• Proceedings of the Korean Society of Applied Pharmacology
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• 2002.07a
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• pp.211-211
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• 2002

• Proceedings of the PSK Conference
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• 2001.10a
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• pp.135.2-136
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• 2001

• Proceedings of the PSK Conference
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• 2002.04a
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• pp.219.2-219.2
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• 2002

• Archives of Pharmacal Research
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• v.25 no.6
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• pp.873-878
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• 2002

OA-8159, a new Phosphodiesterase (PDE) 5 inhibitor, has exhibited potent erectogenic potential in a penile erection test in rats and anesthetized dogs. In this study, we investigated the mechanism of its erectogenic activity by measuring the activity of OA-8159 against a various PDE isozymes and assessing cGMP and cAMP formation in a rabbit corpus cavernosum in vitro. DA-8159 inhibited the PDE 5 activity in rabbit and human platelets, which the $IC_{50}$ was 5.84$\pm$1.70 nM and 8.25$\pm$2.90 nM, respectively. The $IC_{50}$ of DA-8159 on PDE 1, PDE2, PDE 3 and PDE 6 were 870$\pm$57.4 nM, $101\pm$5 $\mu$M, 52.0$\pm$3.53 $\mu$M and 53.3$\pm$2.47 nM, respectively. This suggests that DA-8159 is a potent, highly selective, competitive inhibitor of PDE 5-catalyzed cGMP hydrolysis. The rates of cGMP hydrolysis catalyzed by human platelets-derived PDE 5 as a function of the cGMP concentration (5~100 nM) and two-fixed DA-8159 concentration (11.3 and 18.8 nM) were investigated in order to characterize the mode of PDE 5 inhibition by DA-8159. DA-8159 increased the apparent 4K_{m}$ value for cGMP hydrolysis but had no effect on the apparent $V_{max}$, indicating a competitive mode of inhibition. DA-8159 increased the cGMP concentrations in the rabbit corpus cavernosum dose dependently. In the presence of sodium nitroprusside (SNP), DA-8159 significantly sti\mulated the accu\mulation of cGMP when compared to the control level. This indicated that the enhancement of a penile erection by DA-8159 involved the relaxation of the cavernosal smooth \muscle by NO-sti\mulated cGMP accu\mulation. In conclusion, DA-8159 is a selective inhibitor of PDE 5-catalyzed cGMP hydrolysis and the enhancement of a penile erection by DA-8159 is mediated by the relaxation of the cavernosal smooth \muscle by the NO-sti\mulated cGMP accu\mulation.

• Journal of Korean Neurosurgical Society
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• v.65 no.5
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• pp.665-679
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• 2022

Objective : Patients with mild ischemic stroke experience various sequela and residual symptoms, such as anxious behavior and deficits in movement. Few approaches have been proved to be effective and safe therapeutic approaches for patients with mild ischemic stroke by acute stroke. Sildenafil (SIL), a phosphodiesterase-5 inhibitor (PDE5i), is a known remedy for neurodegenerative disorders and vascular dementia through its angiogenesis and neurogenesis effects. In this study, we investigated the efficacy of PDE5i in the emotional and behavioral abnormalities in rats with mild ischemic stroke. Methods : We divided the rats into four groups as follows (n=20, respectively) : group 1, naïve; group 2, middle cerebral artery occlusion (MCAo30); group 3, MCAo30+SIL-pre; and group 4, MCAo30+SIL-post. In the case of drug administration groups, single dose of PDE5i (sildenafil citrate, 20 mg/kg) was given at 30-minute before and after reperfusion of MCAo in rats. After surgery, we investigated and confirmed the therapeutic effect of sildenafil on histology, immunofluorescence, behavioral assays and neural oscillations. Results : Sildenafil alleviated a neuronal loss and reduced the infarction volume. And results of behavior task and immunofluorescence shown possibility that anti-inflammation process and improve motor deficits sildenafil treatment after mild ischemic stroke. Furthermore, sildenafil treatment attenuated the alteration of theta-frequency rhythm in the CA1 region of the hippocampus, a known neural oscillatory marker for anxiety disorder in rodents, induced by mild ischemic stroke. Conclusion : PDE5i as effective therapeutic agents for anxiety and movement disorders and provide robust preclinical evidence to support the development and use of PDE5i for the treatment of mild ischemic stroke residual disorders.

• Journal of Life Science
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• v.21 no.5
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• pp.647-655
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• 2011

The neurotoxicity of aggregated amyloid ${\beta}$ ($A{\beta}$) has been implicated as a critical cause in the pathogenesis of Alzheimer's disease (AD). It can cause neurotoxicity in AD by evoking a cascade of apoptosis to neuron. Here, we investigated the neuroprotective effects of cilostazol, which acts as a phosphodiesterase III inhibitor, on $A{\beta}_{25-35}$-induced cytotoxicity in mouse neuronal cells and cognitive decline in the C57BL/6J AD mouse model via peroxisome proliferator-activated receptor (PPAR)-${\gamma}$ activation. $A{\beta}_{25-35}$ significantly reduced cell viability and increased the number of apoptotic-like cells. Cilostazol treatment recovered cells from $A{\beta}$-induced cell death as well as rosiglitazone, a PPAR-${\gamma}$ activator. These effects were suppressed by GW9662, an antagonist of PPAR-${\gamma}$ activity, indicative of a PPAR-${\gamma}$-mediated signaling. In addition, cilostazol and rosiglitazone also restored PPAR-${\gamma}$ activity levels that had been altered as a result of $A{\beta}_{25-35}$ treatment, which were antagonized by GW9662. Furthermore, cilostazol also markedly decreased the number of apoptotic-like cells and decreased the Bax/Bcl-2 ratio. Intracerebroventricular injection of $A{\beta}_{25-35}$ in C57BL/6J mice resulted in impaired cognitive function. Oral administration of cilostazol (20 mg/kg) for 2 weeks before $A{\beta}_{25-35}$ injection and once a day for 4 weeks post-surgery almost completely prevented the $A{\beta}_{25-35}$-induced cognitive deficits, as did rosiglitazone. Taken together, our findings suggest that cilostazol could attenuate $A{\beta}_{25-35}$-induced neuronal cell injury and apoptosis as well as promote the survival of neuronal cells, subsequently improving cognitive decline in AD, partly because of PPAR-${\gamma}$ activation. The phosphodiesterase III inhibitor cilostazol may be the basis of a novel strategy for the therapy of AD.

• The Korean Journal of Physiology and Pharmacology
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• v.10 no.3
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• pp.149-154
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• 2006

Selective inhibition of phosphodiesterase (PDE) 5 opened a new therapeutic approach for cardiovascular disorders. Therefore, the effect of PDE5 inhibition on the cardiac function should thoroughly be defined. The purpose of the present study was to define the effects of sildenafil, a selective inhibitor of PDE5, on the atrial cGMP efflux, atrial dynamics, and the release of atrial natriuretic peptide (ANP). By perfusing rabbit left atria to allow atrial pacing, changes in atrial stroke volume and pulse pressure, transmural extracellular fluid translocation, cGMP efflux, and ANP secretion were measured. SIN-I, an NO donor and soluble (s) guanylyl cyclase (GC) activator, and C-type natriuretic peptide (CNP), an activator of particulate (p) GC activator, were used. Sildenafil increased basal levels of cGMP efflux slightly but not significantly. Sildenafil in a therapeutic dose increased atrial dynamics (for atrial stroke volume, $2.84{\pm}1.71%$, n=12, vs $-0.71{\pm}0.86%$, n=21; p<0.05) and decreased ANP release ($-9.02{\pm}3.36%$, n=14, vs $1.35{\pm}3.25%$, n=23; p < 0.05), however, it had no effect on the SIN-1- or CNP-induced increase of cGMP levels. Furthermore, sildenafil in a therapeutic dose accentuated SIN-1-induced, but not CNP-induced, decrease of atrial pulse pressure and ANP release. These data indicate that PDE5 inhibition with sildenafil has a minor effect on cGMP levels, but has a distinct effect on pGC-cGMP- and sGC-cGMP-induced contractile and secretory function.

• Korean Journal of Food Science and Technology
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• v.21 no.1
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• pp.1-8
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• 1989

Ten cultivars of malting barley grown at four locations were malted and assayed for six enzymes involved in the degradation of nucleic acids. Among these enzymes were deoxyrinonuclease, ribonuclease, phosphodiesterase, 3'- and 5'- nucleotidases and phosphomonesterase. Activities of all enzymes in five-day malts were significantly affected by variety and location of growth. The average levels of ribonuclease, deoxyribonuclease, 3'-nucleotidase and 5'-nucleotidase of 80 five-day malts were 11.2, 5.7, 5.6 and 1.2 units per gram of malt, respectively. Six-rowed barley malts contained higher levels of deoxyribonuclease, phosphodiesterase and 3'-nucleotidase than those of two-rowed barley malts, while two-rowed barley malts contained significantly higher ribonuclease levels than those of six-rowed barley malts.

• Tuberculosis and Respiratory Diseases
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• v.73 no.4
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• pp.231-233
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• 2012

Tadalafil is a phosphodiesterase-5 inhibitor (PDE5I), which is widely used to treat erectile dysfunction. Although PDE5Is have excellent safety profiles, and most of the side effects are mild, rare serious adverse events have been reported in association with PDE5Is. Thrombosis is one of those events, and a few previous reports have suggested the association of PDE5Is with thrombosis. We report the case of a 61-year-old male who developed pulmonary embolism combined with pulmonary infarction directly after taking tadalafil. Both the patient and the physician suspected tadalafil as the culprit drug, as the patient was in an otherwise healthy condition. However, after extensive evaluation, we noticed that factor VIII levels were elevated. Prior reports suggesting the association between thrombosis and PDEIs either lack complete information on coagulation factors, or show inconsistencies in their results. Physicians should operate caution prior to accepting the diagnosis of adverse drug reaction.

• Natural Product Sciences
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• v.23 no.3
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• pp.169-174
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• 2017

The aim of this study was to investigate the effect and action mechanism of quercetin on penile corpus cavernosum smooth muscle (PCCSM). PCCSM precontracted with phenylephrine (Phe) was treated with four different concentrations of quercetin ($10^{-7}$, $10^{-6}$, $10^{-5}$ and $10^{-4}M$). PCCSM were preincubated with N-Nitro-L-arginine methyl ester hydrochloride (L-NAME) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) to block nitric oxide synthase and guanylate cyclase, respectively. The changes in PCCSM tension were recorded, and cyclic nucleotides in the perfusate were measured by radioimmunoassay. The interactions of quercetin with phosphodiesterase type 5 inhibitors (PDE5-Is) such as sildenafil, udenafil and mirodenafil, were also evaluated. PCCSM relaxation induced by quercetin occurred in a concentrationdependent manner. The application of quercetin to PCCSM pre-treated with L-NAME and ODQ significantly inhibited the relaxation. Quercetin significantly increased cGMP in the perfusate. Furthermore, quercetin enhanced PDE5-Is-induced relaxation of PCCSM. Quercetin relaxed the PCCSM by activating the NO-cGMP signaling pathway, and it may be a therapeutic candidate or an alternative treatment for patients with erectile dysfunction who do not completely respond to PDE5-Is.