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 vascular collapse and other pathologic features of severe pancreatitis may be related to the induction of nitric oxide synthase (NOS). The rat model of pancreatitis reported by Schmidt et al. was employed. Rats in the experimental groups received pretreatment with known NOS inhibitors, N- Monomethylarginine (NMMA) or Aminoguanidine (AG). Controls included sham- operated rats without pancreatic insult and a diseased control group which received pretreatment with normal saline (NS). Arterial blood pressure was continuously recorded with a femoral arterial catheter connected to a transducer and monitor. Fluid resuscitation for hypotension followed a strict protocol with the administration of 5.0 cc NS for sustained decreases in systolic blood pressure (SBP) below 90 mm Hg at 5-minute intervals. Laboratory parameters and histopathology confirmed the induction of pancreatitis, with 6 to 15-fold increases in serum amylase levels and an average of ~20% decrease in serum ionized Ca⁺⁺ levels. Immunohistochemical studies of the pancreas revealed that pancreatic insult resulted in the induction of NOS. Rats in the saline control group (n=5) became hypotensive (SBP less than 90 mm Hg) between 3 and 4 hours post pancreatic insult and required an average 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 the 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 maintenance fluid over 6 hours. These results may indicate a potential utility of NOS inhibitors for the treatment of severe pancreatitis and possibly an etiologic role of the inducible isoform of NOS in the progression of the pancreatitis disease process.