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


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 micro g x kg(-1) x min(-1); n=8) or NTG (1 and 5 micro g x kg(-1) x min(-1); n=6). Administration of 10 micro g x kg(-1) x 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.


CONCLUSIONS
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.
Boerrigter
Guido
G
Cardiorenal Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA. boerrigter.guido@mayo.edu
Costello-Boerrigter
Lisa C
LC
Cataliotti
Alessandro
A
Tsuruda
Toshihiro
T
Harty
Gail J
GJ
Lapp
Harald
H
Stasch
Johannes-Peter
JP
Burnett
John C
JC
D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006162:Guanylate Cyclase; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000188:drug therapy*; D006334:Heart Function Tests / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects*; D007677:Kidney Function Tests; D008297:Male; D005996:Nitroglycerin / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism*; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects; D000071756:Soluble Guanylyl Cyclase
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D011720:Pyrazoles; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D000804:Angiotensin II; D000450:Aldosterone; D012083:Renin; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D005996:Nitroglycerin