Stimulators and activators of soluble guanylate cyclase: review and potential therapeutic indications.
ABSTRACT The heme-protein soluble guanylyl cyclase (sGC) is the intracellular receptor for nitric oxide (NO). sGC is a heterodimeric enzyme with α and β subunits and contains a heme moiety essential for binding of NO and activation of the enzyme. Stimulation of sGC mediates physiologic responses including smooth muscle relaxation, inhibition of inflammation, and thrombosis. In pathophysiologic states, NO formation and bioavailability can be impaired by oxidative stress and that tolerance to NO donors develops with continuous use. Two classes of compounds have been developed that can directly activate sGC and increase cGMP formation in pathophysiologic conditions when NO formation and bioavailability are impaired or when NO tolerance has developed. In this report, we review current information on the pharmacology of heme-dependent stimulators and heme-independent activators of sGC in animal and in early clinical studies and the potential role these compounds may have in the management of cardiovascular disease.
- SourceAvailable from: jbc.orgJournal of Biological Chemistry 01/1970; 244(23):6354-62. · 4.65 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Nitric oxide gas (NO) increased guanylate cyclase [GTP pyrophosphate-lyase (cyclizing), EC 22.214.171.124] activity in soluble and particulate preparations from various tissues. The effect was dose-dependent and was observed with all tissue preparations examined. The extent of activation was variable among different tissue preparations and was greatest (19- to 33-fold) with supernatant fractions of homogenates from liver, lung, tracheal smooth muscle, heart, kidney, cerebral cortex, and cerebellum. Smaller effects (5- to 14-fold) were observed with supernatant fractions from skeletal muscle, spleen, intestinal muscle, adrenal, and epididymal fat. Activation was also observed with partially purified preparations of guanylate cyclase. Activation of rat liver supernatant preparations was augmented slightly with reducing agents, decreased with some oxidizing agents, and greater in a nitrogen than in an oxygen atmosphere. After activation with NO, guanylate cyclase activity decreased with a half-life of 3-4 at 4 degrees but re-exposure to NO resulted in reactivation of preparations. Sodium azide, sodium nitrite, hydroxylamine, and sodium nitroprusside also increased guanylate cyclase activity as reported previously. NO alone and in combination with these agents produced approximately the same degree of maximal activation, suggesting that all of these agents act through a similar mechanism. NO also increased the accumulation of cyclic GMP but not cyclic AMP in incubations of minces from various rat tissues. We propose that various nitro compounds and those capable of forming NO in incubations activate guanylate cyclase through a similar but undefined mechanism. These effects may explain the high activities of guanylate cyclase in certain tissues (e.g., lung and intestinal mucosa) that are exposed to environmental nitro compounds.Proceedings of the National Academy of Sciences 09/1977; 74(8):3203-7. · 9.74 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Cyclic AMP formation from ATP was stimulated by unpurified and partially purified soluble hepatic guanylate cyclase in the presence of nitric oxide (NO) or compounds containing a nitroso moiety such as nitroprusside, N-methyl-N-nitro-N-nitrosoguanidine (MNNG), nitrosyl ferroheme, and S-nitrosothiols. Cyclic AMP formation was undetectable in the absence of NO or nitroso compounds and was not stimulated by fluoride or glucagon, indicating the absence of adenylate cyclase activity. The nitroso compounds failed to activate, whereas fluoride or glucagon activated, adenylate cyclase in washed rat liver membrane fractions. Cyclic GMP formation from GTP was markedly stimulated by the soluble hepatic fraction in the presence of NO or nitroso compounds. Cyclic AMP formation by partially purified guanylate cyclase was competitively inhibited by GTP and cyclic GMP formation is well-known to be competitively inhibited by ATP. Therefore, it appears that activated guanylate cyclase, rather than adenylate cyclase, was responsible for the formation of cyclic AMP from ATP. Formation of cyclic AMP of cyclic GMP was enhanced by thiols, inhibited by hemoproteins and oxidants, and required the addition of either Mg2+ or Mn2+. Further, several nitrosyl ferroheme compounds and S-nitrosothiols stimulated the formation of both cyclic AMP and cyclic GMP by the soluble hepatic fraction. These observations support the view that soluble guanylate cyclase is capable, under certain well-defined conditions, of catalyzing the conversion of ATP to cyclic AMP.Canadian Journal of Physiology and Pharmacology 01/1981; 58(12):1446-56. · 1.56 Impact Factor
Hindawi Publishing Corporation
Critical Care Research and Practice
Volume 2012, Article ID 290805, 12 pages
Stimulators andActivators of SolubleGuanylate Cyclase:
Reviewand Potential TherapeuticIndications
Bobby Nossaman,1,2EdwardPankey,2and PhilipKadowitz2
1Critical Care Medicine Section, Department of Anesthesiology, Ochsner Medical Center, 1514 Jefferson Highway, New Orleans,
LA 70121, USA
2Department of Pharmacology, SL83, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112-2699, USA
Correspondence should be addressed to Philip Kadowitz, firstname.lastname@example.org
Received 31 July 2011; Revised 18 November 2011; Accepted 19 November 2011
Academic Editor: Hector R. Wong
Copyright © 2012 Bobby Nossaman et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Theheme-protein soluble guanylyl cyclase (sGC)is the intracellular receptor for nitricoxide (NO).sGC is a heterodimeric enzyme
with α and β subunits and contains a heme moiety essential for binding of NO and activation of the enzyme. Stimulation of sGC
mediates physiologic responses including smooth muscle relaxation, inhibition of inflammation, and thrombosis. In pathophysio-
logic states, NO formation and bioavailability can be impaired by oxidative stress and that tolerance to NO donors develops with
continuous use. Two classes of compounds have been developed that can directly activate sGC and increase cGMP formation in
pathophysiologic conditions when NO formation and bioavailability are impaired or when NO tolerance has developed. In this
report, we review current information on the pharmacology of heme-dependent stimulators and heme-independent activators of
sGC in animal and in early clinical studies and the potential role these compounds may have in the management of cardiovascular
Guanylyl cyclase (GC) is an enzyme that catalyzes the forma-
tion of guanosine 3?,5?-monophosphate (cGMP) from gua-
nosine triphosphate (GTP) and is found in tissues through-
out the animal kingdom [1, 2]. Soluble GC (sGC) is the re-
ceptor for nitric oxide (NO) in vascular smooth muscle [3,
4]. In the cardiovascular system, NO is endogenously gen-
erated by endothelial NO synthase (eNOS) from L-arginine
and activates sGC in adjacent vascular smooth muscle cells
to increase cGMP levels and induce relaxation (Figure 1).
NO plays a major role in the regulation of vascular tone and
blood pressure [5, 6]. When released from the endothelium
in response to physiologic stimuli such as shear stress, NO
binds to the normally reduced heme moiety of sGC and
increases the formation of cGMP from GTP leading to a dec-
rease in intracellular calcium and vasodilation [7–10]. More-
over, the NO-sGC-cGMP pathway is essential for the control
of a number of physiologic processes, including neuronal
vascular and platelet homeostasis [11–18].
Initial investigations into the role of NO were conducted
showing that nitrogen-containing compounds such as sod-
ium azide (NaN3), sodium nitrite (NaNO2), hydroxylamine
(NH2OH), nitroglycerin (C3H5N3O9), and sodium nitro-
23] (Figure 2). When tissues were homogenized and sepa-
rated by centrifugation, GC activity was detected in partic-
ulate and soluble fractions [19, 23–31]. As NO was shown
to rapidly activate GC , it was hypothesized that GC
activation may be due to the effect of NO or another sub-
stance that activated the enzyme . Moreover, these nitro-
gen-containing compounds were able to activate sGC, caus-
ing an increase in cGMP, and vascular relaxation [13, 21, 32,
Reduced bioavailability and/or responsiveness to endoge-
nous NO have been implicated in the pathogenesis of many
2Critical Care Research and Practice
Figure 1: Simplified role of NO (nitric oxide) stimulating soluble guanylyl cyclase smooth muscle relaxation. PKB (protein kinase B), NOS
(nitric oxide synthase).
• Inhibition of platelet aggregation
• Anti-inflammatory effect
Figure 2: Role of NO (nitric oxide), inhaled NO, and sGC (soluble
guanylyl cyclase) stimulators in stimulating the reduced heme of
sGC and the role of sGC activators in stimulated oxidized sGC to
gation and an anti-inflammatory effect in the vascular bed.
disease processes [34–36]. NO was originally described as
an endothelial-derived relaxing factor and is a vasodilator in
the pulmonary and systemic circulations [37–40]. The signi-
ficance of NO in the regulation of vasomotor tone has
been demonstrated in experimental animals and in hu-
man subjects by the use of NOS inhibitors [41–48]. Given
the importance of the NO-sGC-cGMP pathway in cardio-
pulmonary diseases, there have been enormous efforts to
improve NO therapy [36, 49–53].
3.1. Nitrates. Although glyceryl trinitrate (GTN) and amyl
heart failure for over 140 years [54, 55], the most commonly
used agents at the present include isosorbide dinitrate,
isosorbide-5-mononitrate, and GTN which are effective in
reducing ventricular preload by increasing peripheral venous
capacitance [56–59]. It is generally believed that the thera-
peutic effect of these drugs involves the release of NO from
nitrite anion, the activation of sGC, and relaxation of capaci-
tance blood vessels [54, 60–63]. These drugs can also dec-
rease pulmonary and systemic vascular resistances but re-
quire higher doses than needed for increasing venous capac-
itance [64–69]. These agents can reduce ventricular filling
pressure, wall stress, and myocardial oxygen consumption
 and may also improve systolic and diastolic ventricu-
lar function by improving coronary flow in patients with
ischemic cardiomyopathy. However, there is as yet no con-
vincing evidence that organic nitrates improve mortality in
patients with acute myocardial infarction [71, 72]. The lim-
itations of this class of agents are well known and include
adverse hemodynamic effects, including tolerance, lack of
selectivity, and limited bioavailability .
Studies in the literature provide evidence that vasore-
laxant responses to GTN are mediated by the formation of
NO or aclosely related S-nitroso molecule [13, 33, 73, 74].
However, the mechanism of this vasorelaxant response to
GTN is uncertain. Although studies in the literature indicate
Critical Care Research and Practice3
that NO contributes to the activation of sGC and vascular
smooth muscle relaxation [75, 76], other studies suggest that
vasorelaxant responses to GTN may be independent of NO
release and cGMP formation .
Studies have shown that the bioactivation of GTN re-
quires the presence of thiols or sulfhydryl-containing com-
pounds and that NO or NO-like compounds are believed
to be the biologically active species [3, 74, 78, 79]. Inter-
actions with GTN and sulfhydryl-containing molecules are
ated administration of GTN produces sulfhydryl depletion
and the development of tolerance [79–81]. Subsequent stud-
ies have demonstrated the release of NO following the de-
composition of an intermediate S-nitrosothiol . Addi-
tional studies suggest that an enzymatic mechanism may be
responsible for the bioactivation of GTN. However, these
enzymatic systems could not catalyze the selective formation
of 1,2-glyceryl dinitrate and nitrite from GTN, and more-
over, no association between the development of enzymatic
over, the discovery (1) that mitochondrial aldehyde dehy-
drogenase (mtALDH) generates 1,2-glyceryl dinitrate and
nitrite from GTN , (2) that this reaction requires a redu-
cing thiol cofactor [60, 90, 91], and (3) that the activity of
this enzyme is reduced in GTN tolerance [53, 61] suggests
that this pathway is responsible for GTN bioactivation in
vascular smooth muscle [53, 77, 89]. However, one difficulty
with these studies has been an inability to detect NO as a
byproduct of GTN metabolism . Moreover, the genera-
tion of NO was observed when the concentrations of GTN
been proposed that once GTN is bioactivated within the
mitochondria, nitrite or an additional action of mtALDH
generates the vasodilatory NO bioactivity . One sugges-
ted mechanism for this vasodilatory activity is that S-nitro-
soglutathione is formed by the reaction of reduced gluta-
thione and nitrite [99, 100]. This molecule subsequently un-
dergoes biotransformation to S-nitrosocysteine [89, 101]
that can release NO . However, excessive amounts of
GTN or S-nitrosothiols can dysregulate protein S-nitrosyla-
Chronic GTN administration has been shown to result in
acetylcholine-induced coronaryvasoconstriction ratherthan
relaxation [104, 105] and induce endothelial dysfunction
. An early event in the development of atherosclerosis
is the impairment of endothelial function or endothelial dys-
function that develops before structural changes and intimal
hyperplasia or lipid deposition occur . Moreover, redu-
ced oxidation of NO occurs through altered endothelial NOS
formation and activity , which can be evidenced by ab-
109]. Therefore, NO deficiency is linked to cardiopulmonary
disease processes and provides justification for the use of
effective NO replacement therapy.
4.Activationof sGCby NO-Like Compounds
The activation of sGC enhances the conversion of GTP to
muscle relaxation and inhibition of platelet aggregation
[13–18]. However, little is known about sGC regulation by
substances other than NO-donors. The recent discovery of
a benzylindazole derivative, YC-1, that was shown to inhibit
platelet aggregation and increase by sixfold intracellular con-
regulation [110, 111]. Subsequent studies found that acti-
vation of sGC by YC-1 was NO-independent and was inde-
pendent of biotransformation [112, 113]. In contrast, orga-
nic nitrates appear to require biotransformation with inter-
mediates (nitrites, nitrosothiols, and organic thionitrates)
liberating NO [91, 114]. These findings with YC-1 as well as
other stimulators of sGC suggest that non-NO compounds
may also activate or modulate sGC activity [115–118]. Cur-
rent NO-donor drugs induce tolerance [34–36, 79–81].
However by increasing the responsiveness of sGC to endoge-
nous NO, YC-1 or YC-1-like compounds may represent a
novel class of drugs that cansensitize the sGC enzyme to res-
pond to NO. In disease states with dysfunctional sGC, it may
be possible to increase the effect of endogenously produced
dent stimulators for sGC have been developed for use in
pathophysiologic conditions when NO formation and bio-
availability are impaired or when NO tolerance has devel-
4.1. sGC Stimulators
4.1.1. Preclinical Studies. Compounds have been developed
that can directly stimulate sGC and increase cGMP forma-
bioavailability are impaired or when NO tolerance has devel-
oped [34–36] (Figure 2). The pyrazolopyridine compound,
BAY 41-8543, is an NO-independent stimulator of sGC that
has been shown to reduce systemic and pulmonary arterial
pressure, and relax isolated vessels from a variety of organ
systems [35, 119, 120]. BAY 41-2272 is closely related to BAY
nificant pulmonary vasodilator activity in a variety of species
[119, 121–125]. BAY 41-2272 has been shown to reduce right
in a chronic hypoxia-induced model of pulmonary hyper-
tension . It has been reported that when either BAY
41-2272 or BAY 41-8543 was administered by inhalation to
awake lambs, the pyrazolopyridine compounds had selec-
tive pulmonary vasodilator activity and BAY 41-8543 could
enhance the magnitude and prolong the duration of the
vasodilator response to inhaled NO [122, 125].
In an intact chest rat model, administration of BAY
41-8543 under control or baseline tone conditions produ-
ced small decreases in pulmonary arterial pressure, larger
dose-dependent decreases in systemic arterial pressure, and
increases in cardiac output . However, under elevated
nist, U46619, BAY 41-8543 produced larger dose-dependent
decreases in pulmonary arterial pressure when tone in the
pulmonary vascular bed was increased . Analyses of
the percent decreases in pulmonary and systemic arterial
pressures in response to BAY 41-8543 under elevated tone
4 Critical Care Research and Practice
conditions induced with U46619-infused animals were not
different, suggesting that the sGC stimulator had similar
vasodilator activity in the pulmonary and systemic vascular
beds in the intact chest rat .
The effect of NOS inhibition with L-NAME on vasodila-
tor responses to BAY 41-8543 was investigated in the intact
chest rat model, and following administration of the NOS
inhibitor, decreases in pulmonary and systemic arterial pres-
sures in response to BAY 41-8543 were reduced when com-
of responses to BAY 41-8543 at the same level of pulmonary
pressure in response to the sGC stimulator are reduced by
more than 50% in L-NAME-treated animals . These
results are consistent with the concept that responses to the
sGC stimulator are NO-independent; however, in the ab-
sence of endogenous NO formation, vasodilator responses to
the sGC stimulator were markedly attenuated. It has been
reported that stimulators of sGC have a dual role of action
in that they directly stimulate the native form of the enzyme
and render it more sensitive to endogenously produced NO
128]. The results in the intact chest rat model are consistent
with these findings [125, 128] that show that vasodilator res-
ponses to BAY 41-8543 are attenuated when endogenous NO
formation is inhibited.
examined in the intact chest model with the NO donor, sod-
ium nitroprusside (SNP). Although separate administration
of BAY 41-8543 and SNP produced significant decreases in
pulmonary and systemic arterial pressures, coadministration
that were significantly greater than the sum of responses to
either agent when administered alone . These results
suggest that BAY 41-8543 synergizes with NO in mediating
vasodilator responses to the sGC stimulator in the pulmo-
nary and systemic vascular beds in the intact rat.
BAY 41-8543 and BAY 41-2272 were synthesized based
upon analysis of the structure of YC-1 [36, 110, 129]. These
pyrazolopyridine stimulators activate sGC in a manner inde-
pendent of NO [35, 36, 121]. These compounds activate
purified sGC and strongly synergize with NO, reflecting sta-
bilization of the nitrosyl-heme complex of the enzyme .
Both BAY 41-8543 and BAY 41-2272 relax vascular smooth
muscle and have vasodilator activity in the pulmonary and
systemic vascular beds [34, 119, 121, 122, 128, 131].
Although BAY 41-8543 had beneficial effects in experi-
mental models of pulmonary hypertension, this agent does
not have favorable pharmacokinetic properties and cannot
be used in clinical trials . In contrast, BAY 63-2521
(Riociguat; Bayer Healthcare AG, Wuppertal, Germany),
a heme-dependent sGC stimulator closely related to BAY 41-
8543, has a better pharmacokinetic profile and has been used
in clinical studies . In respect to interesting similarities
and differences between the actions of BAY 41-8543 and
ted that BAY 41-2272, which is chemically similar to BAY
41-8543, produced greater decreases in pulmonary than
systemic arterial pressure and that pulmonary vasodilator
responses were not attenuated by L-NAME . In the pre-
sent study, BAY 41-8543 produced similar decreases in pul-
monary and systemic arterial pressures in U46619-infused
animals and decreases in both pulmonary and systemic arte-
rial pressures attenuated by L-NAME treatment. In an ovine
fetal model of pulmonary hypertension, chronic infusion of
BAY 41-2272 produced potent sustained decreases in pulmo-
nary arterial pressure that were not attenuated by a NOS
inhibitor, L-NA, and when infused at higher rates, systemic
response to stimulators of sGC in the awake sheep, the ovine
fetal circulation, and intact chest rat are the relative differ-
ences in vasodilator activity in the pulmonary and systemic
vascular beds and the role of endogenously produced NO in
modulating these responses [124, 125]. The reason for the
differences in results in the different experimental models
may involve differences in species, experimental design and
preparation, the BAY compound studied, or more impor-
the present study, BAY 41-8543 had similar vasodilator acti-
vity in the preconstricted pulmonary vascular bed and the
systemic vascular bed and vasodilator responses in both beds
were attenuated when NOS was inhibited with L-NAME.
These data suggest that the role of endogenous NO in the
activation of sGC is similar in both circulations in the
intact chest rat model and may differ from SGC activation
mechanisms in the pulmonary and systemic vascular beds in
the awake sheep and ovine fetal preparation [124, 125].
mulator, BAY 41-2272, was not dependent on the formation
of endogenous NO in the awake sheep model, the response
strongly synergized with inhaled NO . Therefore, the
was, in some respects, similar in the awake sheep and intact
rat models, although the synergism was much greater in the
The present results are consistent with the concept that sGC
NO-donor to produce maximum pulmonary vasodilation
4.1.2. Clinical Investigations. The first sGC simulator to
undergo clinical study was BAY 41-8543 . However,
although systemic blood pressure decreased as expected fol-
macokinetic issues occurred that lead to the development
of additional sGC compounds . Subsequently BAY 63-
2521 was developed, and when administered in 58 healthy
male volunteers as a single oral dose (0.25–5mg), no serious
adverse events were observed . Although both mean
arterial and diastolic pressures were decreased, systolic pres-
sure was not significantly affected. A dose-related increase in
heart rate up to ∼11bpm was observed with the 5-mg
dose; however, this dose was not well tolerated, due to an
increased number of adverse events, including headache,
nasal congestion, flushing, feeling hot, orthostatic hypoten-
sion, and palpitations. Increased levels in the vasoactive hor-
mones, norepinephrine, and plasma renin, but not plasma
Critical Care Research and Practice5
aldosterone or angiotensin II, were observed . Follow-
ing these encouraging findings, a clinical study was per-
formed to evaluate the short-term safety profile of BAY 63-
2561 (Riociguat) to determine the tolerability and efficacy in
patients with moderate to severe pulmonary hypertension
(PH) due to pulmonary arterial hypertension, distal chronic
thromboembolic PH, or PH with mild to moderate intersti-
tial lung disease . Safety and tolerability studies were
performed in 19 subjects with single doses ≤2.5mg. The
administration of the sGC stimulator significantly improved
in patients with PH in a dose-dependent manner, to a
greater extent than following administration of inhaled NO.
Although riociguat had significant systemic blood pressure
effects and demonstrated no selectivity for the pulmonary
circulation, however, mean systolic blood pressure remained
be superior to inhaled NO in the response of the pulmonary
circulation . In a 12-week, phase II study, 75 patients
hypertension or pulmonary arterial hypertension) received
oralriociguat in 0.5mg increments in 2-week intervals from
1mg to a maximum of 2.5mg three times a day that was
titrated to systemic systolic blood pressure (SBP) . The
dose of the sGC stimulator was increased if systemic blood
pressure was greater than 100mmHg, was maintained once
SBP was stable in a range of 90–100mmHg, and decreased if
SBP was less than 90mmHg or with symptoms such as syn-
cope or dizziness. The primary endpoints studied were safety
and tolerability of the sGC stimulator with changes in phar-
macodynamics as the secondary endpoints. Riociguat was
well tolerated, and that asymptomatic hypotension (SBP less
than 90mmHg) occurred in 11/75 (15%) patients, but blood
pressure could be normalized with dose alteration in 2 pa-
tients and without dose alteration in 9 patients . Pul-
monary vascular resistance was significantly reduced. A sig-
nificant improvement in the median 6-minute walking dis-
tance was observed in patients with diagnosis of chronic
thromboembolic pulmonary hypertension (greater than 55
meters; P < 0.0001) and in patients with pulmonary arterial
hypertension (PAH) (greater than 57 meters; P < 0.0001).
Moreover, similar improvements were also observed in pa-
tients on chronic bosentan therapy . The most frequent
observed adverse events were dyspepsia, headache, and
strated a favorable safety profile with significant improve-
ments in pulmonary hemodynamics, and in exercise capac-
ity, but with a high through mild to moderate incidence of
patient symptoms .
4.2. sGC Activators
4.2.1. Preclinical Studies. The oxidation of the heme iron on
sGC decreases the responsiveness of the enzyme to NO and
pounds with a different mode of sGC activation have been
developed and have been shown to target NO receptor
proteins when the heme iron on sGC is in an oxidized (Fe3+
instead of Fe2+) state, or when the heme group is lost [36,
131, 137, 138] (Figure 2). These compounds activate the oxi-
dized or heme-deficient sGC enzyme that is not responsive
to NO . Oxidation of sGC results in loss of activation of
the enzyme [139–142]. Moreover, purified sGC also results
in marked to complete loss of enzyme responsiveness to NO-
donors [143, 144]. However, responsiveness was restored by
the addition of hematin, hemoglobin, or a heat-inactivated
catalase in the presence of a reducing agent [143, 144]. Orga-
development of tolerance limits their therapeutic value [53,
60, 145–147]. The development of compounds that over-
come this limitation that are able to stimulate sGC indepen-
studies indicates that these NO-independent receptors exist
and may become more abundant under pathological condi-
tions associated with oxidative stress [148–150].
Activation of the NO-sGC-cGMP pathway can induce
potent pulmonary and systemic vasodilatation [40, 151–
155]. Two classes of novel drugs have been developed that
can modulate sGC-cGMP signal transduction in an NO-
independent manner. Although stimulators of sGC can en-
hance the sensitivity of reduced sGC to NO , activators
of sGC can increase sGC enzyme activity even when the
52, 156]. In the intact chest rat, intravenous administration
of the sGC activator, BAY 60-2770, produced dose-related
decreases in systemic arterial pressure, increases in cardiac
cardiovascular responses were slow in onset and long in
duration . These observations are comparable to the
findings in the anesthetized dog following administration of
another sGC activator, BAY 41-2272 . These findings
suggest that sGC activators can increase sGC enzyme activity
in vascular beds from different species [123, 157].
Following a preclinical study in rats demonstrating that
Cinaciquat was able to reduce oxidative stress, improve car-
diac performance, and improve impaired cardiac relaxation
in experimentally induced myocardial infarction in rats
, the role of the sGC activator in ischemia-reperfusion
injury was investigated in a canine model of cardioplegic
arrest and extracorporeal circulation . Preconditioning
with the sGC activator improved left- and right-ventricular
contractility and led to a higher coronary blood flow. More-
was improved. These findings suggest that preconditioning
with Cinaciguat could improve myocardial and endothelial
function following cardiopulmonary bypass and could be a
novel therapeutic option in the protection against ischemia-
reperfusion injury in cardiac surgery .
Vasodilator responses to this novel class of drugs have
been studied in experimental models under conditions of
acute pulmonary hypertension (PH) induced with the stable
endoperoxide analogue, U46619 [122, 128]. In the intact
chest rat under elevated pulmonary arterial tone conditions
induced with U46619, administration of BAY 60-2770 pro-
duced significant decreases in both pulmonary and systemic
arterial pressure . Intravenous infusion of the sGC
6 Critical Care Research and Practice
stimulator, BAY 41-2272, or inhalation of the sGC activator,
BAY 58-2667, was able to reduce mean pulmonary arterial
pressure and pulmonary vascular resistance in awake lambs
sure changes observed following administration of the sGC
activator, BAY 58-2667, in the awake lamb , significant
decreases in systemic arterial pressure were observed follow-
ing administration of the sGC activator, BAY 60-2770, in the
intact chest rat model . The differences in results could
be due to the type of sGC activator administered, experi-
mental conditions, or species studied.
4.2.2. Clinical Studies. The development of heart failure due
to a number of etiologies is a common final stage in cardio-
vascular disease that is associated with high morbidity and
development of tolerance, due to the prosthetic heme group
of sGC existing in an oxidized or heme-free state, limits their
clinical effectiveness [161, 162]. BAY 58-2667 (Cinaciguat;
Bayer Healthcare AG, Wuppertal, Germany) has been shown
to preferentially activate sGC when the prostetic heme group
is in an oxidized or heme-free state . As a result,
Cinaciguat induces cGMP generation and vasodilation pref-
tial to induce vasodilation and increase cardiac output in
patients with HF. In the first clinical study with this sGC
macodynamics were analyzed in 76 healthy volunteers .
An intravenous infusion of Cinaciguat in a range of 50 to
250mcg/h was administered for up to 4 hours. During the
infusion period, the sGC activator decreased diastolic blood
pressure and increased heart rate without significantly
reducing systolic blood pressure. No serious adverse events
were observed. However, at the higher infusion rates (150–
250mcg/h), a decrease in mean arterial pressure and an in-
crease in plasma cGMP levels were observed. The findings
both preload and after load suggested that further investiga-
tion should occur in patients with HF . In a multicenter
phase II study, patients with a diagnosis of acute decompen-
sated heart failure received 6-hour intravenous infusions of
Cinaciguat which produced significant reductions in pul-
monary capillary wedge pressure, mean right atrial pressure,
mean pulmonary artery pressure, pulmonary vascular resis-
tance, and systemic vascular resistance, and cardiac output
by 1.7L/min while only increasing heart rates by 4bpm
. Cinaciguat was well tolerated in these patients, with
approximately one-fourth of the patients reporting adverse
events of mild to moderate intensity, with hypotension as
the most common adverse event . These results clearly
demonstrate the clinical efficacy of the sCG activator.
As sGC stimulators have been shown to stimulate sGC in-
dependently of NO donors, this class of agonists could have
increase in pulmonary vascular tone can occur during sym-
pathetic overstimulation following major surgery that would
be refractory to conventional NO-donor therapy, such as in
patients who develop ARDS and are refractory to inhaled
NO (iNO). The application of sGC stimulators would then
make iNO therapy more effective in the treatment of acute
pulmonary hypertension and possibly decease the incidence
of associated right ventricular heart failure.
In contrast to the benefits from sGC stimulators, the ap-
therapeutic management of chronic-diseased blood vessels
with extended periods of efficacy such as seen in systemic
hypertension, atherosclerosis, diabetes mellitus, angina, and
heart failure. Moreover, the use of this class of drugs may
reduce the development of oxidative stress from NO-donor
therapy and may reduce the common side effects from NO-
donor therapy such as headache that would improve patient
Research has shown that heme-dependent drugs are effective
effects are diminished under pathological conditions associ-
ated with increased oxidative stress and the development of
pendent compounds has been shown to higher affinities for
the oxidized form of sGC, and they are being developed
for the treatment of acute decompensated heart failure and
pulmonary hypertension. These two classes of drugs, sGC
stimulators and sGC activators, have been studied in animal
studies. These compounds are now undergoing preliminary
clinical trials and may be available for clinical use within the
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