Nitric oxide-independent stimulation of soluble guanylate cyclase with BAY 41-2272 in cardiovascular disease

Guido Boerrigter, John C Jr. Burnett

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic 3′,5′-guanosine monophosphate (cGMP) pathway plays an important role in cardiovascular regulation by promoting vasodilation and inhibiting vascular smooth muscle cell growth, platelet aggregation, and leukocyte adhesion. In pathophysiological states with endothelial dysfunction this signaling pathway is impaired. Activation of sGC has traditionally been achieved with nitrovasodilators; however, these drugs are associated with the development of tolerance and potentially deleterious cGMP-independent actions. In this review the actions of BAY 41-2272, the prototype of a new class of NO-independent sGC stimulators, in cardiovascular disease models is discussed. BAY 41-2272 binds to a regulatory site on the α-subunit of sGC and stimulates the enzyme synergistically with NO. BAY 41-2272 had antihypertensive actions and attenuated remodeling in models of systemic arterial hypertension. It also unloaded the heart in experimental congestive heart failure. BAY 41-2272 reduced pulmonary vascular resistance in acute and chronic experimental pulmonary arterial hypertension. Furthermore, BAY 41-2272 inhibited platelet aggregation in vitro and leukocyte adhesion in vivo.These findings make direct sGC stimulation with BAY 41-2272 a promising new therapeutic strategy for cardiovascular diseases and warrant further studies. Finally, the significance of the novel NO- and heme-independent sGC activator BAY 58-2667, which activates two forms of NO-insensitive sGC, is briefly discussed.

Original languageEnglish (US)
Pages (from-to)30-45
Number of pages16
JournalCardiovascular Drug Reviews
Volume25
Issue number1
DOIs
StatePublished - Mar 2007

Fingerprint

Nitric Oxide
Cardiovascular Diseases
Platelet Aggregation
Leukocytes
Cardiovascular Models
3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
Soluble Guanylyl Cyclase
Heme
Vascular Smooth Muscle
Pulmonary Hypertension
Vasodilation
Vascular Resistance
Antihypertensive Agents
Smooth Muscle Myocytes
Heart Failure
Hypertension
Enzymes
Growth
Pharmaceutical Preparations
3'-guanylic acid

Keywords

  • BAY 41-2272
  • BAY 58-2667
  • Blood vessels
  • Cyclic guanosine monophoshate
  • Endothelial dysfunction
  • NO
  • Soluble guanylate cyclase

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Pharmacology

Cite this

Nitric oxide-independent stimulation of soluble guanylate cyclase with BAY 41-2272 in cardiovascular disease. / Boerrigter, Guido; Burnett, John C Jr.

In: Cardiovascular Drug Reviews, Vol. 25, No. 1, 03.2007, p. 30-45.

Research output: Contribution to journalArticle

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