Date of Award

1987

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Physiology

College

College of Graduate Studies

First Advisor

George E. Tempel

Second Advisor

J. A. Cook

Third Advisor

Perry V. Halushka

Abstract

Increased activity of the alpha adrenergic nervous system may be a significant factor promoting tissue ischemia in endotoxic shock. The suggestion that increased sympathetic activity affects prostaglandin synthesis prompted investigation of the potential interaction between the adrenergic nervous system and arachidonic acid metabolites during endotoxemia and septicemia. In addition, the possibility that the underlying patterns of arachidonic acid metabolites seen in two different shock models may provide a rationale for therapeutic intervention designed to block either or both the synthesis of arachidonic acid metabolites or the activity of the adrenergic nervous system was examined. Studies were undertaken to determine the effects of the alpha receptor antagonist, phenoxybenzamine (POB), and the cyclooxygenase inhibitor, indomethacin (INDO), on plasma thromboxane (TxA2) and prostacyclin (PGI2) in endotoxin-induced shock. Rats were pretreated with POB (1 mg/kg i.v.) and/or INDO (10 mg/kg i.v.) 30 minutes prior to i.v. administration of 8 mg/kg S. enteritidis endotoxin (LD80). Animals were bled at 30 minutes and 4 hours post-endotoxin for determination of blood glucose, plasma beta-glucuronidase (BG), aspartate amino transferase (AST), and hematocrit as indicators of shock severity. Plasma was also taken at these intervals for radioimmunoassay of the stable immunoreactive metabolites of TxA2 and PGI2, iTxB2 and i6-keto-PGF1a, respectively. Pretreatment with INDO alone reduced endotoxin-induced hypoglycemia (P<0.05). POB pretreatment reduced hypoglycemia, hemoconcentration and beta glucuronidase (P<0.05). The combination of POB and INDO resulted in the improvement of all these indices of shock severity (P<0.05). Rats pretreated with POB and INDO alone or conjointly also exhibited significantly (P<0.05) enhanced survival compared to shocked control rats. Elevations in arachidonic acid metabolites were attenuated by POB pretreatment. In endotoxin-treated rats (15 mg/kg i.v.), the mean plasma iTxB2 value at 30 mins post-endotoxin was 1532 ± 319 pg/ml (N=10). POB pretreatment decreased iTxB2 to 719 ± 114 pg/ml (N=10) (P<.05). Plasma i6-keto-PGF1a was increased at 4 hrs after endotoxin to 4161 ± 885 pg/ml (N=5) in shocked controls. POB attenuated this increase to 1184 ± 363 pg/ml (N=4) (P<0.05). The data demonstrate that the alpha receptor antagonist POB inhibits the increased synthesis of arachidonic acid metabolites seen in endotoxemia. The reduction in more indices of shock severity in rats receiving combined POB and INDO pretreatment suggest that nonsteroidal anti-inflammatory agents may be an effective adjunct to alpha adrenergic blocking agents in endotoxin shock. Other experiments were undertaken to: 1) determine the effects of POB and INDO, individually, on mean arterial pressure (MAP), heart rate (HR), and MAP response to injected norepinephrine (NE) in control rats and endotoxin shocked rats, 2) assess the effect of POB on iTxB2 and i6-keto-PGF1a synthesis, and 3) determine the effects of POB and INDO, independently and conjointly, on survival from shock induced by intraperitoneal injection of feces. The data demonstrate that POB (1 mg/kg) leads to a reduction in MAP in unshocked rats, but does not significantly exacerbate endotoxin-induced hypotension. POB administration also effected a 60% - 90% reduction in the MAP response to injection of NE in shocked and unshocked rats. No consistent effect on heart rate in shocked and unshocked animals was observed with POB. Pretreatment with INDO (10 mg/kg) did not significantly alter MAP, HR, or the MAP response to exogenous NE in normal rats and rats challenged with endotoxin. In the intraabdominal sepsis model (LD100 within 48 hrs), pretreatment with POB did not increase survival time while INDO, independently or conjointly with POB, prolonged survival time compared to controls and animals treated only with POB (P<0.05). Treatments did not alter mortality (100% within 48 hrs). The effect of the combination of INDO + POB on survival time was not significantly different from that of INDO alone (P>0.05). Preliminary results suggest that POB pretreatment may suppress the elevations of iTxB2 and i6-keto-PGF1a in this shock model. The results are consistent with the hypothesis that the prevailing plasma levels of iTxB2 and i6-keto-PGF1a, which have different patterns in the two shock models studied, may play a role in determining the therapeutic efficacy of POB.

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