Effects of nitroglicerin and sidenalfil citrate on spontaneous an imnducerd contra ctions of isolated rat myometrium

Year 2002, Volume: 33 Issue: 3, 4 - 11, 01.04.2002

Niyazi Tuğ Hüsnü Çelik Ahmet Ayar S. Sırrı Kılıç M. Ziya Doymaz

Abstract

Objective: Bacterial infection in pregnancy induces premature uterine contractions. Promising results were achieved from the investigations performed on novel therapeutic agents used in the treatment of preterm labor, nitric oxide donors and phosphodiesterase inhibitors. In this study, effects of nitroglycerine and sildenafil citrate on spontaneous and induced myometrial contractions were investigated in the rat Material and Methods: Lipopolysaccharide 50 $\mu$g/kg intraperitoneally and I or nitroglycerine 5 $\mu$g transdermal and I or placebo were given to 56 Wistar albino rats randomly at their 16th day of gestation. Myometrial strips taken from the rats were hanged under l g passive tension within isolated organ bath containing saline under physiological conditions. Spontaneous or induced contractions of the strips were recorded following a 30 minutes accomodation period, as 10 minute periods for each of 0, 50,100 and 200 mg/ml sildenafil concentrations. Statistical comparisons were performed and the figures were drawn using microgal origin 5.0 and SPSS 10.0 software programs. Results: Lipopolysaccharide and PGF2 alpha increased the amplitudes and the frequencies of contractions in a similar manner (nl=25, n2= 25; p

Keywords

Myometrium, Rats, Wistar, Pregnancy, Phosphodiesterase Inhibitors, Piperazines, Dinoprost, Nitroglycerin

İzole sıçan miyometriyumunda spontan ve lipopolisakkarit ile indüklenmiş kasılmalar üzerine nitrogliserin ve sildenafil sitratin etkileri

Abstract

Giriş: Gebelikte bakteriyel enfeksiyon prematür miyometriyal kasılmaları indüklemektedir. Erken doğum tedavisinde nitrik oksit donörleri ve fosfodiesteraz inhibitörleri ile yapılan çalışmalardan umut verici sonuçlar elde edilmiştir. Bu çalışmada, sıçanda spontan ve İndüklenmiş miyometriyal kasılmalar üzerinde nitrogliserin ve sildenafil sitratın etkileri araştırılmıştır. Materyal ve Metod: Wistar-albino cinsi, 56 adet sıçana, gebeliklerinin 16. gününde rast gele 50 $\mu$g/kg intraperitoneal lipopolisakkarid ve/veya 5 $\mu$g transdermal nitrogliserin ve/veya plasebo verilmiştir. Sıçanlardan alınan miyometriyum kesitleri, fizyolojik şartlarda tuzlu su eriyiği içeren organ banyosunda, l g istirahat gerimi altında asılmış; spontan ve l $\mu$M PGF2 alfa ile indüklenen kasılmalar, 30 dakikalık uyum periyodunu takiben onar dakikalık periyodlar halinde 0, 50, 100 ve 200 $\mu$g/ml sildenafil konsantrasyonlarında kaydedilmiştir. Verilerin istatistiksel analizi ve şekiller, paired t, tek yönlü varyans analizi ve post hoc LSD testleri ile, Microgal origin 5.0 ve SPSS 10.0 programları kullanılarak yapılmıştır. Bulgular: Lipopolisakkarit ve PGF2 alfa, miyometriyal kasılmaların amplitüd ve frekanslannı benzer ölçülerde arttırmıştır (nl= 25, n2= 25; p

Keywords

Miyometriyum, Sıçan, Wistar, Gebelik, Fosfodiesteraz inhibitörleri, Piperazinler, Dinoprost, Nitrogliserin

References

• 1 Creasy RK, IamsJD. Preterm labor and delivery. In: Creasy RK, Resnik R eds. Maternal-fetal medicine. 4th ed. Philadelphia: WB Sounders Company, 1999: 494-531
• 2 Cunningham FG, MacDonald FC, Gant NF, Leveno KJ, Gilstarp III LC, Hankins GDV, Clark SI. Williams Obstetrics 20th ed. Connecticut: Appleton & Lange, 1997: 797-827
• 3. McCormick MC. The contribution of low birth weight to infant mortality and childhood morbidity. N Englf Med 1985; 312: 82-90
• 4. Danti L, Lojacono A, TanziP, Cavagnini A, Sacconi A, Bianchi UA. New perspectives in the treatment of preterm labour: GTN versus ritodrine, a clinical trial. Prenat Neonat Med 1999; 2: S10
• 5. Gibbs RS, Eschenbach DA. Use of antibiotics to prevent preterm birth
• Am] Obstet Gynecol 1997; 177: 375-380
• 6. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. New Engl j Med 2000; 342: 1500-1507
• 7. Keirse M. Indomethacin tocolysis in preterm labour. In: Enkin M, Keirse M, Neilson J eds. Pregnancy and child birth modulate of the cochrane Database of Systemic Reviews London BMJ Publishing Group, 1995:23-42
• 8. KingJF, Grant A, Keirse MJNC, Chalmers I. Beta-mimetics in preterm labor: an overview of the randomised controlled trials. Br J Obstet Gynaecol 1988; 95: 211-212
• 9. Papatsonis DNM, van Geijn HP, Blecker OP, Lange FM, Ader HJ, Dekker GA. Tocolytic efficacy of nifedipine versus ritodrine: Results of a ran¬ domised trial. Amj Obstet Gynecol 1996; 174: 306
• 10. Lettieri L, Vintzileos AM, Rodis JF, Albini SM, Salafia CM. Does "idiopathic" preterm labor resulting in preterm birth exists? Amf Obstet Gynecol 1993; 168: 1480-1485
• 11. Lamont RF. New approaches in the management of preterm labour of infective aetiology. Br] Obstet Gynaecol 1998; 105: 134-137
• 12. Errol RN, Jussian NR, John RG, Challis FRSC. The control of labor. N Engl] Med 1999; 341: 660-666
• 13. Ledingham MA, Thomson A], Greer IA, Norman JE. Nitric oxide in partirution. BrJ Obstet Gynaecol 2000; 107: 581-593
• 14. Leszczy-ska-Gorzelak B, Laskowska M, Marciniak B, Oleszczuk J
• Nitric oxide for treatment of threatened preterm labor. IntJ Gynec Obstet 2001; 73: 201-206
• 15. Bardou M, CortijoJ, Loustalot C, Taylor S, Perales-Martin A, Mercier FJ, et al. Pharmacological and biochemical study on the effects of selective phosphodiesterase inhibitors on human term myometrium. Naunyn Schmiedebergs Arch Pharmacol 1999; 360: 457-463
• 16. Stacey P, Rulten S, Dapling A, Phillips SC. Molecular cloning and expression of human cGMP-binding cGMP-specific phosphodiesterase (PDE5). Biochem Biophys Res Commun 1998; 247: 249 254
• 17. Beatty CH, Bocek RM, Herrington PT. Regulation of cyclic nucleotide phosphodiesterase activity in myometrium from pregnant and spayed rhesus monkeys. J Reprod Fertil 1979; 55: 391-400
• 18. Park K, Moreland RB, Goldstein I, Atala A, Traish A. Sildenafil inhibits phosphodiesterase type 5 in human clitoral corpus cavernosum smooth muscle. Biochem Biophys Res Commun 1998; 249: 612-617
• 19. Prasad S, Wilkinson J, Gatzoulis MA. Sildenafil in primary pulmonary hypertension. New EnglJ Med 2000; 343:1342
• 20. Rostaing L, Tran-Van T, Ader JL. Increased glomerular filtration rate in kidney-transplant recipients who take sildenafil. New Engl J Med 2000; 342: 1679-1680
• 21. Corbin ]D, Francis SH. Cyclic GMP Phosphodiesterase-5: Target of Sildenafil. J Biol Chem 1999; 274: 13729-13732
• 22. Ballard SA, Gingell CJ, Tang K, Turner LA, Price ME, Naylor AM. Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the. activities of cyclic nucleotide phosphodiesterase isozymes. J Urol 1998; 159: 2164-2171
• 23. Sher G, FischJD. Vaginal sildenafil (Viagra): a preliminary report of a novel method to. improve uterine artery blood flow and endometrial development in patients undergoing IVF. Hum Reprod 2000; 15: 806-809
• 24. Gomez R, Romero R, Edwin SS, David C. Pathogenesis of preterm labor and premature rupture of membranes associated with intraamniotic infection. Infect Dis Clin North Am 1997; 11: 135-176
• 25. Novy MJ, LigginsGC. Role of prostaglandin, prostacycline and thromboxanes in the physiologic control of partirution in primates. Semin Perinaiol 1980; 4: 45-66. 26. Keirse MJNC. Prostaglandins in partirution. In: Keirse M, Anderson A, Gravenhorst J, eds., Human partirution. Nijhoff: The Hague, Martinus
• 1979: 101
• 27. Lopez-Ilasaca M. Signaling from G-protein-coupled receptors to mitogen activated protein (MAP)-kinase cascades. Biochem Pharmacol 1998; 56: 269 277
• 28. Okawa T, Suzuki H, Yaanagida K, Sato A, Vedernikov Y, Saade G, et al
• Effect of lipopolysaccharide on uterine contractions and prostaglandin produc¬ tion in pregnant rats. Amj Obştet Gynecol 2001; 184: 84-89
• 29. Bennet WA, Terrone DA, Rinehart BK, Kassab S, Martin JN Jr, Granger JP. Intrauterine endotoxin infusion in rat pregnancy induces preterm delivery and increases placenta! prostaglandin F2a metabolite levels. Amj Obstet Gynecol 2001; 182: 1496-1501
• 30. Dong Y, Dai BS, Singh P, Yallampalli C. Involvement of nitric oxid pathway in prostaglandin F2a-induced preterm labor in rats. Am J Obstet Gynecol 1997; 177: 907-917
• 31. Salvemini D, Mollace V, Pistelli A, Anggard E, VaneJ. Metabolism of glyceryl trinitrate to nitric oxide by endothelial cells and smooth muscle cells and its induction by Escherichia coli lipopolysaccharide
• Pharmacology 1991; 89: 982-986
• 32. Salvemini D. Regulation of cyclooxygenase enzymes by nitric oxide. Cell Mol Life Sci 1997; 53: 576-582
• 33. Salvemini D, Currie MG, Mollace V. Nitric oxide-mediated cyclooxy¬ genase activation. J Clin Invest 1996; 97: 2562-2568
• 34. Bradley KK, Buxton ILO, Barber JE, McGaw T, Bradley ME. Nitric oxide relaxes myometrium by a cGMP-independent mechanism. Am J Physiol 1998; 275: C1668-C1673
• 35. Okawa T, Longo M, Vedernikov YP, Chwalisz K, Saade GR, Garfield RE. Role of nucleotide cyclases in the inhibition of pregnant rat uterine contractions by the openers of potassium channels. Am J Obstet Gynecol 2000; 182: 913-918
• 36. Okawa T, Vedernikov YP, Saade GR, Longo M, Olson GL, Chwalsz K, et al
• Roles of potassium channels and nitric oxide in modulation of uterine contractions in rat pregnancy. Amj Obstet Gynecol 1999; 181: 649-655
• 37. Corbin JD, Francis SH. Cyclic GMP Phosphodiesterase-5: Target of Sildenafil J Biol Chem 1999; 274:13729-13732
• 38. Ballard SA, Gingell CJ, Tang K, Turner LA, Price ME, Naylor AM
• Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes
• J Urol 1998; 159: 2164-2171. 39. Plested CP, Bernal AL. Desensitization of the oxytocin receptors in the human myometrium. Exp Physiol 2001; 86: 303-312
• 40. Ziegler JW, Ivy DD, Fox JJ, Kinsella JP, Clarke WR, Abman SH
• Dipyramidole, a cGMP phosphodiesterase inhibitor, causes pulmonary vasodilation in the ovine fetus. Amj Physiol 1995; 269: H473-H479
• 41. Petros A, Lamb G, Leone A. Effect of nitric oxide synthase inhibitor in humans with septic shock. Cardiovasc Res 1994; 28: 34-39
• 42. Münzel T, Li H, Mollnau H, Hink U, 'Matheis E, Hartmann M, et al
• Effects of long-term nitroglycerine treatment on endothelial nitric oxide synthase (NOS III) gene expression, NOS Ill-mediated superoxide production, and vascular NO bioavailibility. Circ Res 2000; 86: e7-el2
• 43. Boerth NJ, Dey NB, Cornwell TL, Lincoln TM. Cyclic cGMP-dependent protein kinase regulates vascular smooth muscle cell phenotype. J Vase Res 1997; 34:245-249