BAY 41-2272, a Direct Activator of Soluble Guanylate Cyclase, Reduces Right Ventricular Hypertrophy and Prevents Pulmonary Vascular Remodeling during Chronic Hypoxia in Neonatal Rats

Deruelle, Philippe; Balasubramaniam, Vivek; Kunig, Anette M.; Seedorf, Gregory J.; Markham, Neil E.; Abman, Steven H.

doi:10.1159/000092518

Cited by 62 publications

(43 citation statements)

References 64 publications

(54 reference statements)

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“…Chronic hypoxia can impair pulmonary vascularization and alveolar formation in neonatal rats and humans (14,15). Alveolar hypoxia in this model reduced pulmonary vessel density, RAC and increased mean Lm.…”

Section: Discussionmentioning

confidence: 75%

Chronic Hypoxia and Rat Lung Development: Analysis by Morphometry and Directed Microarray

Truog

Ekekezie

et al. 2008

Pediatr Res

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It is unclear how sublethal hypoxia affects lung development. To investigate the effects of chronic hypoxia on postnatal lung remodeling, we treated neonatal rats with FIO 2 of 0.12 for 10 d and analyzed lung development by morphometry and gene expression by DNA microarray. Our results showed the neonatal rats exposed to hypoxia reduced body weight by 42% and wet lung weight by 32% compared with the neonatal rats exposed to normoxia. In the neonatal rats exposed to hypoxia, the radial alveolar counts were decreased to 5.6 from 7.9 and the mean linear intercepts were increased to 56.5 m from 38.2 m. In DNA microarray analysis, approximately half of probed genes were unknown. Chronic hypoxia significantly regulated expression of genes that are involved in pathogenesis of pulmonary hypertension and postnatal lung remodeling. Chemokine ligand 12, jagged 2 were among those upregulated; c-kit, ephrin A1, and Hif-2␣ were among those downregulated. The altered expression of those genes was correlated with the lung development and remodeling. (Pediatr Res 64: 56-62, 2008)

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Section: Discussionmentioning

confidence: 75%

Chronic Hypoxia and Rat Lung Development: Analysis by Morphometry and Directed Microarray

Truog

Ekekezie

et al. 2008

Pediatr Res

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“…The former sGC stimulator BAY 41-2272 has demonstrated similar efficacy in experimental PAH induced by hypoxia in mice [12] and hypoxia in neonatal rats [45]. Acute vasoreactivity testing revealed a strong reduction in pulmonary vascular resistance which was shown in different species, such as mice [12] or sheep [11,46], which indicates strong biological relevance of sGC in regulating pulmonary vascular tone.…”

Section: Discussionmentioning

confidence: 87%

Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension

Schermuly

Jp²,

Pullamsetti³

et al. 2008

Eur Respir J

218

168

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Alterations of the nitric oxide receptor, soluble guanylate cyclase (sGC) may contribute to the pathophysiology of pulmonary arterial hypertension (PAH). In the present study, the expression of sGC in explanted lung tissue of PAH patients was studied and the effects of the sGC stimulator BAY 63-2521 on enzyme activity, and haemodynamics and vascular remodelling were investigated in two independent animal models of PAH.Strong upregulation of sGC in pulmonary arterial vessels in the idiopathic PAH lungs compared with healthy donor lungs was demonstrated by immunohistochemistry. Upregulation of sGC was detected, similarly to humans, in the structurally remodelled smooth muscle layer in chronic hypoxic mouse lungs and lungs from monocrotaline (MCT)-injected rats. BAY 63-2521 is a novel, orally available compound that directly stimulates sGC and sensitises it to its physiological stimulator, nitric oxide. Chronic treatment of hypoxic mice and MCT-injected rats, with fully established PAH, with BAY 63-2521 (10 mg?kg) partially reversed the PAH, the right heart hypertrophy and the structural remodelling of the lung vasculature.Upregulation of soluble guanylate cyclase in pulmonary arterial smooth muscle cells was noted in human idiopathic pulmonary arterial hypertension lungs and lungs from animal models of pulmonary arterial hypertension. Stimulation of soluble guanylate cyclase reversed right heart hypertrophy and structural lung vascular remodelling. Soluble guanylate cyclase may thus offer a new target for therapeutic intervention in pulmonary arterial hypertension.KEYWORDS: BAY 63-2521, cardiovascular diseases, nitric oxide, pharmacology, pulmonary arterial hypertension, smooth muscle P ulmonary arterial hypertension (PAH) is a disabling disease, with high mortality, characterised by sustained elevation in pulmonary arterial pressure (Ppa) and pulmonary vascular remodelling due to proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) [1]. Imbalance of vasodilatory and vasoconstrictive mediators has been implicated in these changes. Reduced urinary excretion of prostaglandin (PG)I 2 and augmented excretion of thromboxane metabolites were found in patients with idiopathic PAH (IPAH) [2], and immunohistological studies have shown reduced expression of PGI 2 synthase in the pulmonary vessels originating from those patients [3]. Another important mediator in the regulation of vascular tone is nitric oxide (NO), which is synthesised by NO synthases. Local NO production from endothelium and epithelium regulates pulmonary perfusion, depending on alveolar ventilation to assure optimised ventilation/perfusion distribution [4][5][6]. In patients with IPAH, it has been reported that the expression of endothelial NO synthase is downregulated [7], while other reports show an upregulation in plexiform lesions of IPAH patients [8]. However, little is known about the expression and regulation of soluble guanylate cyclase (sGC) which operates as a receptor for NO. Typically, sGC is found as a hetero...

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“…BAY 41-2272 is closely related to BAY 41-8543, and this sGC stimulator has been shown to have significant pulmonary vasodilator activity in a variety of species (9,10,13,15,34,37). BAY 41-2272 has been shown to reduce right ventricular hypertrophy and pulmonary vascular remodeling in a chronic hypoxia-induced model of pulmonary hypertension (8). 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 selective pulmonary vasodilator activity, and BAY 41-8543 could enhance the magnitude and prolong the duration of the vasodilator response to inhaled NO (9,13).…”

mentioning

confidence: 99%

Pulmonary and systemic vasodilator responses to the soluble guanylyl cyclase stimulator, BAY 41-8543, are modulated by nitric oxide

Badejo

Nossaman

Pankey

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Responses to intravenous injections of BAY 41-8543 were investigated under baseline and elevated tone conditions and when NO synthase (NOS) was inhibited with N -nitro-L-arginine methyl ester (L-NAME). Under baseline conditions, intravenous injections of BAY 41-8543 caused small decreases in pulmonary arterial pressure, larger decreases in systemic arterial pressure, and increases in cardiac output. When pulmonary arterial pressure was increased to ϳ30 mmHg with an intravenous infusion of U-46619, intravenous injections of BAY 41-8543 produced larger dose-dependent decreases in pulmonary arterial pressure, and the relative decreases in pulmonary and systemic arterial pressure in response to the sGC stimulator were similar. Treatment with L-NAME markedly decreased responses to BAY 41-8543 when pulmonary arterial pressure was increased to similar values (ϳ30 mmHg) in U-46619-infused and in U-46619-infused plus L-NAME-treated animals. The intravenous injection of a small dose of sodium nitroprusside (SNP) when combined with BAY 41-8543 enhanced pulmonary and systemic vasodilator responses to the sGC stimulator in L-NAME-treated animals. The present results indicate that BAY 41-8543 has similar vasodilator activity in the systemic and pulmonary vascular beds when pulmonary vasoconstrictor tone is increased with U-46619. These results demonstrate that pulmonary and systemic vasodilator responses to BAY 41-8543 are significantly attenuated when NOS is inhibited by L-NAME and show that vasodilator responses to BAY 41-8543 are enhanced when combined with a small dose of SNP in L-NAME-treated animals. The present results are consistent with the concept that pulmonary and systemic vasodilator responses to the sGC stimulator are NO-independent; however, the vasodilator activity of the compound is greatly diminished when endogenous NO production is inhibited with L-NAME. These data show that BAY 41-8543 has similar vasodilator activity in the pulmonary and systemic vascular beds in the rat. soluble guanylyl cyclase stimulator; pulmonary and systemic vascular beds; U-46619; N -nitro-L-arginine methyl ester; sodium nitroprusside THE HEME-PROTEIN SOLUBLE GUANYLYL cyclase (sGC) is the intracellular receptor for nitric oxide (NO) (16 -20, 23, 25, 26). The sGC is a heterodimetric enzyme with ␣-and ␤-subunits (3,6,22,26,30). The enzyme contains a heme moiety that is essential for the binding of NO and activation of the enzyme (2,7,19,31). The activation of sGC enhances the conversion of GTP to cGMP that mediates physiological responses, including smooth muscle relaxation and inhibition of platelet aggregation (1,4,16,21,27,28). Compounds have been developed that can directly stimulate sGC and increase cGMP formation in pathophysiological conditions when NO formation and bioavailability are impaired or when NO tolerance has developed (14,35,38). The pyrazolopyridine compound BAY 41-8543 is a NO-independent stimulator of sGC that has been shown to reduce systemic and pulmonary arterial pressure and relax isolated vessels from a vari...

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BAY 41-2272, a Direct Activator of Soluble Guanylate Cyclase, Reduces Right Ventricular Hypertrophy and Prevents Pulmonary Vascular Remodeling during Chronic Hypoxia in Neonatal Rats

Cited by 62 publications

References 64 publications

Chronic Hypoxia and Rat Lung Development: Analysis by Morphometry and Directed Microarray

Chronic Hypoxia and Rat Lung Development: Analysis by Morphometry and Directed Microarray

Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension

Pulmonary and systemic vasodilator responses to the soluble guanylyl cyclase stimulator, BAY 41-8543, are modulated by nitric oxide

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