Effects of Theophylline and Non-selective Xanthine Derivatives on PDE Isoenzymes and Cellular Function

Dent, Gordon; Rabe, Klaus F.

doi:10.1016/b978-012210720-7/50005-8

Cited by 10 publications

(5 citation statements)

References 181 publications

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“…Our ®nding that YC-1 is a novel PDE inhibitor con®rms and extends the results of a recent study that suggested YC-1 inhibited cyclic AMP break down in myocardium (Wegener et al, 1997). YC-1 does not show structural similarity to any known PDE inhibitor; however, its potency is low, ranging between the non-selective PDE inhibitors 3-isobutyl-1-methylxanthine (IBMX) and theophylline (Dent & Rabe, 1996). Low potency, together with its low selectivity, make YC-1, however, an unattractive lead compound for further development of related PDE inhibitors.…”

Section: Discussionsupporting

confidence: 58%

Effects of the soluble guanylyl cyclase activator, YC‐1, on vascular tone, cyclic GMP levels and phosphodiesterase activity

Galle

Zabel

Hübner

et al. 1999

British J Pharmacology

163

107

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1 The vasomotor and cyclic GMP-elevating activity of YC-1, a novel NO-independent activator of soluble guanylyl cyclase (sGC), was studied in isolated rabbit aortic rings and compared to that of the NO donor compounds sodium nitroprusside (SNP) and NOC 18. 2 Similarly to SNP and NOC 18, YC-1 (0.3 ± 300 mM) caused a concentration-dependent, endothelium-independent relaxation that was greatly reduced by the sGC inhibitor 1-H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ 10 mM; 59% inhibition of dilation induced by 100 mM YC-1) suggesting the activation of sGC as one mechanism of action.3 Preincubation with YC-1 (3 and 30 mM) signi®cantly increased the maximal dilator responses mediated by endogenous NO in aortic rings that was released upon exposure to acetylcholine, and enhanced the dilator response to the exogenous NO-donors, SNP and NOC 18, by almost two orders of magnitude. 4 Vasoactivity induced by SNP and YC-1 displayed dierent kinetics as evidenced by a longlasting inhibition by YC-1 (300 mM) on the phenylephrine (PE)-induced contractile response, which was not fully reversible even after extensive washout (150 min) of YC-1, and was accompanied by a long-lasting elevation of intracellular cyclic GMP content. In contrast, SNP (30 mM) had no eect on the vasoconstrictor potency of PE, and increases in intravascular cyclic GMP levels were readily reversed after washout of this NO donor compound.5 Surprisingly, YC-1 not only activated sGC, but also aected cyclic GMP metabolism, as it inhibited both cyclic GMP break down in aortic extracts and the activity of phosphodiesterase isoforms 1 ± 5 in vitro. 6 In conclusion, YC-1 caused persistent elevation of intravascular cyclic GMP levels in vivo by activating sGC and inhibiting cyclic GMP break down. Thus, YC-1 is a highly eective vasodilator compound with a prolonged duration of action, and mechanisms that are unprecedented for any previously known sGC activator.

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Section: Discussionsupporting

confidence: 58%

Effects of the soluble guanylyl cyclase activator, YC‐1, on vascular tone, cyclic GMP levels and phosphodiesterase activity

Galle

Zabel

Hübner

et al. 1999

British J Pharmacology

163

107

View full text Add to dashboard Cite

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“…Figures represent the values of IC 50 (μM) for each inhibitor reported previously. Superscript letters represent references(:) a, Beavo (1995); b, Loughney et al (1998); c, Kotera et al (2000a); d, Dent and Rabe (1996); e, Murray (1993); f, Hetman et al (2000); g, Soderling et al (1998); h, Fisher et al (1998); i, Fujishige et al (1999); j, Fawcett et al (2000); k, Yuasa et al (2000).…”

Section: Discussionmentioning

confidence: 99%

Phosphodiesterase inhibitors are neuroprotective to cultured spinal motor neurons

Nakamizo

Kawamata

Yoshida

et al. 2002

J of Neuroscience Research

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We have previously reported that cyclic guanosine-3',5'-monophosphate (cGMP) protects spinal motor neurons against acute reactive oxygen species (ROS)-induced toxicity but not against chronic ROS-induced or glutamate (Glu)-induced toxicity. In this study, we investigated the effects of phosphodiesterase (PDE) inhibitors on the survival of cultured spinal motor neurons. Selective PDE5 inhibitors (dipyridamole, T-1032, and zaprinast) as well as a nonselective PDE inhibitor (aminophylline) protected motor and nonmotor neurons against both acute ROS-induced and chronic Glu-induced neurotoxicity, whereas selective inhibitors of PDE1-4 offered no protection. 8-Bromo-cGMP (8br-cGMP), a cGMP analogue, protected both motor and nonmotor neurons against acute ROS-induced toxicity but protected only nonmotor neurons against chronic Glu-induced toxicity. This neuroprotection was blocked by KT5823, a cGMP-dependent protein kinase (PKG) inhibitor. Immunohistochemical staining confirmed that PDE5 and PKG are located in almost all rat lumbar spinal neurons. Furthermore, semiquantitative analysis of the immunostaining intensity revealed that PDE5 was more abundant in motor neurons than in nonmotor neurons. Our results suggest that this difference in the amount of PDE5 may be responsible for the vulnerability of motor neurons to chronic excitotoxicity. In addition, the results of this study raise the possibility that PDE5 inhibitors might be used as a treatment for amyotrophic lateral sclerosis.

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“…[10,11] It has also been shown that cAMP phosphodiesterase inhibitors suppress the production of pro-inflammatory cytokines such as TNF-a, IL-2 and interferon g, and stimulate the anti-inflammatory cytokine IL-10. [12,13] In animal studies, it has been shown that long-term dietary supplementation with caffeine or coffee suppresses LPS induced elevation of serum AST and ALT levels in D-galactosamine (D-GalN) sensitised rats. [14,15] In the present study, we investigated the effects of caffeine with single-time administration on LPS/D-GalN induced acute liver injury in rats, by examining survival rates and plasma AST, ALT, TNF-a and IL-10 levels.…”

Section: Introductionmentioning

confidence: 99%

Protective effects of coffee-derived compounds on lipopolysaccharide/D-galactosamine induced acute liver injury in rats

et al. 2009

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Effects of Theophylline and Non-selective Xanthine Derivatives on PDE Isoenzymes and Cellular Function

Cited by 10 publications

References 181 publications

Effects of the soluble guanylyl cyclase activator, YC‐1, on vascular tone, cyclic GMP levels and phosphodiesterase activity

Effects of the soluble guanylyl cyclase activator, YC‐1, on vascular tone, cyclic GMP levels and phosphodiesterase activity

Phosphodiesterase inhibitors are neuroprotective to cultured spinal motor neurons

Protective effects of coffee-derived compounds on lipopolysaccharide/D-galactosamine induced acute liver injury in rats

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