No- and haem-independent activation of soluble guanylyl cyclase: Molecular basis and cardiovascular implications of a new pharmacological principle

Johannes Peter Stasch, Peter Schmidt, Cristina Alonso-Alija, Heiner Apeler, Klaus Dembowsky, Michael Haerter, Markus Heil, Torsten Minuth, Elisabeth Perzborn, Ulrich Pleiss, Matthias Schramm, Werner Schroeder, Henning Schröder, Elke Stahl, Wolfram Steinke, Frank Wunder

Research output: Contribution to journalArticlepeer-review

240 Scopus citations

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 (α/β) 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 (α-subunit) and 231-310 (β-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.

Original languageEnglish (US)
Pages (from-to)773-783
Number of pages11
JournalBritish Journal of Pharmacology
Volume136
Issue number5
DOIs
StatePublished - 2002

Keywords

  • BAY 41-2272
  • BAY 58-2667
  • Blood pressure
  • Cyclic GMP
  • Haemodynamics
  • Nitrate tolerance
  • Nitric oxide
  • Photoaffinity labelling
  • Soluble guanylate cyclase
  • YC-1

Fingerprint

Dive into the research topics of 'No- and haem-independent activation of soluble guanylyl cyclase: Molecular basis and cardiovascular implications of a new pharmacological principle'. Together they form a unique fingerprint.

Cite this