Inhibition of inducible nitric oxide synthase-derived nitric oxide as a therapeutical target for acute pancreatitis induced by secretory phospholipase A(2)

Author(s)

Camargo, E. A. ^[1] ; Santana, D. G. ^[1] ; Silva, C. I. ^[2] ; Teixeira, S. A. ^[2] ; Toyama, M. H. ^[3] ; Cotrim, C. ^[3] ; Landucci, E. C. T. ^[4] ; Antunes, E. ^[4] ; Muscara, M. N. ^[2] ; Costa, S. K. P. ^[2]

Affiliation

^[1] Univ Fed Sergipe, Dept Physiol, Sao Cristovao - Brazil

^[2] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, BR-05508 Sao Paulo - Brazil

^[3] Univ Sao Paulo State UNESP, Sao Vicente Unit, Sao Vicente - Brazil

^[4] State Univ Campinas UNICAMP, Fac Med Sci, Dept Pharmacol, Sao Paulo - Brazil

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF PAIN; v. 18, n. 5, p. 691-700, MAY 2014.
• Web of Science Citations: 11

Abstract

Background Nitric oxide is a key signalling molecule in the pathogenesis of inflammation, but its role in acute pancreatitis and related abdominal pain induced by secretory phospholipase A(2) (sPLA(2)) from Crotalus durissus terrificus (Cdt) venom has not been investigated. Methods Male Wistar rats were i.v. injected with L-NAME (20 mg/kg), aminoguanidine (AG, 50 mg/kg), 7-nitroindazole (7-NI, 10 mg/kg) or vehicle 10 min before or 60 min after the injection of sPLA(2) (300 mu g/kg) into the common bile duct. After 4 h of sPLA(2) injection, abdominal hyperalgesia and inflammation were assessed in addition to serum amylase, nitrite/nitrate (NOx), pancreas lipoperoxidation and 3-nitrotyrosine (3-NT) contents. Results sPLA(2)-induced acute pancreatitis, related abdominal hyperalgesia, hyperamylasemia and increased concentration of NOx were not correlated with lipoperoxidation or increased 3-NT in the pancreas. Pretreatment with all the nitric oxide synthase (NOS) inhibitors significantly reduced abdominal mechanical hyperalgesia, but only iNOS blockade by AG suppressed pancreas oedema and serum NOx increase. The therapeutic approach with all the NOS inhibitors produced a similar reduction pattern of the abdominal hyperalgesia, but AG treatment also inhibited serum hyperamylasemia and NOx concentrations and pancreatic myeloperoxidase. The nNOS blockade by 7-NI treatment also inhibited myeloperoxidase activity in both pancreas and lung. Conclusions Therapeutic blockade of iNOS or nNOS provides benefits in terms of inhibition of the acute pancreatitis-related abdominal hyperalgesia, while iNOS inhibition also ameliorates the inflammatory cell influx to the pancreas and reduces the resultant hyperamylasemia and NOx levels, thus representing alternative pharmacological strategies for treatment of clinical pancreatitis associated with increased PLA(2). (AU)

• FAPESP's process: 07/00529-0 - Pharmacological investigation of neurovascular mechanisms involved in the secretory phospholipases A2-induced acute pancreatitis
• Grantee: Soraia Katia Pereira Costa
• Support Opportunities: Regular Research Grants