC stimulator BAY 41-2272 potently unloaded the heart, increased cardiac output, and preserved glomerular filtration rate without activation of the renin-angiotensin-aldosterone system in experimental CHF. These beneficial properties make direct sGC stimulation with BAY 41-2272 a promising new strategy for the treatment of cardiovascular diseases such as CHF.

AB - Background - BAY 41-2272 is a recently introduced novel orally available agent that directly stimulates soluble guanylate cyclase (sGC) and sensitizes it to its physiological stimulator, nitric oxide. To date, its therapeutic actions in congestive heart failure (CHF) remain undefined. We characterized the cardiorenal actions of intravenous BAY 41-2272 in a canine model of CHF and compared it to nitroglycerin (NTG). Methods and Results - CHF was induced by rapid ventricular pacing for 10 days. Cardiorenal and humoral function were assessed at baseline and with administration of 2 doses of BAY 41-2272 (2 and 10 μg · kg-1 · min-1; n=8) or NTG (1 and 5 μg · kg-1 · min-1; n=6). Administration of 10 μg · kg-1 · min-1 BAY 41-2272 reduced mean arterial pressure (113±8 to 94±6 mm Hg; P<0.05), pulmonary artery pressure (29±2 to 25±2 mm Hg; P<0.05), and pulmonary capillary wedge pressure (25±2 to 20±2 mm Hg; P<0.05). Cardiac output (2.1±0.2 to 2.3±0.2 L/min; P<0.05) and renal blood flow (131±17 to 162±18 mL/min; P<0.05) increased. Glomerular filtration rate was maintained. There were no changes in plasma renin activity, angiotensin II, or aldosterone. NTG mediated similar hemodynamic changes and additionally decreased right atrial pressure and pulmonary vascular resistance. Conclusion - The new sGC stimulator BAY 41-2272 potently unloaded the heart, increased cardiac output, and preserved glomerular filtration rate without activation of the renin-angiotensin-aldosterone system in experimental CHF. These beneficial properties make direct sGC stimulation with BAY 41-2272 a promising new strategy for the treatment of cardiovascular diseases such as CHF.

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