title: NO- and haem-independent activation of soluble guanylyl cyclase: molecular basis and cardiovascular implications of a new pharmacological principle.
abstract: 1. Soluble guanylyl cyclase (sGC) is the only proven receptor for the ubiquitous biological messenger nitric oxide (NO) and is intimately involved in many signal transduction pathways, most notably in regulating vascular tone and platelet function. sGC is a heterodimeric (alpha/ss) protein that converts GTP to cyclic GMP; NO binds to its prosthetic haem group. Here, we report the discovery of a novel sGC activating compound, its interaction with a previously unrecognized regulatory site and its therapeutic implications. 2. Through a high-throughput screen we identified BAY 58-2667, an amino dicarboxylic acid which potently activates sGC in an NO-independent manner. In contrast to NO, YC-1 and BAY 41-2272, the sGC stimulators described recently, BAY 58-2667 activates the enzyme even after it has been oxidized by the sGC inhibitor ODQ or rendered haem deficient. 3. Binding studies with radiolabelled BAY 58-2667 show a high affinity site on the enzyme. 4. Using photoaffinity labelling studies we identified the amino acids 371 (alpha-subunit) and 231 - 310 (ss-subunit) as target regions for BAY 58-2667. 5. sGC activation by BAY 58-2667 results in an antiplatelet activity both in vitro and in vivo and a potent vasorelaxation which is not influenced by nitrate tolerance. 6. BAY 58-2667 shows a potent antihypertensive effect in conscious spontaneously hypertensive rats. In anaesthetized dogs the hemodynamic effects of BAY 58-2667 and GTN are very similar on the arterial and venous system. 7. This novel type of sGC activator is a valuable research tool and may offer a new approach for treating cardiovascular diseases.
authors.affiliation: Institute of Cardiovascular Research, Bayer AG, Germany. Johannes-Peter.Stasch.JS@bayer-ag.de
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.forename: Peter
authors.initials: P
authors.lastname: Schmidt
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: Michael
authors.initials: M
authors.lastname: Haerter
authors.forename: Markus
authors.initials: M
authors.lastname: Heil
authors.forename: Torsten
authors.initials: T
authors.lastname: Minuth
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Perzborn
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pleiss
authors.forename: Matthias
authors.initials: M
authors.lastname: Schramm
authors.forename: Werner
authors.initials: W
authors.lastname: Schroeder
authors.forename: Henning
authors.initials: H
authors.lastname: Schröder
authors.forename: Elke
authors.initials: E
authors.lastname: Stahl
authors.forename: Wolfram
authors.initials: W
authors.lastname: Steinke
authors.forename: Frank
authors.initials: F
authors.lastname: Wunder
mesh_terms: D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects / Q000378:metabolism*; D004285:Dogs; D020536:Enzyme Activators / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006162:Guanylate Cyclase; D006418:Heme / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase
chemical_list: D020536:Enzyme Activators; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006418:Heme; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase