[논문]Mechanism of Erectogenic Effect of the Selective Phosphodiesterase Type 5 Inhibitor, DA-8159

Doh, Hyoun-Mie; Shin, Chang-Yell; Son, Mi-Won; Ko, Jun-Il; Yoo, Moo-Hi; Kim, Soon-Hoe; Kim, Won-Bae

doi:10.1007/bf02977007

[국내논문] Mechanism of Erectogenic Effect of the Selective Phosphodiesterase Type 5 Inhibitor, DA-8159 원문보기

Archives of pharmacal research : a publication of the Pharmaceutical Society of Korea, v.25 no.6, 2002년, pp.873 - 878

Doh, Hyoun-Mie (Research Laboratories, Dong-A Pharm. Co. Ltd.) , Shin, Chang-Yell (Research Laboratories, Dong-A Pharm. Co. Ltd.) , Son, Mi-Won (Research Laboratories, Dong-A Pharm. Co. Ltd.) , Ko, Jun-Il (Research Laboratories, Dong-A Pharm. Co. Ltd.) , Yoo, Moo-Hi (Research Laboratories, Dong-A Pharm. Co. Ltd.) , Kim, Soon-Hoe (Research Laboratories, Dong-A Pharm. Co. Ltd.) , Kim, Won-Bae (Research Laboratories, Dong-A Pharm. Co. Ltd.)

Abstract ▼ AI-Helper

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.

Keyword

AI 본문요약
AI-Helper

* AI 자동 식별 결과로 적합하지 않은 문장이 있을 수 있으니, 이용에 유의하시기 바랍니다.

가설 설정

In this study, the mechanism of action of DA-8159 was investigated. First, the selectivity of DA-8159 for the major PDE isozymes was examined.

제안 방법

First, the selectivity of DA-8159 for the major PDE isozymes was examined. Second, its kinetic mode of inhibitory action was examined.
(Rana catesbeiana). The procedure used was a slightly modification of the method reported by H니「ley and Stryer. (Hurley and Stryer, 1982).
Some fractions exhibiting the PDE 5 enzyme activity were pooled and used for the cGMP hydrolysis assay. In order to characterize the mode of PDE 5 inhibition by DA-8159, the rates of cGMP hydrolysis catalyzed by the human platelets-derived PDE 5 were determined using the cGMP concentration (10-100 nM) and two-fixed DA- 8159 concentration (11.3 and 18.8 nM). In the absence of DA-8159, the 麻 value for PDE 5 was 7.
cGMP synthesis in the isolated corp니s cavernosum of the rabbit was assess in order to further investigate me사lanism of DA-8159 action. Fig.
, 1998). In this study, human platelets were used as the PDE 5 source for studying the DA-8159 inhibition kinetics. The enzyme preparation had a Km value of 7.

대상 데이터

M게e New Zealand White rabbits (2.8~3.2 kg) were used in this study. All rabbits were housed in a room maintained at a constant temparature/huminity (21 ±2℃, 50%) on a 12/12 h light/ dark cycle with food and water available ad libitum.

성능/효과

Second, its kinetic mode of inhibitory action was examined. Finally, its effect on the increase in the endogeno니s cGMP levels in the rabbit smooth muscle of the corpus cavemosum tissue in vitro was measured.

참고문헌 (26)

Andersson, K-E. and Wagner, G., Physiology of penile erection. Physiol. Rev., 75, 191- 236 (1995)

상세보기
Artemyev, O. A., Arshavsky, V. Y. and Cote, R. H., Photoreceptor phosphodiesterase: interaction of inhibitory gamma subunit and cyclic GMP with specific binding sites on catalytic subunits. Methods, 14, 93-104 (1998)

상세보기
Azadzoi, K. M. and De Tajeda, I. S., Hypercholestroemia impairs endothelium-dependent relaxation of rabbit corpus cavernosum smooth muscle. J. Urol., 146, 238-240 (1991)

상세보기
Ballard, S. T., Gingell, C. J.,Tang, K., Turner, L. A., Price, M. E. and Naylor A. M., Effects of Sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. J. Urol., 159, 2164-2171 (1998)

상세보기
Beavo, J. A., Cyclic nucleotide phophodiesterase: functional implications of multiple isoform. Physiol. Rev., 75, 725-748 (1995)

상세보기
Burentt, A. L., Role of nitric oxide in the physiology of erection. Biol. Reprod., 52, 485-489 (1995)

상세보기
Burnett, A L., Lowenstein, C. J., Bredt, D. S., Chang, T. S. K. and Snyder, S. H., Nitric oxide: a physiologic mediator of penile erection. Scinece, 257, 401-403 (1992)

상세보기
Corbin, J. D. and Francis, S. H., Cyclic GMP phosphodiesterase-5: target of sildenafil. J. Biol. Chem., 274, 13729-13732 (1999)

상세보기
Corbin, J. D., Turko, I. V, Beasley, A and Francis, S. H., Phosphorylation of phosphodiesterase-5 by cyclic nucleotidedependent protein kinase alters its catalytic and allosteric cGMP-binding activities. Eur. J. Biochem., 267, 2760-2767 (2000)

상세보기
De Tajeda, I. S., Goldstein I., Adazoi, K., Krane, R. J. and Cohen, R. A., Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N. Engl. J. Med., 320, 1025-1030 (1989)

상세보기
Dishy, V., Sofowora, G., Harris, P. A., Kandcer, M., Zhan, F., Wood, A. J. and Stein, C. M., The effect of sildenafil on nitric oxide-mediated vasodilation in healthy men. Clin. Pharmacol. Ther., 70(3), 270-279 (2001)

상세보기
Dousa, T. P., Cyclic-3',5'-nucleotide phosphodiesterase isozymes in cell biology and pathophysiology of the kidney. Kidney Int., 55, 2962 (1999)
Ekholm, D., Belfrage, P., Manganiello, V. and Degerman, E., Protein kinase A-dependent activation of PDE4 (cAMP-specific nucleotide phosphodiesterase) in cultured bovine vascular smooth muscle cells. Biochim. Biophys. Acta, 1356, 6470 (1997)
Finberg, J. P. M., Levy, S. and Vardi, Y, Inhibition of nerve stimulation-induced vasodilation in corpora cavernosa of the pithed rat by blockade of nitric oxide synthetase. Br. J. Pharmacol., 108, 1038-1042 (1993)

상세보기
Fink, T. L., Francis, S. H., Beasley, A., Grimes, K. A and Corbin, J. Expression of an active, monomeric catalytic domain of the cGMP- binding cGMP-specific phosphodiesterase (PDE5). J. Biol. Chem., 274, 34613-34620 (1999)

상세보기
Freelish, M. and Noack, E., Correlation between nitric acid formation during degradation of organic nitrates and activation of guanylate cyclase. Eur. J. Pharmacol., 139, 19-30 (1987)

상세보기
Gillespie, P. G., and Beavo J. A, Inhibition and stimulation of photoreceptor by dipyridamol and M&B. Mol. Pharm., 36, 773-781 (1989)
Hidaka, H. and Asano, T., Human blood platelet 3 ': 5'-cyclic nucleotide phosphodiesterase. Isolation of low-Km and high-Km phosphodiesterase. Biochim. Biophys. Acta, 429, 485-497 (1976)

상세보기
Hidaka, H. and Shibuya, M., A new assay of cyclic nucleotide phosphodiesterase; its application to human serum. Biochem. Med., 10, 301-311 (1974)

상세보기
Hurley, J. B. and Stryer, L., Purification and characterization of the gamma regulatory subunit of the cyclic GMP phosphodiesterase from retinal rod outer segments. J. Biol. Chemistry, 257, 11094-11099 (1982)
Hurwitz, R L., Bunt-Milam, A. H., Chang, M. L. and Beavo, J. A, cGMP phosphodiesterase in rod and cone outer segments of the retina. J. Mol. Biol., 260, 568-573 (1985)
Jeremy, J. Y., Ballard, S. A., Naylor, A. M., Miller, M. A. W. and Angelini, G. D., Effects of Sildenafil, a type-5 cGMP phosphodiesterase inhibitor, and papaverine on cyclic GMP and cyclic Amp levels in the rabbit corpus cavernosum in vitra. Br. J. Urol., 79, 958-963 (1997)

상세보기
Lim, J., Pahlke, G. and Conti, M., Activation of the cAMPspecific phosphodiesterase PDE4D3 by phosphorylation: identification and function of an inhibitory domain. J. Biol. Chem., 274, 19677-19685 (1999)

상세보기
Lue, T. F, Hemodynamics of erection in the monkey. J. Urol., 130, 1237-1241(1983)

상세보기
Trigo-Rocha, F, Hsu, G. L., Donatucci, C. F. and Lue, T. F., The role of cyclic adenosine monophosphate, cyclic guanosine monophosphate, endothelium and nonadrenergic, noncholinergic, neurotranasmission in canine penile erection. J. Urol., 149, 872-877 (1993)

상세보기
Wang, J. H., Teo, T. S., Ho, H. C., and Stevens, F. S., Bovine heart protein activator of cyclic nucleotide phosphodiesterase. Adv. in Cyclic Nucleotide Res., 5., 179-194 (1975)

활용도 분석정보

상세보기

다운로드

내보내기

활용도 Top5 논문

해당 논문의 주제분야에서 활용도가 높은 상위 5개 콘텐츠를 보여줍니다.
더보기 버튼을 클릭하시면 더 많은 관련자료를 살펴볼 수 있습니다.

내보내기 구분	파일저장 인쇄 메일전송
구성항목	기본정보 상세정보 관리번호, 논문명, 저널/프로시딩명, 저자 , 발행년, 권, 호, 시작페이지, 끝페이지, 발행기관 관리번호, 논문명, 대등논문명, 저자 , 저널/프로시딩명, 발행기관, 발행년, 발행언어, 권, 호, 시작페이지, 끝페이지, ISBN, ISSN, 주제분야, 키워드, 초록(한글), 초록(영문), 저자(소속기관)
저장형식	Text(ASCII format) Excel format RefWorks Direct Export RIS format (for Reference Manager, ProCite, EndNote), Scholar's Aids, Mendeley
메일정보	받는사람 (필수) @ 보내는사람 (선택) @ 제목 내용 KISTI 검색결과 이메일 서비스
안내	총 건의 자료가 검색되었습니다. 다운받으실 자료의 인덱스를 입력하세요. (1-10,000) 검색결과의 순서대로 최대 10,000건 까지 다운로드가 가능합니다. 데이타가 많을 경우 속도가 느려질 수 있습니다.(최대 2~3분 소요) 다운로드 파일은 UTF-8 형태로 저장됩니다. 파일의 내용이 제대로 보이지 않을실 때는 웹브라우저 상단의 보기 -> 인코딩 -> 자동선택 여부를 확인하십시오. ~ Text(ASCII format) Excel format

연합인증