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C A R B A C H O L I N D U C E S N I T R I C O X I D E G E N E R A T I O N I N G U I N E A - P I G G A L L B L A D D E R

Yıl 2002, Cilt: 15 Sayı: 1, 7 - 14, 03.12.2016

Öz

Objective: Acetylcholine is one of the major
contractile transmitters in gallbladder; whereas, it
is also innervated by non-adrenergic noncholinergic
nerves which mediate relaxation. It
was postulated that nitric oxide (NO) which
activates soluble guanylate cyclase to increase
cyclic GMP (cGMP) levels in the target cells may
be involved in these processes. This study was
designed to investigate whether muscarinic
receptor stimulation via carbachol (CCh) induces
NO-mediated cGMP synthesis in guinea-pig
gallbladder.
Methods: cGMP levels were measured via
radioimmunoassay in gallbladder slices
incubated with carbachol (CCh) (10 6-10 3 mol/l)
in the presence and absence of NO synthase
(NOS) inhibitor L-NAME or muscarinic antagonist
scopolamine. The effect of L-NAME and another
NOS inhibitor L-NMMA on carbachol-induced
contractions were also investigated in an in vitro
organ bath.
Results: Carbachol stimulated cGMP formation
in guinea-pig gallbladder slices significantly.
CCh-induced cGMP formation was abolished by
both L-NAME (1mmol/l) and scopolamine (108-
106 mol/l). In contraction experiments, L-NAME
(3x10-4 mol/l) did not produce any change in the
resting tension of the strips and the
concentration-response curves to carbachol,
whereas L-NMMA (3x10-4 mol/l) induced a slight,
but significant contraction (6.3+1.9 % of
carbachol (106 mol/l)-induced response). When
carbachol was added to the bath after L-NMMAinduced
increase in tension reached its

maximum, the amplitude of the contractile response at the end was 108.0+4.0 % of the control.
Conclusion: Therefore, it may be concluded that muscarinic receptor activation by carbachol stimulates NO production in guinea-pig gallbladder and the subsequent increase in cGMP counteracts with carbachol-induced contractions. However, it seems likely that an intact enteric nervous system is required for such an interaction to be prominent. The muscarinic receptor subtype(s) involved in this interaction remains to be elucidated.
Key Words: cGMP, NO, Guinea-pig,
gallbladder, L-NAME, L-NMMA

Kaynakça

  • Furchgott RF, Zawadski JV, Cherry I'D. Role of endothelium in vasodilator response to acetylcholine. In: Vanhoutte P, Leusen I, eds. Vasodilatation. New York: Raven Press, 1981: 49-66.
  • Ignarro LJ, Lippton ti, Edwards JC, et al. Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Ther 1981; 218: 739-749.
  • Palmer RMJ, Ashton DS, Moncada S. Vascular enodthelial cells synthesize nitric oxide from L-arginine. Nature 1988; 333: 664-666.
  • Moncada S, Palmer RMJ, fliggs A. Biosynthesis of nitric oxide from L-arginine. Biochem Pharmacol 1989; 38: 1709-1715.
  • Ciruelter CA, Oruetter DY, Lyon JE, Radowitz PJ, Ignarro LF. Relationship between cyclic guanosine 3-5-monophosphate formation and relaxation of coronary arterial smooth muscle by glyceryl trinitrate, nitroprusside, nitrite and nitric oxide: effects of methylene blue and methemoglobin. J Pharmacol Exp Ther 1981; 219; 181-186.
  • Rukovetz WR, Pöch G, flolzmann S. Cyclic nucleotides and relaxation of vascular smooth muscle. In: Vanhoutte P, Leusen I, eds. Vasodilatation. New York: Raven Press, 1981: 339-353.
  • Rapaport RM, Murad F. Agonist-induced endothelium dependent relaxation in rat thoracic aorta may be mediated through cGMP. Circ Res 1983; 52: 352-357.
  • Davison JS, Farasham A, Pearson GT, Peterson OH. Dibutyryl cGMP: a specific inhibitor of the action of CCR-like peptides on the pancreas, gallbladder and ileum. J Physiol (Lond) 1980; 305: 77-78.
  • Behar J, Biancani P. Pharmacology of biliary
  • tract. In: Shultz SG, Wood JD, Rauner BB, eds. Handbook of Physiology, Section 6: The
  • Gastorlntestinal System. New York: Oxford University Press, 1989: 1103-1131.
  • Mourelle M, Guarner F, Molero X, Moncada S, Malagelada JR. Regulation of gallbladder motility by the arginine-nitric oxide pathway in guinea-pigs. Gut 1993; 34: 911-915.
  • Göçer F, Yarış E, Tuncer M. The action of amyl nitrite and isosorbide dlnitrate on the contractility of sphincter of Oddi of guinea- pigs. Gen Pharmacol 1994; 25: 995-999.
  • ¡2. Wotta DR, Birnbaum AK, Wilcox GL, Eide R, Law PY. u-Opioid receptor regulates CTFR coexpressed in Xenopus oocytes in a cAMP independent manner. Mol Brain Res 1997; 44: 55-65.
  • Afdhal NH, La Mont JT. Pathogenesis of gallstones. In: Gitnick G, ed. Principles and Practices of Gastroenterology and Hepatology. New York: Elsevier, 1994: 561-571, ed2.
  • Raufman HS, Shermak MA, May CA, Pitt HA, Lillemoe RD. Nitric oxide Inhibits resting sphincter of Oddi activity. Am J Surg 1993; 165: 74-80.
  • Grozdanovic Z, Mayer ZB, Baumgarten HG, Bruning G. Nitric oxide synthase-containing nerve fibers and neurons in the gallbladder and biliary pathways of the guinea-pig. Neuroreport 1994; 5: 837-840.
  • Mourelle M, Guarner F, Moncada S, Malagelada JR. The arglnine/nitric oxide pathway modulates sphincter of Oddi motor activity in guinea-pigs and rabbits. Gastroenterology 1993; 105: 1299-1305.
  • 7. Salomons H, Reaveny AP, Henihan R, et at. Nitric oxide and gallbladder motility in prairie dogs. Am J Physiol 1997; 272: G770-G778.
  • Dufour JF, Turner TJ, Arias IM. Nitric oxide blocks bile canalicular contraction by inhibiting inositol triphosphate-dependent Ca2* mobilization. Gastroenterology 1995; 108: 841-849.
  • Murthy RS, Makhlouf GM. Interaction of cA- klnase and cG-kinase in mediating relaxation of dispersed smooth muscle cells. Am J Physiol 1995;268:C I 71-Cl 80.
  • Stark ME, Szurszewski JH. Role of nitric oxide In gastrointestinal and hepatic function and disease. Gastroenterology 1992; 103:1928- 1949.
  • !. Ôzkutlu U, Alican i, Rarahan F, et al. Are m- cholinoceptors of guinea-pig gallbladder smooth muscle of m^ subtype? Pharmacology 1993;46:308-314.
  • Von Schrenck T, Sievers J, Mirau S, Raedler A, Greten H. Characterization of muscarinic receptors on guinea-pig gallbladder smooth muscle. Gastroenterology 1993,105:1341- 1349.
  • Von Schrenck T, Mackensen B, Mende U, et al. Signal transduction pathway of the muscarinic receptors mediating gallbladder contraction. Naunyn-Schmied Arch Pharmacol 1994;349:346-354.
  • Takahashi T, Rurosawa S, Owyang C. Regulation of PI hydrolysis and cAMP
  • 3
  • E c e İ s k e n d e r , e t a l
  • formation by muscarinic M3 receptor in guinea-pig gallbladder. Am J Physiol 1994:267 -.G523-G528.
  • Barocelli E, Ballabeni V, Chiavarini M, Molina E, Impicciatore M. Functional comparison between nuvenzepine and pirenzepine on different guinea pig isolated smooth muscle preparations. Pharmacol Res 1994;30:161 - 170.
  • Eltze M, Bönig El, Ullrich B, Grebe T. Contraction of guinea-pig gallbladder: muscarinic Mj or M^ receptors? Eur J Pharmacol 1997;332:77-87.
  • Oktay 5- Cabadak 11, iskender E, et al. Evidence for the presence of muscarinic M2 and M4 receptors in guinea-pig gallbladder smooth muscle. J Auton Pharmacol 1998,18:195-204.
  • Baraalp A, Aktct A, Akbulut ft, Ulusoy HB, Oktay g. Distinct functional muscarinic receptors in guinea-pig gallbladder, ileum and atria. Pharmacol Res 1999:39:389-395.
  • Parkman HP, Pagano AP, Ryan JP. Subtypes of muscarinic receptors regulating gallbladder cholinergic contractions. Am J Physiol 1999;2 76:G 1243-G1250.
  • Felder CC. Muscarinic acetylcholine receptors: signal transduction through multiple effectors. EASEBJ 1995;9:619-625,
  • Eglen RM, Hegde SS, Watson H. Muscarinic receptor subtypes and smooth muscle function. Pharmacol Rev 1996;48:531-565.
  • Ignarro LJ, Byrns RE, Buga GM, Wood BS, Chaudhuri G. Pharmacological evidence that endothelium-derived relaxing factor is nitric oxide: use of pyrogallol and superoxide dismutase to study endothelium-dependent and nitric oxide-elicited vascular smooth muscle relaxation. J Pharmacol Exp Ther 1988;244:181-189.
  • Eurchgott RE, Vanhoutte P. Endothelium- derived relaxing and contracting factors. EASEBJ 1989;3:2007-2018.
  • George WJ, WHkerson RD, Badowitz PJ. Influence of acetylcholine on contractile force
  • and cyclic nucleotide levels in the isolated perfused rat heart. J Pharmacol Exp Ther 1973;184:228-235.
  • Balligand JL, Belly RA, Marsden PA, Smith TW, Michel T. Control of cardiac muscle cell function by an endogenous nitric oxide signalling system. Proc Hat I Acad Sci USA 1993;90:347-351.
  • Castoldi AE, Manzo L, Costa LG. Cyclic GMP
  • formation induced by muscarinic receptors is mediated by nilric oxide synthesis in rat cortical primary cultures. Brain Res
  • ;610:57-61.
  • Hu J, El-Fakahany EE. Role of intercellular and intracellular communication by nitric oxide in coupling of muscarinic receptors to activation of guanylate cyclase in neuronal cells. J Heurochem 1993;61:578-585.
  • Dauphin E, Linville DG, Hamel E. Cholinergic
  • dilatation and constriction of feline cerebral blood vessels are mediated by stimulation of phosphoinositidc metabolism via two
  • different muscarinic receptor subtypes. J Heurochem 1994;63:544-551.
  • Eglen RM, Whiting RL. Heterogeneity of vascular muscarinic receptors. J Auton Pharmacol 1990;10:233-245.
  • Dodds WJ, Hogan WJ, Geenen JE. Motility of the biliary system. In: Schultz SG, Wood JD, Rauner BB, eds. Handbook of Physiology, Section 6: The Gastrointestinal System. Hew York: Oxford University Press, 1989:1055- 1 101.
  • Mourelle M, Guarner E, Moncada S, Malagelada JR. Regulation of sphincter of Oddi motor activity by nitric oxide. Eur J Gastroenterol Hepatol 1991 ;3:S64.
  • Hellmich B, Gyermek L. H^ -Hitro-L-arginine
  • methyl ester: a muscarinic receptor
  • antagonist? Eundam Clin Pharmacol 1997; 1 1:305-314.
  • Buxton 1LO, Cheek DJ, Eckman D, Westfall DP, Sanders BM, Beef BD. HG-Hitro L-arginine methyl ester and other alkyl esters of arginine are muscarinic recepto
Yıl 2002, Cilt: 15 Sayı: 1, 7 - 14, 03.12.2016

Öz

Kaynakça

  • Furchgott RF, Zawadski JV, Cherry I'D. Role of endothelium in vasodilator response to acetylcholine. In: Vanhoutte P, Leusen I, eds. Vasodilatation. New York: Raven Press, 1981: 49-66.
  • Ignarro LJ, Lippton ti, Edwards JC, et al. Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Ther 1981; 218: 739-749.
  • Palmer RMJ, Ashton DS, Moncada S. Vascular enodthelial cells synthesize nitric oxide from L-arginine. Nature 1988; 333: 664-666.
  • Moncada S, Palmer RMJ, fliggs A. Biosynthesis of nitric oxide from L-arginine. Biochem Pharmacol 1989; 38: 1709-1715.
  • Ciruelter CA, Oruetter DY, Lyon JE, Radowitz PJ, Ignarro LF. Relationship between cyclic guanosine 3-5-monophosphate formation and relaxation of coronary arterial smooth muscle by glyceryl trinitrate, nitroprusside, nitrite and nitric oxide: effects of methylene blue and methemoglobin. J Pharmacol Exp Ther 1981; 219; 181-186.
  • Rukovetz WR, Pöch G, flolzmann S. Cyclic nucleotides and relaxation of vascular smooth muscle. In: Vanhoutte P, Leusen I, eds. Vasodilatation. New York: Raven Press, 1981: 339-353.
  • Rapaport RM, Murad F. Agonist-induced endothelium dependent relaxation in rat thoracic aorta may be mediated through cGMP. Circ Res 1983; 52: 352-357.
  • Davison JS, Farasham A, Pearson GT, Peterson OH. Dibutyryl cGMP: a specific inhibitor of the action of CCR-like peptides on the pancreas, gallbladder and ileum. J Physiol (Lond) 1980; 305: 77-78.
  • Behar J, Biancani P. Pharmacology of biliary
  • tract. In: Shultz SG, Wood JD, Rauner BB, eds. Handbook of Physiology, Section 6: The
  • Gastorlntestinal System. New York: Oxford University Press, 1989: 1103-1131.
  • Mourelle M, Guarner F, Molero X, Moncada S, Malagelada JR. Regulation of gallbladder motility by the arginine-nitric oxide pathway in guinea-pigs. Gut 1993; 34: 911-915.
  • Göçer F, Yarış E, Tuncer M. The action of amyl nitrite and isosorbide dlnitrate on the contractility of sphincter of Oddi of guinea- pigs. Gen Pharmacol 1994; 25: 995-999.
  • ¡2. Wotta DR, Birnbaum AK, Wilcox GL, Eide R, Law PY. u-Opioid receptor regulates CTFR coexpressed in Xenopus oocytes in a cAMP independent manner. Mol Brain Res 1997; 44: 55-65.
  • Afdhal NH, La Mont JT. Pathogenesis of gallstones. In: Gitnick G, ed. Principles and Practices of Gastroenterology and Hepatology. New York: Elsevier, 1994: 561-571, ed2.
  • Raufman HS, Shermak MA, May CA, Pitt HA, Lillemoe RD. Nitric oxide Inhibits resting sphincter of Oddi activity. Am J Surg 1993; 165: 74-80.
  • Grozdanovic Z, Mayer ZB, Baumgarten HG, Bruning G. Nitric oxide synthase-containing nerve fibers and neurons in the gallbladder and biliary pathways of the guinea-pig. Neuroreport 1994; 5: 837-840.
  • Mourelle M, Guarner F, Moncada S, Malagelada JR. The arglnine/nitric oxide pathway modulates sphincter of Oddi motor activity in guinea-pigs and rabbits. Gastroenterology 1993; 105: 1299-1305.
  • 7. Salomons H, Reaveny AP, Henihan R, et at. Nitric oxide and gallbladder motility in prairie dogs. Am J Physiol 1997; 272: G770-G778.
  • Dufour JF, Turner TJ, Arias IM. Nitric oxide blocks bile canalicular contraction by inhibiting inositol triphosphate-dependent Ca2* mobilization. Gastroenterology 1995; 108: 841-849.
  • Murthy RS, Makhlouf GM. Interaction of cA- klnase and cG-kinase in mediating relaxation of dispersed smooth muscle cells. Am J Physiol 1995;268:C I 71-Cl 80.
  • Stark ME, Szurszewski JH. Role of nitric oxide In gastrointestinal and hepatic function and disease. Gastroenterology 1992; 103:1928- 1949.
  • !. Ôzkutlu U, Alican i, Rarahan F, et al. Are m- cholinoceptors of guinea-pig gallbladder smooth muscle of m^ subtype? Pharmacology 1993;46:308-314.
  • Von Schrenck T, Sievers J, Mirau S, Raedler A, Greten H. Characterization of muscarinic receptors on guinea-pig gallbladder smooth muscle. Gastroenterology 1993,105:1341- 1349.
  • Von Schrenck T, Mackensen B, Mende U, et al. Signal transduction pathway of the muscarinic receptors mediating gallbladder contraction. Naunyn-Schmied Arch Pharmacol 1994;349:346-354.
  • Takahashi T, Rurosawa S, Owyang C. Regulation of PI hydrolysis and cAMP
  • 3
  • E c e İ s k e n d e r , e t a l
  • formation by muscarinic M3 receptor in guinea-pig gallbladder. Am J Physiol 1994:267 -.G523-G528.
  • Barocelli E, Ballabeni V, Chiavarini M, Molina E, Impicciatore M. Functional comparison between nuvenzepine and pirenzepine on different guinea pig isolated smooth muscle preparations. Pharmacol Res 1994;30:161 - 170.
  • Eltze M, Bönig El, Ullrich B, Grebe T. Contraction of guinea-pig gallbladder: muscarinic Mj or M^ receptors? Eur J Pharmacol 1997;332:77-87.
  • Oktay 5- Cabadak 11, iskender E, et al. Evidence for the presence of muscarinic M2 and M4 receptors in guinea-pig gallbladder smooth muscle. J Auton Pharmacol 1998,18:195-204.
  • Baraalp A, Aktct A, Akbulut ft, Ulusoy HB, Oktay g. Distinct functional muscarinic receptors in guinea-pig gallbladder, ileum and atria. Pharmacol Res 1999:39:389-395.
  • Parkman HP, Pagano AP, Ryan JP. Subtypes of muscarinic receptors regulating gallbladder cholinergic contractions. Am J Physiol 1999;2 76:G 1243-G1250.
  • Felder CC. Muscarinic acetylcholine receptors: signal transduction through multiple effectors. EASEBJ 1995;9:619-625,
  • Eglen RM, Hegde SS, Watson H. Muscarinic receptor subtypes and smooth muscle function. Pharmacol Rev 1996;48:531-565.
  • Ignarro LJ, Byrns RE, Buga GM, Wood BS, Chaudhuri G. Pharmacological evidence that endothelium-derived relaxing factor is nitric oxide: use of pyrogallol and superoxide dismutase to study endothelium-dependent and nitric oxide-elicited vascular smooth muscle relaxation. J Pharmacol Exp Ther 1988;244:181-189.
  • Eurchgott RE, Vanhoutte P. Endothelium- derived relaxing and contracting factors. EASEBJ 1989;3:2007-2018.
  • George WJ, WHkerson RD, Badowitz PJ. Influence of acetylcholine on contractile force
  • and cyclic nucleotide levels in the isolated perfused rat heart. J Pharmacol Exp Ther 1973;184:228-235.
  • Balligand JL, Belly RA, Marsden PA, Smith TW, Michel T. Control of cardiac muscle cell function by an endogenous nitric oxide signalling system. Proc Hat I Acad Sci USA 1993;90:347-351.
  • Castoldi AE, Manzo L, Costa LG. Cyclic GMP
  • formation induced by muscarinic receptors is mediated by nilric oxide synthesis in rat cortical primary cultures. Brain Res
  • ;610:57-61.
  • Hu J, El-Fakahany EE. Role of intercellular and intracellular communication by nitric oxide in coupling of muscarinic receptors to activation of guanylate cyclase in neuronal cells. J Heurochem 1993;61:578-585.
  • Dauphin E, Linville DG, Hamel E. Cholinergic
  • dilatation and constriction of feline cerebral blood vessels are mediated by stimulation of phosphoinositidc metabolism via two
  • different muscarinic receptor subtypes. J Heurochem 1994;63:544-551.
  • Eglen RM, Whiting RL. Heterogeneity of vascular muscarinic receptors. J Auton Pharmacol 1990;10:233-245.
  • Dodds WJ, Hogan WJ, Geenen JE. Motility of the biliary system. In: Schultz SG, Wood JD, Rauner BB, eds. Handbook of Physiology, Section 6: The Gastrointestinal System. Hew York: Oxford University Press, 1989:1055- 1 101.
  • Mourelle M, Guarner E, Moncada S, Malagelada JR. Regulation of sphincter of Oddi motor activity by nitric oxide. Eur J Gastroenterol Hepatol 1991 ;3:S64.
  • Hellmich B, Gyermek L. H^ -Hitro-L-arginine
  • methyl ester: a muscarinic receptor
  • antagonist? Eundam Clin Pharmacol 1997; 1 1:305-314.
  • Buxton 1LO, Cheek DJ, Eckman D, Westfall DP, Sanders BM, Beef BD. HG-Hitro L-arginine methyl ester and other alkyl esters of arginine are muscarinic recepto
Toplam 55 adet kaynakça vardır.

Ayrıntılar

Bölüm Original Research
Yazarlar

Ece İskender Bu kişi benim

Hülya Cabadak Bu kişi benim

Ahmet Akıcı Bu kişi benim

Zafer Gören Bu kişi benim

Atila Karaalp Bu kişi benim

Nefise Ulusoy Bu kişi benim

Beki Kan Bu kişi benim

Esam El-fakahany Bu kişi benim

Şule Oktay Bu kişi benim

Yayımlanma Tarihi 3 Aralık 2016
Yayımlandığı Sayı Yıl 2002 Cilt: 15 Sayı: 1

Kaynak Göster

APA İskender, E., Cabadak, H., Akıcı, A., Gören, Z., vd. (2016). C A R B A C H O L I N D U C E S N I T R I C O X I D E G E N E R A T I O N I N G U I N E A - P I G G A L L B L A D D E R. Marmara Medical Journal, 15(1), 7-14.
AMA İskender E, Cabadak H, Akıcı A, Gören Z, Karaalp A, Ulusoy N, Kan B, El-fakahany E, Oktay Ş. C A R B A C H O L I N D U C E S N I T R I C O X I D E G E N E R A T I O N I N G U I N E A - P I G G A L L B L A D D E R. Marmara Med J. Mart 2016;15(1):7-14.
Chicago İskender, Ece, Hülya Cabadak, Ahmet Akıcı, Zafer Gören, Atila Karaalp, Nefise Ulusoy, Beki Kan, Esam El-fakahany, ve Şule Oktay. “C A R B A C H O L I N D U C E S N I T R I C O X I D E G E N E R A T I O N I N G U I N E A - P I G G A L L B L A D D E R”. Marmara Medical Journal 15, sy. 1 (Mart 2016): 7-14.
EndNote İskender E, Cabadak H, Akıcı A, Gören Z, Karaalp A, Ulusoy N, Kan B, El-fakahany E, Oktay Ş (01 Mart 2016) C A R B A C H O L I N D U C E S N I T R I C O X I D E G E N E R A T I O N I N G U I N E A - P I G G A L L B L A D D E R. Marmara Medical Journal 15 1 7–14.
IEEE E. İskender, H. Cabadak, A. Akıcı, Z. Gören, A. Karaalp, N. Ulusoy, B. Kan, E. El-fakahany, ve Ş. Oktay, “C A R B A C H O L I N D U C E S N I T R I C O X I D E G E N E R A T I O N I N G U I N E A - P I G G A L L B L A D D E R”, Marmara Med J, c. 15, sy. 1, ss. 7–14, 2016.
ISNAD İskender, Ece vd. “C A R B A C H O L I N D U C E S N I T R I C O X I D E G E N E R A T I O N I N G U I N E A - P I G G A L L B L A D D E R”. Marmara Medical Journal 15/1 (Mart 2016), 7-14.
JAMA İskender E, Cabadak H, Akıcı A, Gören Z, Karaalp A, Ulusoy N, Kan B, El-fakahany E, Oktay Ş. C A R B A C H O L I N D U C E S N I T R I C O X I D E G E N E R A T I O N I N G U I N E A - P I G G A L L B L A D D E R. Marmara Med J. 2016;15:7–14.
MLA İskender, Ece vd. “C A R B A C H O L I N D U C E S N I T R I C O X I D E G E N E R A T I O N I N G U I N E A - P I G G A L L B L A D D E R”. Marmara Medical Journal, c. 15, sy. 1, 2016, ss. 7-14.
Vancouver İskender E, Cabadak H, Akıcı A, Gören Z, Karaalp A, Ulusoy N, Kan B, El-fakahany E, Oktay Ş. C A R B A C H O L I N D U C E S N I T R I C O X I D E G E N E R A T I O N I N G U I N E A - P I G G A L L B L A D D E R. Marmara Med J. 2016;15(1):7-14.