EFFECTS OF ALPHA-TRINOSITOL ON SYSTEMIC INFLAMMATION AND RENAL-FUNCTION IN-OVINE BACTERIAL SEPSIS

Neuronally secreted peptides are important mediators of hemodynamic ch anges in the systemic inflammatory response. The inositol derivative D -myo-inositol[1,2,6]triphosphate (alpha-trinositol) has been demonstra ted to be a specific nonpeptide antagonist of vasoconstriction induced by neuropeptide Y. We induced sepsis by a 48 h continuous infusion of Pseudomonas aeruginosa (10(6) colony-forming unit/min intravenously [ i.v.]) in 12 chronically instrumented, conscious sheep. After 24 h, th e animals were randomized to receive either alpha-trinositol (i.v. bol us of 2 mg/kg, followed by a continuous infusion of 3.5 mg/kg/h) or th e saline carrier. alpha-Trinositol increased the heart rate (108 +/- 4 to 152 +/- 9 beats per minute) and reduced the stroke volume index (6 5 +/- to 5 to 49 +/- 2 mL/beat/m(2)) but did not change cardiac index. Left ventricular stroke work decreased significantly (80 +/- 9 to 58 +/- 7 g.m/m(2)). All blood flows except the infrarenal aortic flow wer e increased after 24 h, but treatment decreased only the flow to the h ind limb region. Urine output and fractional sodium excretion signific antly increased without osmotic diuretic effects after alpha-trinosito l. In treated animals, we found significantly lower leukocyte counts i n all organ tissues. We conclude that alpha-trinositol modulates the c ardiac performance and the local inflammatory response in tissues, and improves the fluid balance in septic sheep.