• 대한약리학회지
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• 제27권2호
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• pp.183-189
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• 1991

본 연구에서는 흰쥐의 착상지연을 유도하여 착상기간동안 자궁조직내 prostaglandin (PG) 생합성이 어떠한 인자에 의해서 조절되는가를 관찰하여 다음과 같은 결과를 얻었다. 흰쥐의 착상지연과정동안 estradiol을 처리하면 처리후 4시간만에 자궁조직내의 cAMP의 농도가 급격하게 증가하였다. PGE와 $PGF_2{\alpha}$의 농도는 estradiol을 처리한 후 12시간이 경과하였을때 증가하였으나 $PGF_2{\alpha}$의 증가는 통계적으로 유의하지는 않았다. 또한 indomethacin을 estradiol과 동시에 처리하면 estradiol 처리로 인한 PGE와 $PGF_2{\alpha}$의 농도 증가는 나타나지 않았으나 cAMP 농도는 증가하였다. dbcAMP를 처리하면 자궁내 PGE 및 $PGF_2{\alpha}$의 농도가 증가하기 시작하여 estradiol이 투여시에 비하여 4시간 빨리 8시간후에 최고치에 도달하였으며 phosphodiesterase inhibitor인 theophylline을 전처치하면 estradiol만 투여한 것에 비하여 자궁조직내 PGE 및 $PGF_2{\alpha}$의 농도가 유의하게 증가하였다. 이상의 결과로 보아 흰쥐의 착상지연과정동안 estradiol이 자궁의 prostaglandin 합성을 증가시키며 이러한 증가는 cAMP의 증가를 매개하는 것으로 생각된다.

• The Korean Journal of Physiology and Pharmacology
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• 제1권6호
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• pp.673-679
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• 1997

It has been generally accepted that glutamate mediates the ischemic brain damage, excitotoxicity, and induces release of neurotransmitters, including norepinephrine(NE), in ischemic milieu. In the present study, the role of nitric oxide(NO) in the ischemia-induced $[^3H]norepinephrine([^3H]NE)$ release from cortex slices of the rat was examined. Ischemia, deprivation of oxygen and glucose from $Mg^{2+}-free$ artificial cerebrospinal fluid, induced significant release of $[^3H]NE$ from cortex slices. This ischemia-induced $[^3H]NE$ release was significantly attenuated by glutamatergic neurotransmission modifiers. $N^G-nitro-L-arginine$ methyl ester(L-NAME), $N^G-monomethyl-L-arginine$ (L-NMMA) or 7-nitroindazole, nitric oxide synthase inhibitors attenuated the ischemia-evoked $[^3H]NE$ release. Hemoglobin, a NO chelator, and 5, 5- dimethyl-L-pyrroline-N-oxide(DMPO), an electron spin trap, inhibited $[^3H]NE$ release dose-dependently. Ischemia-evoked $[^3H]NE$ release was inhibited by methylene blue, a soluble guanylate cyclase inhibitor, and potentiated by 8-bromo-cGMP, a cell permeable cGMP analog, zaprinast, a cGMP phosphodiesterase inhibitor, and S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide generator. These results suggest that the ischemia-evoked $[^3H]NE$ release is mediated by NMDA receptors, and activation of NO system is involved.

• 대한수의학회지
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• 제22권1호
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• pp.1-8
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• 1982

The effect of acetylcholine, oxytocin and prostaglandin $F_{2{\alpha}}$ ($PGF_{2{\alpha}}$) on cyclic nucleotide levels in estrogen-primed rabbit whole uterus were studied in the presence and absence of 1-methyl-3-isobutyl xanthine (MIX), a phosphodiestrase inhibitor, and indomethacin, a prostagandin inhibitor. In the absence of MIX, acetylcholine increased guanosine 3', 5'-cyclic monophosphate (cGMP), but had no effect on adenosine 3', 5'-cyclic monophosphate (cAMP) levels. In contrast, oxytocin had no influence on cGMP, but decreased cAMP levels. $PGF_{2{\alpha}}$ increased cGMP and decreased cAMP levels. MIX increased both cAMP and cGMP levels. Oxytocin and $PGF_{2{\alpha}}$ further increased cGMP levels, indicating activation of guanylate cyclase activity. The ratio of cAMP/cGMP was decreased by uterine stinulants both in presence and absence of MIX. Indomethacin elevated cAMP and cGMP revels. The effects of uterine stimulants in the presence of indomethacin on cyclic nucleotide levels were varied from tissue to tisse. In general, oxytocin decreased cGMP and $PGF_{2{\alpha}}$ increased cAMP/cGMP levels, but the effects were statisically nonsignicficant. The cAMP/cGMP ratio was increased by uterine stimulant in the presence of indomethacin. In conclusion, uterine stimulants eased cAMP/cGMP ratio which indicates that the uterine stimulants have opposing effects on adenylate cyclase and guanylate cyclase activities. The endometrium plays a role in the regulation of cyclic nucleotide levels and uterine contraction by means of PG synthesis. Indomethacin has an unknown activities besides both of PG synthetase and phosphodiesterase inhibitions.

• Journal of Korean Neurosurgical Society
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• 제59권3호
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• pp.259-268
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• 2016

Objective : Accumulation of advanced glycation end-products (AGE) and mitochondrial glycation is importantly implicated in the pathological changes of the brain associated with diabetic complications, Alzheimer disease, and aging. The present study was undertaken to determine whether sildenafil, a type 5 phosphodiesterase type (PDE-5) inhibitor, has beneficial effect on neuronal cells challenged with AGE-induced oxidative stress to preserve their mitochondrial functional integrity. Methods : HT-22 hippocampal neuronal cells were exposed to AGE and changes in the mitochondrial functional parameters were determined. Pretreatment of cells with sildenafil effectively ameliorated these AGE-induced deterioration of mitochondrial functional integrity. Results : AGE-treated cells lost their mitochondrial functional integrity which was estimated by their MTT reduction ability and intracellular ATP concentration. These cells exhibited stimulated generation of reactive oxygen species (ROS), disruption of mitochondrial membrane potential, induction of mitochondrial permeability transition, and release of the cytochrome C, activation of the caspase-3 accompanied by apoptosis. Western blot analyses and qRT-PCR demonstrated that sildenafil increased the expression level of the heme oxygenase-1 (HO-1). CoPP and bilirubin, an inducer of HO-1 and a metabolic product of HO-1, respectively, provided a similar protective effects. On the contrary, the HO-1 inhibitor ZnPP IX blocked the effect of sildenafil. Transfection with HO-1 siRNA significantly reduced the protective effect of sildenafil on the loss of MTT reduction ability and MPT induction in AGE-treated cells. Conclusion : Taken together, our results suggested that sildenafil provides beneficial effect to protect the HT-22 hippocampal neuronal cells against AGE-induced deterioration of mitochondrial integrity, and upregulation of HO-1 is involved in the underlying mechanism.

• Reproductive and Developmental Biology
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• 제35권4호
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• pp.435-439
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• 2011

Sildenafil citrate (SIL) a phosphodiesterase 5 inhibitor (PDE5I) has been used for long time as a first line oral drug for erectile dysfunction. Though it has beneficial effects on erectile organ it also has some adverse effects in other cells and/or tissues related to reproductive system when exposed to longer duration. The objective of the present study is to evaluate the long term effect of SIL on sperm parameters in Wistar albino rat. The animals are divided into two groups, for group I - rats were treated with saline (vehicle alone) and group - II oral administration of 5 mg/kg b.w. of SIL was administrated orally once in a day for 120 days. At the end of the trial period animals were sacrificed and epididymal sperm were subjected to various analysis. Results showed significant reduction in sperm count, motility, viability and morphologically intact sperm in long term PDE5I exposed animals when compared to control. Acrosomal status and fertility test also showed significant reduction in long term PDE5I exposed animals. The present study clearly indicated that long term SIL has shown to induce alteration in sperm quality and quantity, leading to decline in fertility rate. Indicate that SIL impinge on spermatogenesis as well as epididymal function. Understanding the molecular down-stream events involved in long-term exposure to PDE5 inhibitor can be valuable to supervise on related infertility issues and to suggest corrective measures.

• 한국임상약학회지
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• 제3권2호
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• pp.147-155
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• 1993

The cardiac effects of PAF antagonist Ginkgolide B(BN 52051) have been investigated on the isolated perfused guinea pig hearts maintained at the constant hydrostatic perfusion pressure of 80 cm water. PDE(Phosphodiesterase) inhibitor KR-30289 was used as a positive control to see the positive inotropic effects on the perfused hearts. In this expriments, Ginkgolide $B(10^{-5}-SM)$ showed negative inotropic effects by decreasing of LVP, LVDP, LV dp/dt, HR and RPP(Rate Pressure Product). Ginkgolide B also decreased the number of extrasystole by $51.9\%(from\;23.75\pm9.22/min\;to\;11.43\pm435/min)$ induced by global ischemia and reperfusion. The rate, [-dp/dt]/[+dp/dt] increased in preischemia but decreased in postischemia. 1n the separated study the injection of 1ml of Ginkgolide B$(10^{-4M})$ on the isolated heart, increased coronary flow(CF) by $11.8\%(from\;7.5\pm7.65ml/min\;to\;8.5\pm0.29ml/min)$ and decreased the number of extrasystole by $47.6\%(from\;21\pm5.92/min\;to\;11\pm5.27/min)$. In conclusion, Ginkgolide B showed antiarrhythmic and protective effects by decreasing the number of extrasystole and by increasing the coronary flow, respectively.

• Archives of Pharmacal Research
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• 제28권6호
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• pp.675-679
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• 2005

Eight furoquinoline alkaloids were purified from two plants belonging to the Rutaceae family. Kokusaginine. skimmianine, evolitrine, and confusameline were purified from Melicope confusa, and haplopine, robustine, dictamine, and $\gamma$-fagarine from Dictamnus albus. In this study, the eight furoquinoline alkaloids were examined for inhibitory potency against human phos-phodiesterase 5 (hPDE5A) in vitro. DNA encoding the catalytic domain of human PDE5A was amplified from the mRNA of T24 cells by RT-PCR and was fused to GST in an expression vector. GST-tagged PDE5A was then purified by glutathione affinity chromatography and used in inhibition assays. Of the eight alkaloids, $\gamma$-fagarine was the most potent inhibitor of PDE5A, and its single methoxy group at the C-8 position was shown to be critical for inhibitory activity. These results clearly illustrate the relationship between PDE5A inhibition and the methoxy group position in furoquinoline alkaloids.

• 한국동물학회지
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• 제30권2호
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• pp.117-139
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• 1987

The present experiments were carried out to investigate the mode of cAMP regulation of cumulus expansion in pig. Intracellular level of cAMP in the cumulus cells was modulated by culturing porcine cumulus oocyte complexes (COC's) with forskolin, an adenylate cyclase stimulator and 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor. The role of calcium in the hormone induced cumulus expansion process was also studied. Forskolin in the medium stimulated cumulus expansion from the concentration of 0.01 $\mu$M and induced full expansion at l-10 $\mu$M In contrast, IBMX in the medium (20-180 $\mu$M) failed to induce the expansion. Verapamil, a calcium ion transport blocker, suppressed follicle stimulating hormone(FSH)-induced cumulus expansion in a dose dependent fashion (0.002-0. 2 mM) when the COC's were exposed to the drugs during culture period (32 hr). But verapamil did not interfere with the triggering action of FSH during early four hours of culture period. The data presented here showed that adenylate cyclase in the porcine cumulus cells may play a key role in the regulation of the intracellular cAMP level and calcium ion may be involved in the later period of cumulus expansion process.

• The Korean Journal of Physiology and Pharmacology
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• 제20권1호
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• pp.9-14
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• 2016

Adenosine 3',5'-cyclic monophosphate (cAMP) participates in the regulation of numerous cellular functions, including the $Na^+-K^+$-ATPase (sodium pump). Ouabain, used in the treatment of several heart diseases, is known to increase cAMP levels but its effects on the atrium are not understood. The aim of the present study was to examine the effect of ouabain on the regulation of atrial cAMP production and its roles in atrial endothelin-1 (ET-1) secretion in isolated perfused beating rabbit atria. Our results showed that ouabain ($3.0{\mu}mol/L$) significantly increased atrial dynamics and cAMP levels during recovery period. The ouabain-increased atrial dynamics was blocked by KB-R7943 ($3.0{\mu}mol/L$), an inhibitor for reverse mode of $Na^+-Ca^{2+}$ exchangers (NCX), but did not by L-type $Ca^{2+}$ channel blocker nifedipine ($1.0{\mu}mol/L$) or protein kinase A (PKA) selective inhibitor H-89 ($3.0{\mu}mol/L$). Ouabain also enhanced atrial intracellular cAMP production in response to forskolin and theophyline ($100.0{\mu}mol/L$), an inhibitor of phosphodiesterase, potentiated the ouabain-induced increase in cAMP. Ouabain and 8-Bromo-cAMP ($0.5{\mu}mol/L$) markedly increased atrial ET-1 secretion, which was blocked by H-89 and by PD98059 ($30{\mu}mol/L$), an inhibitor of extracellular-signal-regulated kinase (ERK) without changing ouabain-induced atrial dynamics. Our results demonstrated that ouabain increases atrial cAMP levels and promotes atrial ET-1 secretion via the mitogen-activated protein kinase (MAPK)/ERK signaling pathway. These findings may explain the development of cardiac hypertrophy in response to digitalis-like compounds.

• Tuberculosis and Respiratory Diseases
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• 제78권4호
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• pp.321-325
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• 2015

Background: The adverse effects of the phosphodiesterase-4 inhibitor roflumilast, appear to be more frequent in clinical practice than what was observed in chronic obstructive pulmonary disease (COPD) clinical trials. Thus, we designed this study to determine whether adverse effects could be reduced by starting roflumilast at half the dose, and then increasing a few weeks later to $500{\mu}g$ daily. Methods: We retrospectively investigated 85 patients with COPD who had taken either $500{\mu}g$ roflumilast, or a starting dose of $250{\mu}g$ and then increased to $500{\mu}g$. We analyzed all adverse events and assessed differences between patients who continued taking the drug after dose escalation and those who had stopped. Results: Adverse events were reported by 22 of the 85 patients (25.9%). The most common adverse event was diarrhea (10.6%). Of the 52 patients who had increased from a starting dose of $250{\mu}g$ roflumilast to $500{\mu}g$, 43 (82.7%) successfully maintained the $500{\mu}g$ roflumilast dose. No difference in factors likely to affect the risk of adverse effects, was detected between the dose-escalated and the discontinued groups. Of the 26 patients who started with the $500{\mu}g$ roflumilast regimen, seven (26.9%) discontinued because of adverse effects. There was no statistically significant difference in discontinuation rate between the dose-escalated and the control groups (p=0.22). Conclusion: Escalating the roflumilast dose may reduce treatment-related adverse effects and improve tolerance to the full dose. This study suggests that the dose-escalated regimen reduced the rate of discontinuation. However, longer-term and larger-scale studies are needed to support the full benefit of a dose escalation strategy.