Wellcome Trust Career Development Fellow, Wolfson Institute for Biomedical Research, University College London,Cruciform Building, Gower Street, London WC1E 6AEBritish Journal of Pharmacology (2002) 136, 637–640Keywords: Soluble guanylate cyclase; nitric oxide; cGMP; blood pressure; platelet aggregation; glyceryl trinitrateThe heterodimeric haemoprotein soluble guanylate cyclase(sGC) acts as the principal intracellular receptor for nitricoxide (NO) and facilitates the formation of the secondmessenger cyclic guanosine-3’,5’-monophosphate (cGMP),which in turn governs many aspects of cellular function viainteraction with specific kinases, ion channels and phospho-diesterases (PDEs; Hobbs & Ignarro, 1996; Hobbs, 1997).This signal transduction pathway underlies the majority ofphysiological actions attributed to NO and is important inthe regulation of the cardiovascular, gastrointestinal, urogen-ital, nervous and immune systems. As a consequence,aberrant sGC-dependent signalling may be fundamental tothe aetiology of a wide variety of pathologies; agents that canmodulate enzyme activity in a selective manner shouldtherefore possess considerable therapeutic potential.Yet sGC can hardly be described as a novel therapeutictarget! The use of organic nitrates (e.g. glyceryl trinitrate,GTN; isosorbide dinitrate) for the treatment of conditionssuch as angina and heart failure has been advocated for overa century (Brunton, 1867), although the mechanism of actionof such compounds was not elucidated until the late 1970sand found to involve metabolic conversion to NO andsubsequent activation of sGC (Ignarro et al., 1981). Incontrast, recent attempts to manipulate sGC signalling formedical benefit have focused almost exclusively towardinhibition of NO synthesis; in terms of novel therapeutics,however, this has proven to be somewhat of a fruitlessexercise. Surprisingly perhaps, little attention has focused onthe identification of selective sGC-modulating compounds(indeed, they have been notoriously hard to come by!),particularly enzyme activators that are probably of greaterinterest therapeutically. This is despite the fact that sGCdysfunction is likely to have an equivalent impact onpathogenesis as inappropriate NO production and tissue-specific distribution of sGC isoforms (Budworth et al., 1999)may provide a means of targeting drug therapy.Although clinicians have at their disposal organic nitrates(and other NO-donor or ‘nitrovasodilator’ drugs), whichrelease the endogenous ligand NO to activate sGC, the use ofsuch compounds is problematic. First, NO-donor com-pounds, particularly organic nitrates, su•er from thedevelopment of tolerance following prolonged administration.The mechanism(s) underlying this tachyphylaxis remainunclear but may be linked to decreased metabolic activationof the compounds (Needleman & Johnson, 1973), excessivesuperoxide, endothelin or angiotensin II levels (Buchmuller-Rouiller & Mauel, 1991; Munzel et al., 1996), or a reductionin the sensitivity/activity of the NO receptor, sGC (Hussain etal., 1999). Second, the use of NO-donors in vivo is potentiallytroublesome due to non-specific interaction of NO with otherbiological molecules; reactions that are di†cult to control dueto the spontaneous release of NO from nitrovasodilators andits free di•usion in biological systems. Current dogmasuggests that the beneficial (physiological) actions of NOare mediated predominantly via activation of sGC (i.e.cGMP-dependent) and the detrimental (pathological) actionsof NO are exerted primarily via direct (i.e. cGMP-independent) modifications of proteins (e.g. nitrosation,nitration), lipids (e.g. peroxidation) and nucleic acids (e.g.DNA strand breaks). Thus, the use of NO-based therapeuticswill always represent a double-edged sword. Even if doses aretitred to minimize these side e•ects, the majority are notreadily reversible and will accumulate over time, potentiallymanifesting as long-term problems. Moreover, persistentinhibition of oxidative phosphorylation by NO may triggerapoptosis and cell death (Beltran et al., 2000). In light ofthese shortcomings, compounds which can activate sGC in anNO-independent manner, and not su•er from tachyphylaxis,will therefore o•er a considerable advance on currenttherapy.Stasch et al. (2002a, b) have reported just such a series ofcompounds in a succession of papers in this journal andothers (Stasch et al., 2001; Becker et al., 2001; Straub et al.,2001) in which they have identified and characterized novelnon NO-based sGC activators. This family of reagents isbased loosely on YC-1 (Figure 1), a recently described sGCactivator with hypotensive and anti-platelet properties (Ko etal., 1994; Mulsch et al., 1997; Rothermund et al., 2000).However, the BAY series of compounds are considerablymore potent and do not appear to inhibit PDE activity (atleast at therapeutic doses) thus o•ering significantly greaterselectivity. The authors have conducted a thorough pharma-cological evaluation of these compounds both in vitro and invivo and they appear to fall into two distinct classes: haem-dependent and haem-independent activators.The haem-dependent sGC activators, exemplified by BAY41-2272 and BAY 41-8543, activate purified enzyme in asynergistic fashion with NO and require the presence of haem(sensitive to blockade by the sGC inhibitor, ODQ). These
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