NO-induced modulation of calcium-oscillations in pulmonary vascular smooth muscle

Pauvert, Olivier; Marthan, Roger; Savineau, Jean‐Pierre

doi:10.1054/ceca.2000.0123

Cited by 14 publications

(14 citation statements)

References 23 publications

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“…Nonetheless, this increase in PKG activity is consistent with increased vascular PKG-1 expression as assessed by quantitative immunohistochemistry. Alternatively, some investigators (13,29) have reported that PKG activity may not be essential to the NO/cGMP vasodilatory response. Fouty et al (13) have suggested that the inhibitory influence of NO on vascular tone is dependent on cGMP formation in the pulmonary circulation of both normotensive and hypertensive rats but is not dependent on PKG activation.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, consistent with the current study, Fouty and colleagues (13) demonstrate that the PKG inhibitor H-8 significantly, albeit modestly, inhibited 8-BrcGMP-mediated vasodilation in isolated lungs. Moreover, Pauvert et al (29) demonstrated that NO-mediated dilation in rat main pulmonary arterial rings involves cGMP but appears to be independent of PKG activation. These investigators show that the sGC inhibitor ODQ abolished sodium nitroprusside relaxation in ATP-preconstricted rings, but PKG inhibition with 1 M KT-5823 did not.…”

Section: Discussionmentioning

confidence: 99%

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Pulmonary PKG-1 is upregulated following chronic hypoxia

Jernigan

Walker

Resta

2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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. Pulmonary PKG-1 is upregulated following chronic hypoxia. Am J Physiol Lung Cell Mol Physiol 285: L634-L642, 2003. First published May 23, 2003 10.1152/ ajplung.00328.2002.-Recent studies from our laboratory indicate that pulmonary vasodilatory responses to exogenous nitric oxide (NO) are attenuated following chronic hypoxia (CH) and that this NO-dependent vasodilation is mediated by cGMP. Similarly, we have demonstrated that CH attenuates vasodilatory responses to the cGMP analog 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP). We hypothesized that attenuated pulmonary vasodilation to 8-BrcGMP following CH is mediated by decreased protein kinase G-1 (PKG-1) expression/activity. Therefore, we examined vasodilatory responses to 8-BrcGMP (1 M) in isolated, saline-perfused lungs from control and CH (4 wk at barometric pressure of 380 mmHg) rats in the presence of the competitive PKG inhibitor Rp-␤-phenyl-1, N2-etheno-8-bromoguanosine 3',5'-cyclic monophosphorothionate (30 M) or the highly specific PKG inhibitor KT-5823 (10 M). PKG-1 expression and activity were determined in whole lung homogenates from each group, and vascular PKG-1 levels were assessed by quantitative immunohistochemistry. PKG inhibition with either Rp-8-Br-PET-cGMPS or KT-5823 diminished vasodilatory responses to 8-BrcGMP in lungs from both control and CH rats, thus indicating a role for PKG in mediating reactivity to 8-BrcGMP in each group. However, in contrast to our hypothesis, PKG-1 levels were approximately twofold greater in lungs from CH rats vs. controls, and furthermore, this upregulation was localized to the vasculature. This correlates with an increase in PKG activity following CH. We conclude that PKG-1 is involved in 8-BrcGMPmediated vasodilation; however, attenuated pulmonary vasodilation following CH is not associated with decreased expression/activity of PKG-1. isolated rat lung; nitric oxide; pulmonary hypertension; 8-bromoguanosine 3',5'-cyclic monophosphate; KT-5823; Rp-␤-phenyl-1, N2-etheno-8-bromoguanosine 3',5'-cyclic monophosphorothioate CHRONIC EXPOSURE TO HYPOXIA has been shown to augment pulmonary vasodilatory responses to endothelium-derived nitric oxide (EDNO)-dependent vasodilators (18, 26, 28, 32-34, 36, 37). EDNO is synthesized in the vasculature by endothelial nitric oxide synthase (eNOS), and several studies have demonstrated that chronic hypoxia (CH) is associated with increased pulmonary eNOS levels, gene expression, and activity (18,21,26,33,34,39,46). Consistent with elevated eNOS levels, nitric oxide (NO) synthesis appears to be greater in lungs isolated from CH rats compared with controls (18,26,44). In contrast to enhanced reactivity to our laboratory (19,34) and others (35) have demonstrated impaired responsiveness to exogenous NO following CH. However, the mechanism(s) responsible for this diminished reactivity is not fully understood.NO leads to pulmonary vascular smooth muscle (VSM) relaxation by stimulating soluble guanylyl cyclase (sGC) (7). The subsequent elevation in cGMP activates prot...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pulmonary PKG-1 is upregulated following chronic hypoxia

Jernigan

Walker

Resta

2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…For contraction experiments, main pulmonary artery (MPA) rings (3 mM in length) were prepared and mounted in vertical 5 ml organ baths of a computerized isolated organ bath system (IOS, EMK Technologies, Paris, France) previously described (Pauvert et al, 2000). Baths were filled with Krebs Henseleit (KH) solution (composition in mM: 118.4 NaCl, 4.7 KCl, 2.5 CaCl 2 , 1.2 MgSO 4 , 25 NaHCO 3 , 1.2 KH 2 PO 4 , 11.1 D-glucose, pH 7.4) maintained at 371C and bubbled with a 95% O 2 À 5% CO 2 gas mixture.…”

Section: Isometric Contraction Measurementsmentioning

confidence: 99%

“…Baths were filled with Krebs Henseleit (KH) solution (composition in mM: 118.4 NaCl, 4.7 KCl, 2.5 CaCl 2 , 1.2 MgSO 4 , 25 NaHCO 3 , 1.2 KH 2 PO 4 , 11.1 D-glucose, pH 7.4) maintained at 371C and bubbled with a 95% O 2 À 5% CO 2 gas mixture. Tissues were set at optimal length by equilibration against a passive load of 10 mN (Pauvert et al, 2000).…”

Section: Isometric Contraction Measurementsmentioning

confidence: 99%

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Effect of sildenafil on cyclic nucleotide phosphodiesterase activity, vascular tone and calcium signaling in rat pulmonary artery

Pauvert

Lugnier

Keravis

et al. 2003

British J Pharmacology

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1 Sildenafil (viagra) is a potent PDE5 inhibitor and thus a relaxant drug in corpus carvernosum smooth muscle. In the present work, we evidenced the presence of PDE5 isozyme and investigated the effect of sildenafil on the specific cyclic nucleotide phosphodiesterase (PDE) activity, smooth muscle tone and calcium signaling in the rat main pulmonary artery (MPA). 2 The PDE activity was measured in cytosolic and microsomal fractions. Total cAMP and cGMP-PDE activities were mainly present in the cytosolic fraction. Sildenafil (0.1 mM) reduced by 72% cGMP-PDE activity, whereas zaprinast (10 mM), a relatively selective PDE5 inhibitor, reduced this activity by 63%. Sildenafil (0.1 mM) also inhibited significantly (22%) the cAMP-PDE activity. 3 Western blot analysis revealed the expression of PDE5 mainly in the cytosolic fraction of MPA. Sildenafil concentration-dependently inhibited (IC 50 ¼ 3.4 nM) the activity of MPA PDE5 partially purified by HPLC. 4 Sildenafil (0.1 nM-50 mM) concentration-dependently relaxed MPA rings precontracted with phenylephrine (0.5 mM). The potency of sildenafil (IC 50 ¼ 11 nM) was similar to that of a nitric oxide donor, sodium nitroprusside, but higher than that of zaprinast (IC 50 ¼ 600 nM). The vasorelaxant effect of sildenafil was not altered by endothelium removal or in the presence of KT 5823 (1 mM) and H89 (1 mM), potent inhibitors of PKG and PKA, respectively. 5 In isolated MPA myocytes, which had been loaded with the calcium fluorophore indo-1, sildenafil (10 -100 nM) antagonized ATP-and endothelin-1-induced calcium oscillations but had no effect on the transient caffeine-induced [Ca 2+ ] i response. 6 This study demonstrates the presence of a functional and highly sildenafil-sensitive PDE5 isozyme in rat MPA. Inhibition of this isozyme mainly accounts for the potent pulmonary vasodilator action of sildenafil, which involves alteration in the inositol triphosphate-mediated calcium signaling pathway.

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The vasorelaxant effects of 1-nitro-2-phenylethane involve stimulation of the soluble guanylate cyclase-cGMP pathway

Brito

Lima

Aragão

et al. 2013

Biochemical Pharmacology

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1-Nitro-2-phenylethane is the first organic NO₂-containing molecule isolated from plants. It possesses interesting hypotensive, bradycardic, and vasodilator properties, but the mode by which it induces vasorelaxation is still unknown. The underlying mechanism involved in the vasodilator effect of 1-nitro-2-phenylethane was investigated in rat aorta. The vasorelaxant effects of 1-nitro-2-phenylethane did not depend on endothelial layer integrity, and the effects were refractory to L-N(G)-nitroarginine methyl ester (L-NAME)-induced nitric oxide synthase inhibition. Vasorelaxation was similarly resistant to treatment with indomethacin, cis-N-(2-phenylcyclopentyl)-azacyclotridec-1-en-2-amine hydrochloride (MDL-12330A), and KT5720, indicating that neither prostaglandin release nor adenylyl cyclase activation is involved. Conversely, methylene blue- and ODQ-induced guanylate cyclase inhibition reduced the vasorelaxation induced by 1-nitro-2-phenylethane. The pharmacological blockade of K(+) channels with tetraethylammonium, glybenclamide, and 4-aminopyridine also blunted vasorelaxation induced by 1-nitro-2-phenylethane. The effects of 1-nitro-2-phenylethane were reversed by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and comparable to the effects induced by sodium nitroprusside. In silico analysis using an Ns H-NOX subunit of guanylate cyclase revealed a pocket on the macromolecule surface where 1-nitro-2-phenylethane preferentially docked. In vitro, 1-nitro-2-phenylethane increased cyclic guanosine 3',5'-monophosphate (cGMP) levels in rat aortic rings, an effect also reversed by ODQ. In conclusion, 1-nitro-2-phenylethane produces vasodilator effects by stimulating the soluble guanylate cyclase-cGMP pathway.

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NO-induced modulation of calcium-oscillations in pulmonary vascular smooth muscle

Cited by 14 publications

References 23 publications

Pulmonary PKG-1 is upregulated following chronic hypoxia

Pulmonary PKG-1 is upregulated following chronic hypoxia

Effect of sildenafil on cyclic nucleotide phosphodiesterase activity, vascular tone and calcium signaling in rat pulmonary artery

The vasorelaxant effects of 1-nitro-2-phenylethane involve stimulation of the soluble guanylate cyclase-cGMP pathway

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