title: Pharmacological actions of a novel NO-independent guanylyl cyclase stimulator, BAY 41-8543: in vitro studies.
abstract: BAY 41-8543 is a novel, highly specific and so far the most potent NO-independent stimulator of sGC. Here we report the effects of BAY 41-8543 on the isolated enzyme, endothelial cells, platelets, isolated vessels and Langendorff heart preparation. BAY 41-8543 stimulates the recombinant sGC concentration-dependently from 0.0001 microM to 100 microM up to 92-fold. In combination, BAY 41-8543 and NO have synergistic effects over a wide range of concentrations. Similar results are shown in implying that BAY 41-8543 stimulates the sGC directly and furthermore makes the enzyme more sensitive to its endogenous activator NO. In vitro, BAY 41-8543 is a potent relaxing agent of aortas, saphenous arteries, coronary arteries and veins with IC(50)-values in the nM range. In the rat heart Langendorff preparation, BAY 41-8543 potently reduces coronary perfusion pressure from 10(-9) to 10(-6) g ml(-1) without any effect on left ventricular pressure and heart rate. BAY 41-8543 is effective even under nitrate tolerance conditions proved by the same vasorelaxing effect on aortic rings taken either from normal or nitrate-tolerant rats. BAY 41-8543 is a potent inhibitor of collagen-mediated aggregation in washed human platelets (IC(50)=0.09 microM). In plasma, BAY 41-8543 inhibits collagen-mediated aggregation better than ADP-induced aggregation, but has no effect on the thrombin pathway. BAY 41-8543 is also a potent direct stimulator of the cyclic GMP/PKG/VASP pathway in platelets and synergizes with NO over a wide range of concentrations. These results suggest that BAY 41-8543 is on the one hand an invaluable tool for studying sGC signaling in vitro and on the other hand its unique profile may offer a novel approach for treating cardiovascular diseases.
authors.affiliation: Institute of Cardiovascular Research, Bayer AG, Pharma Research Center, Wuppertal, Germany. Johannes-Peter.Stasch.JS@bayer-ag.de
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.forename: Cristina
authors.initials: C
authors.lastname: Alonso-Alija
authors.forename: Heiner
authors.initials: H
authors.lastname: Apeler
authors.forename: Klaus
authors.initials: K
authors.lastname: Dembowsky
authors.forename: Achim
authors.initials: A
authors.lastname: Feurer
authors.forename: Torsten
authors.initials: T
authors.lastname: Minuth
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Perzborn
authors.forename: Matthias
authors.initials: M
authors.lastname: Schramm
authors.forename: Alexander
authors.initials: A
authors.lastname: Straub
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology; D003331:Coronary Vessels / Q000187:drug effects / Q000201:enzymology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D020536:Enzyme Activators / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D005268:Femoral Vein / Q000187:drug effects / Q000201:enzymology; D006162:Guanylate Cyclase / Q000378:metabolism*; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013552:Swine; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; C450679:BAY 41-8543; D020536:Enzyme Activators; D009025:Morpholines; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D009569:Nitric Oxide; D006162:Guanylate Cyclase