Published Online
on February 26, 2007

A more recent version of this article appeared on May 1, 2007

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Submitted on October 31, 2006
Revised on November 19, 2006

Targeting Heme-Oxidized Soluble Guanylate Cyclase in Experimental Heart Failure

Guido Boerrigter^*; Lisa C. Costello-Boerrigter; Alessandro Cataliotti; Harald Lapp; Johannes-Peter Stasch; and 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.

^* To whom correspondence should be addressed. E-mail: boerrigter.guido{at}mayo.edu.

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.

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

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Thomas Münzel, Sabine Genth-Zotz, and Ulrich Hink
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