PAF-induced bowel necrosis. Effects of vasodilators
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1Department of Pathology, Children's Memorial Hospital, Northwestern University Medical School, Chicago, Illinois 60614.
Abstract:
Ischemic bowel necrosis in the rat is produced by injecting platelet-activating factor (PAF) intravenously. Since intestinal hypoperfusion is observed after PAF injection, we hypothesize that mesenteric vasoconstriction is the mechanism of bowel injury. We thus studied the effects of vasodilators in this model. We found that: (1) Phenoxybenzamine, prazosin, ICI 198615 (leukotriene antagonist) and PGE1 counteracted the PAF-induced mesenteric flow reduction and ameliorated the bowel injury. However, phenoxybenzamine and prazosin were relatively ineffective in correcting PAF-induced hypotension, showing that bowel injury can be prevented independently of the hypotensive state. (2) Nitroglycerin failed to prevent bowel injury, although it improved the mesenteric blood flow. Thus, in opposition to our initial hypothesis, correction of the mesenteric flow reduction induced by PAF does not always prevent intestineal necrosis. (3) Only phenoxybenzamine, prazosin, ICI 198615, and PGE1 ameliorated PAF-induced hemoconcentration and bowel injury. This suggests a correlation between vascular injury (expressed by "leaky" vessels and the consequent hemoconcentration) and bowel necrosis. (4) Although both nitroglycerin and hydralazine relax smooth muscle, hydralazine seemed to aggravate bowel necrosis. The mechanism remains unclear.
Insights
Platelet-activating factor (PAF) causes ischemic bowel necrosis by reducing mesenteric blood flow. Vasodilators like phenoxybenzamine and PGE1 protected against injury, suggesting vascular leakage, not just hypoperfusion, is key.
Area of Science:
- Gastroenterology
- Vascular Biology
- Pharmacology
Background:
- Ischemic bowel necrosis is a severe condition.
- Platelet-activating factor (PAF) induces this condition in rats via mesenteric vasoconstriction and hypoperfusion.
- The precise mechanism and potential therapeutic targets remain under investigation.
Purpose of the Study:
- To investigate the role of mesenteric vasoconstriction in PAF-induced ischemic bowel necrosis.
- To evaluate the efficacy of various vasodilators in preventing this injury.
- To explore the relationship between vascular permeability, hemoconcentration, and bowel necrosis.
Main Methods:
- Induction of ischemic bowel necrosis in rats using intravenous PAF.
- Administration of vasodilators including phenoxybenzamine, prazosin, ICI 198615, PGE1, nitroglycerin, and hydralazine.
- Assessment of mesenteric blood flow, systemic blood pressure, hemoconcentration, and histological evidence of bowel injury.
Main Results:
- Phenoxybenzamine, prazosin, ICI 198615, and PGE1 ameliorated bowel injury and reduced mesenteric flow reduction, independent of systemic hypotension.
- Nitroglycerin improved mesenteric blood flow but did not prevent bowel necrosis, challenging the initial hypothesis.
- These agents also counteracted PAF-induced hemoconcentration, indicating a link between vascular leakiness and necrosis.
- Hydralazine appeared to worsen bowel necrosis, with the mechanism undetermined.
Conclusions:
- PAF-induced bowel necrosis involves more than just mesenteric hypoperfusion; vascular injury and increased permeability are critical.
- Certain vasodilators and a leukotriene antagonist show therapeutic potential by mitigating vascular leakage.
- Further research is needed to elucidate the mechanism of hydralazine's adverse effect and optimize vasodilator therapy for ischemic bowel conditions.