Effect of DMPPO, a phosphodiesterase type 5 inhibitor, on hypoxic pulmonary hypertension in rats

Eddahibi, Saadia; Raffestin, Bernadette; Gouville, Anne-Charlotte Le Monnier de; Adnot, Serge

doi:10.1038/sj.bjp.0702124

Cited by 25 publications

(14 citation statements)

References 24 publications

(34 reference statements)

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“…However, these results are at odds with previously published observations from our laboratory and others demonstrating no significant effect of CH on vasodilatory responsiveness to NO-donors (26) or inhaled NO (25,8) in isolated lungs from male rats. Furthermore, Isaacson et al (12) reported that CH enhanced vasodilatory responses to arterial boluses of saturated NO solution in isolated lungs.…”

Section: Discussioncontrasting

confidence: 99%

“…Levels of cGMP are further regulated by the rate of degradation by cGMP-specific phosphodiesterase type 5 (PDE5), which plays a significant role in modulating pulmonary VSM tone (5,6,8,13,21,40). Once formed, cGMP can mediate VSM relaxation through several mechanisms involving a decrease in intracellular calcium and/or decreased sensitivity of the contractile apparatus to calcium (17).…”

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confidence: 99%

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Chronic hypoxia attenuates cGMP-dependent pulmonary vasodilation

Jernigan

Resta

2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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Jernigan, Nikki L., and Thomas C. Resta. Chronic hypoxia attenuates cGMP-dependent pulmonary vasodilation. Am J Physiol Lung Cell Mol Physiol 282: L1366-L1375, 2002. First published January 18, 2002 10.1152/ajplung.00273. 2001.-Chronic hypoxia (CH) augments endothelium-derived nitric oxide (NO)-dependent pulmonary vasodilation; however, responses to exogenous NO are reduced following CH in female rats. We hypothesized that CH-induced attenuation of NO-dependent pulmonary vasodilation is mediated by downregulation of vascular smooth muscle (VSM) soluble guanylyl cyclase (sGC) expression and/or activity, increased cGMP degradation by phosphodiesterase type 5 (PDE5), or decreased VSM sensitivity to cGMP. Experiments demonstrated attenuated vasodilatory responsiveness to the NO donors S-nitroso-N-acetylpenicillamine and spermine NONOate and to arterial boluses of dissolved NO solutions in isolated, saline-perfused lungs from CH vs. normoxic female rats. In additional experiments, the sGC inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, blocked vasodilation to NO donors in lungs from each group. However, CH was not associated with decreased pulmonary sGC expression or activity as assessed by Western blotting and cGMP radioimmunoassay, respectively. Consistent with our hypothesis, the selective PDE5 inhibitors dipyridamole and T-1032 augmented NO-dependent reactivity in lungs from CH rats, while having little effect in lungs from normoxic rats. However, the attenuated vasodilatory response to NO in CH lungs persisted after PDE5 inhibition. Furthermore, CH similarly inhibited vasodilatory responses to 8-bromoguanosine 3Ј5Ј-cyclic monophosphate. We conclude that attenuated NO-dependent pulmonary vasodilation after CH is not likely mediated by decreased sGC expression, but rather by increased cGMP degradation by PDE5 and decreased pulmonary VSM reactivity to cGMP. isolated rat lung; nitric oxide; soluble guanylate cyclase; phosphodiesterase; pulmonary hypertension CHRONIC EXPOSURE TO HYPOXIA results in structural as well as functional alterations in the pulmonary vasculature, leading to the development of pulmonary hypertension and right ventricular hypertrophy. The principal mediators of chronic hypoxia (CH)-induced pulmonary hypertension are polycythemia, pulmonary arterial remodeling, and arterial constriction. Among the corresponding functional alterations is responsiveness to vasoactive factors. Studies from our laboratory (23,24,26) and others (12,20,22,28,29) have shown that CH augments pulmonary vasodilatory responses to endothelium-derived nitric oxide (EDNO)-dependent vasodilators. EDNO is synthesized in the vasculature by endothelial nitric oxide synthase (eNOS), and several studies have demonstrated that CH is associated with increased pulmonary eNOS levels, gene expression, and activity (12,15,20,23,24,32,39). Consistent with elevated eNOS levels, nitric oxide (NO) synthesis appears to be greater in lungs isolated from CH rats compared with normoxic controls (12,20,30,36). Despite enhanced reactivit...

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Section: Discussioncontrasting

confidence: 99%

mentioning

confidence: 99%

Chronic hypoxia attenuates cGMP-dependent pulmonary vasodilation

Jernigan

Resta

2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…29) Other PDE5 inhibitors also have pulmonary selectivity in the model of PH. 30,31) These observations support that selective PDE5 inhibitors such as T-1032 show pulmonary selectivity in PH. When we determined the pulmonary selectivity using RVSP and MAP, other hemodynamic changes such as cardiac output and contraction should be considered, because these parameters influence RVSP.…”

Section: Discussionsupporting

confidence: 53%

Acute and Chronic Effects of T-1032, a Novel Selective Phosphodiesterase Type 5 Inhibitor, on Monocrotaline-Induced Pulmonary Hypertension in Rats.

Inoue

Yano

Noto

et al. 2002

Biological & Pharmaceutical Bulletin

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Pulmonary hypertension (PH) is a fatal disease, characterized by the progressive elevation of pulmonary arterial resistance. Although the causes of this disorder are complicated, abnormal vasoconstriction appears to be a primary factor in the development of PH. 1,2) Although some kinds of vasodilators, such as calcium blockers and prostacyclin, have been used in the treatment of PH, 3,4) they cause several side effects due to systemic vasodilation. Recent studies have demonstrated that nitric oxide inhalation produces selective pulmonary vasodilation without affecting systemic blood pressure in patients with PH. 5,6) However, since the safety of nitric oxide inhalation has not been established, 7) its doses have been restricted. Phosphodiesterases (PDEs) are enzymes, which break down cAMP and/or cGMP, and they play a key role in the regulation of intracellular cyclic nucleotide levels. A phosphodiesterase type 5 (PDE5) is classified as cGMP-bind, cGMP-specific phosphodiesterase. 8,9) PDE5 is abundantly expressed in some specific tissues, including the lung and pulmonary artery.10-12) Therefore, the inhibition of PDE5 is considered to produce an increase in cGMP levels in the lung and pulmonary artery. It has been reported that PDE5 inhibitors such as zaprinast, E-4021 and sildenafil preferably dilate the pulmonary artery in vivo and in vitro experimental conditions. [13][14][15][16][17][18] T-1032 (methyl 2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate) is a novel inhibitor of PDE5 (IC 50 ϭ0.001 mM; canine lung). The selectivity for PDE5 over other PDEs in T-1032 is similar to that of sildenafil (IC 50 : PDE1; 3 mM, PDE2; 9.7 mM, PDE3; Ͼ100 mM, PDE4; 3.3 mM).19) T-1032 shows potentiating effects on the nitric oxide/cGMP signaling pathway in isolated rat aorta and rabbit corpus cavernosum. 20) In addition, an intraduodenal administration of T-1032 potentiates the penile tumescence induced by pelvic nerve stimulation, probably through the blockade of PDE5 in anesthetized dogs.21) These results suggest that T-1032 potentiates a nitric oxide/cGMP pathway inhibitor and is orally active compound in animal studies.The acute hemodynamic effects by PDE5 inhibitors on pulmonary circulation have been examined in animal models with PH. 13,15,18) However, only a few studies have reported whether the chronic treatment is effective for improving cardiac remodeling and its related death in an animal model with PH. 22) In this study, we first examined the hemodynamic properties of T-1032 in MCT-induced PH rats, and we next evaluated the chronic effect of T-1032 on cardiac remodeling and its related death in MCT-induced PH rats. MATERIAL AND METHODSThis study was approved by the Animal Research Committee of Tanabe Seiyaku Co., Ltd.Animal Preparation Monocrotaline (MCT, 70 mg/kg) was subcutaneously administered in male Wistar rats weighing 94-107 g, as described previously. 23)Acute Hemodynamic Effects in MCT Rats Twenty-six days after MCT (70 mg/kg) or vehicle...

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“…This pathophysiological adaptation of the pulmonary circulation to maintain hypoxia is a complicated process for which no curative treatment, except heart -lung transplantation, is currently available. Since PDEs are present in the pulmonary artery wall (Rabe et al, 1994;Maclean et al, 1997) and that cGMP-PDE activity is mainly because of the action of PDE5 (Rabe et al, 1994), some PDE5 inhibitors have been administered to counteract PAHT development both in animals and human (Eddahibi et al, 1998;Ziegler et al, 1998;Hanasato et al, 1999). Very recently, pioneer clinical trials with sildenafil have been performed in PAHT (Abrams et al, 2000;Ichinose et al, 2001;Zhao et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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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Effect of DMPPO, a phosphodiesterase type 5 inhibitor, on hypoxic pulmonary hypertension in rats

Cited by 25 publications

References 24 publications

Chronic hypoxia attenuates cGMP-dependent pulmonary vasodilation

Chronic hypoxia attenuates cGMP-dependent pulmonary vasodilation

Acute and Chronic Effects of T-1032, a Novel Selective Phosphodiesterase Type 5 Inhibitor, on Monocrotaline-Induced Pulmonary Hypertension in Rats.

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

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