NITRIC-OXIDE SYNTHASE INHIBITORS N-MONOMETHYLARGININE AND AMINOGUANIDINE PREVENT THE PROGRESSIVE AND SEVERE HYPOTENSION ASSOCIATED WITH A RAT MODEL OF PANCREATITIS

The objective of this study was to determine whether the observed vasc ular collapse and other pathologic features of severe pancreatitis may be related to the induction of nitric oxide synthase (NOS). The rat m odel of pancreatitis reported by Schmidt et al. was employed. Rats in the experimental groups received pretreatment with known NOS inhibitor s, N-Monomethylarginine (NMMA) or Aminoguanidine (AG). Controls includ ed sham-operated rats without pancreatic insult and a diseased control group which received pretreatment with normal saline (NS). Arterial b lood pressure was continuously recorded with a femoral arterial cathet er connected to a transducer and monitor. Fluid resuscitation for hypo tension followed a strict protocol with the administration of 5.0 cc N S for sustained decreases in systolic blood pressure (SBP) below 90 mm Hg at 5-minute intervals. Laboratory parameters and histopathology co nfirmed the induction of pancreatitis, with 6 to 15-fold increases in serum amylase levels and an average of similar to 20% decrease in seru m ionized Ca++ levels. Immunohistochemical studies of the pancreas rev ealed that pancreatic insult resulted in the induction of NOS. Rats in the saline control group (n=5) became hypotensive (SBP less than 90 m m Hg) between 3 and 4 hours post pancreatic insult and required an ave rage of 110.0 cc (3-4 x blood volume) of NS fluid resuscitation. Rats which were not resuscitated (n=5) did not survive. Rats treated with t he NOS inhibitors AG (n=5) or NMMA (n=5) and sham-operated rats (n=5) remained normotensive throughout the 6 hour duration of the experiment , requiring 8.0 cc NS for blood sample replacement and 6.0 cc of maint enance fluid over 6 hours. These results may indicate a potential util ity of NOS inhibitors for the treatment of severe pancreatitis and pos sibly an etiologic role of the inducible isoform of NOS in the progres sion of the pancreatitis disease process.