• 약학회지
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• 제41권3호
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• pp.345-351
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• 1997

The purpose of this investigation was to determine the inhibition of $Na^+,\;K^+$-ATPase, cyclicAMP phophodiesterase and platelet activation by secondary metabolites isolated from mar ine organisms. The secondary metabolites were isolated and identified as six diterpenoids(1 : astrogorgin, 2 : ophirin, 3 : calicophirin B, 4, 5 and 6 : cladiellin) from the dichloromethane extract of Muricellajsp., four ceramides(1,2,3, and 4) from Acabaria undulata and three antharaquinones(1,2 : crysophanol, and 3 : physcion) from Urechis unicintus. The results demonstrated that diterpenoids(2,3, and 4) showed the inhibition of cyclicAMP phosphodiesterase, and ceramides(1,3, and 4) showed the inhibition of cyclicAMP phosphodiesterase and thrombin(0.1 units/ml)-induced aggregation of washed rabbit platelet, and anthrapuinones((1,2, and 3) showed the inhibition of $Na^+,\;K^+$-ATPase. Among the anthraquionones, 1,2-dimethoxy-3-methyl-8-hydroxy-anthraquinone(1) showed the inhibition of collagen(1.0 ${\mu}g$/ml)-induced aggregation in a concenration-dependent manner with IC50 value of 42.8 ${\mu}g$M.

• 약학회지
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• 제49권1호
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• pp.109-113
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• 2005

In the present study treatment of IBMX, a phosphodiesterase (PDE) inhibitor, alone induced osteoclast formation in co-cultures of mouse bone marrow cells and calvarial osteoblasts. However, treatment of IBMX in combination with prostaglandin $E_2\;(PGE_2)$ inhibited osteoclast formation in a dose-dependent manner. Among various isozyme-specific PDE inhibitors, a PDE4 specific inhibitor, rolipram, showed similar effects as IBMX on osteoclast formation. To address the involvement of cyclic adenosine monophosphate (cAMP) in osteoclast formation, cAMP concentration in calvarial osteoblasts was investigated. When calvarial osteoblasts were co-cultured with IBMX alone or in combination with $PGE_2$, the patterns of cAMP concentration in calvarial osteoblasts were differ each other suggesting that cAMP in calvarial osteoblasts subtly regulates osteoclast formation.

• 한국식품영양과학회지
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• 제29권2호
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• pp.329-334
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• 2000

Two major oleananesaponins in Bupleuri radix, saikosaponin $\alpha$ and d, were extracted at various solvent compositions and leaching temperatures. Solvent composition was varied at 0 to 100%(v/v) of ethanol-water and methanol-water, whereas leaching temperature was adjusted to te range of 25~45$^{\circ}C$. The most effective extractant and leaching temperature were 70% ethanol and 45$^{\circ}C$, respectively. However, no major differences in saikosaponin content and cAMP phosphodiesterase inhibition were found at various leaching times. The cAMP phosphodiesterase inhibitions were alo the highest when 70% ethanol was used as the extractant.

• 약학회지
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• 제41권5호
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• pp.547-553
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• 1997

The purpose of this investigation was to determine the inhibition on $Na^+,\;K^+$-ATPase, cyclic AMP phosphodiesterase and platelet activation by marine sterols isolated from octocorals. Three marine polyhydroxysterols, 7${\alpha},\;8{\alpha}-epoxy-3b{\beta},\;5{\alpha},\;6{\alpha}-trihydroxycholestane (1),\;24-methyl-7{\alpha},\;8{\alpha}-epoxy-3{\beta},\;5{\alpha},\;6{\alpha}-trihydroxycholest-22-ene (2),\;and\;7{\alpha},\;8{\alpha}-epoxy-3{\beta},\;5{\alpha},\;6{\alpha}-trihydroxycholest-22-ene (3)$, were isolated from the Gorgonian Acabaria undulata. Five marine sterols(compound 4, 5, 6, 7, 8) were isolated from the soft coral Alcyonium gracillimum. Three marine polyhydroxysterols (1, 2, 3) and pregna-1. 20-diene-3-one (8) exhibit a potent inhibitory effect on rabbit platelet aggregation induced by collagen and thrombin. Those polyhydroxysterols also exhibit a potent inhibitory effect on cyclic AMP phosphodiesterase. Compound 6 with an unusual cyclic enolether exhibit a inhibitory effect on $Na^+,\;K^+$-ATPase.

• 대한수의학회지
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• 제43권4호
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• pp.615-624
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• 2003

Vascular smooth muscle relaxation is modulated by an increase in cGMP subsequent to nitric oxide (NO) production by endothelial cells. The effects of cAMP and cGMP phosphodiesterase (PDE) inhibitors were investigated in phenylephrine-precontracted rat aorta rings by using the specific inhibitors of PDE I, III, IV and V as relaxing agents (calmodulin-activated PDE inhibitors, IBMX and $W_7$, type I; cAMP-specific PDE inhibitors, milrinone, type IV; Ro 20-1724, type III and cGMP-specific PDE inhibitor, zaprinast, type V). All the PDE inhibitors produced a concentration-dependent relaxation in the ring with intact endothelium (+E). Except for milrinone, all the PDE inhibitors-induced relaxations were inhibited by removal of extracellular $Ca^{2+}$, $N^G$-nitro-L-arginine, $N^G$-nitro-L-arginine methyl ester, methylene blue (MS) or nifedipine. The specific PDE I and PDE IV inhibitors both produced endothelium-independent relaxations which were inhibited by MS in -E rings. However, zaprinast had no effect in -E rings. Except for milrinone, sodium nitroprusside (a NO donor)-induced relaxation was significantly augmented by all PDE inhibitors in +E rings. The results suggest that I) the vasorelaxant properties of IBMX, $W_7$, Ro 20-1724 and zaprinast are dependent on endothelium or on interaction with $Ca^{2+}$ regulation, 2) each PDE is differently distributed in vascular tissues (endothelial and smooth muscle cells), 3) the vasodilations of PDE inhibitors are due to the increase of cAMP and cGMP formation through inhibition of cAMP- and cGMP-PDE and 4) the vasodilation action of milrinone does not involve in endothelial-cyclic nucleotide system.

• Parasites, Hosts and Diseases
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• 제28권2호
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• pp.71-78
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• 1990

세포내 cAMP의 농도 변화가 Toxoplasma의 성장 및 증식에 미치는 영향을 검토하기 위하여 끽접 cAMP와 cAMP의 analogue를 첨가하거나 간접적으로 세포내 cAMP의 합성이나 분해를 담당한 효소들의 활성을 변화시 킴으로써 CAMP의 농도를 조절하여 그 효과를 측정하였다. HL-60세포를 숙주 세포로 사용하여 동수의 Toxoplasma를 첨가하여 배양하였으며, 처리 효과는 배양 세포계에서 Toxoplnsma에만 특이하게 표지되는 $^3H-uracil$과 Toxoplasma및 HL-60세포에 공통으로 표지되는 $^3H-thymidine$을 각각 매 12시간마다 2시간씩 배양하여 그 표지량을 측정하여 비교 분석하였다. 직접 cAMP와 cAMP의 analogue인 dbcAMP 및 br-cAMP를 첨가하였을 때, 각각 특이한 농도에서, 즉 1 mM, 0.5~5mM 및 0.1mM에서 Toxoplasma의 성장 및 증식을 향상시켰다. 이때, 성장 및 증식을 유도하는 시기 및 그 증가도에서도 차이가 있는 것으로 나타났다. 이 결과들은 세포내 cAMP의 농도를 증가시키도록 cAMP의 합성 및 분해에 관여하는 효소들의 황성을 변화 시켰을 때에도 같은 양상으로 나타났다. cAMP의 합성 효소인 adenylate cyclase의 활성제인 pNHppG, cAMP의 분해 효소인 cAMP phosphodiesterase의 활성제인 A23187과 imidazole 및 억제제인 IBMX, compound 48/80 및 theophylline을 각각 처리하였는데, 세포내 cAMP의 농도가 증가되었을 대에는 Toxoplasmn의 성장 및 증식 을 향상시켰으나, cAMP의 농도를 감소시켰을 때에는 억제하였다. 이 때 배양계에 독성을 일으키는 농도 이하에서 농도 의존성의 경향을 보였으며, 유도 시기 및 그 증가도에는 차이가 있었다. 따라서 세포 내에서 향상된 수준의 cAMP가 어떤 기전을 활성화시키며, 그 결과 세포질에서의 Toxcplasma의 성장 및 증식을 자극하게 된다는 것을 시사하였다.

• 한국미생물·생명공학회지
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• 제34권4호
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• pp.289-298
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• 2006

3',5'-cyclic adenosine monophosphate (cAMP) is an important molecule, which mediates diverse cellular processes. For example, it is involved in regulation of sugar uptake/catabolism, DNA replication, cell division, and motility in various acterial species. In addition, cAMP is one of the critical regulators for syntheses of virulence factors in many pathogenic bacteria. It is believed that cAMP acts as a signal for environmental changes as well as a regulatory factor for gene expressions. Therefore, intracellular concentration of cAMP is finely modulated by according to its rates of synthesis (by adenylate cyclase), excretion, and degradation (by cAMP phosphodiesterase). In the present review, we discuss the bacterial physiological characteristics governed by CAMP and the molecular mechanisms for gene regulation by cAMP. Furthermore, the effect of cAMP on phosphotransferase system is addressed.

• 대한약리학회지
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• 제29권2호
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• pp.253-261
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• 1993

Streptozotocin으로 당뇨병을 유발시킨 흰쥐를 모델로 하여 당뇨병으로 인한 인슐린의 antilipolytic action을 매개하는 insulin-sensitive cyclic nucleotide phosphodiesterase의 역할의 변화 가능성을 연구하였다. 흰쥐의 epididymal adipose tissue로부터 분리한 지방세포를 여러 약물과 toxin으로 전처치한 다음, insulin을 처치 또는 처치하지 않고 $37^{\circ}C$에서 15분 동안 incubation하였다. 그리고 나서 differential centrifugation으로 3 fractions로 분리한 다음 cAMP phosphodiesterase activity를 assay하였다. Insulin에 의한 PDE activities의 증가는 당뇨병군과 대조군 모두 crude microsomal (P2) fraction에서만 볼 수 있었다. P2 fraction을 2 nM insulin, $100\;{\mu}M$ isoproterenol, 또는 두 약물을 함께 처치하여 나타난 maximal effect는 두 군 모두에서 유의한 차이가 없었다. 그러나 basal PDE activities는 당뇨병균이 대조군에 비해 증가한 것으로 나타났다. 당뇨병군의 P2 fraction의 insulin-sensitive PDE activities는 $A_{1}$ adenosine receptor agonist 인 PIA에 의해서 영향을 받지 않은 반면, 대조군의 경우 PIA에 의해 basal PDE activities와 같게 감소하였다. 그리고 지방세포의 pertussis toxin에 대한 sensitivity는 당뇨병군이 대조군보다 더욱 민감하였다. 그러나 cholera toxin에 대한 sensitivity는 당뇨병군과 대조군 사이에 큰 차이를 볼 수 없었다. 이러한 결과로 보아 streptozotocin으로 당뇨병을 유발시킨 흰쥐의 지방세포에서, adenosine receptor와 같은 inhibitory receptor를 경유한 signalling의 감소는 $G_{i}$ proteins의 소실 또는 기능의 감소와 관련이 있으며, 또한 basal state에서 insulin-dependent PDE의 활성을 증가시키는 것으로 사료된다.

• 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.

• The Korean Journal of Physiology and Pharmacology
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• 제3권3호
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• pp.275-282
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• 1999

Muscle strips and muscle cells from cat stomach were used to investigate whether spontaneously formed cyclic nucleotides were involved in the inhibition of gastric smooth muscle contraction. A phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), increased the levels of both cyclic GMP (cGMP) and cyclic AMP (cAMP) in resting state cells, while decreasing acetylcholine-induced muscle contraction. Under the influence of IBMX, SQ22536, an adenylyl cyclase inhibitor and methylene blue, a guanylyl cyclase inhibitor completely blocked increases in cAMP and cGMP respectively, without any effect on contraction. However, the combination of SQ22536 and methylene blue completely blocked increases in both cAMP and cGMP levels and stimulated contractions markedly even in the presence of IBMX. Muscle contraction inhibitors such as isoprenaline, vasoactive intestinal polypeptide and sodium nitroprusside also appeared to increase cyclic nucleotide levels which decreased contraction. Which nucleotide increased the most was dependent on the agonist used. Therefore, irrespective of the cyclic nucleotide class, the spontaneous formation of cyclic nucleotides should be considered in evaluating the mechanism of gastric smooth muscle relaxation.