Evidence for a possible role of endogenous catecholamines in the vascular changes produced in rat intestine by x-rays.

Abstract

= 9 + re of rat abdomen to a 1000-r dose of x rays the intestinal vessels developed increased permeability to circulating protein-bound trypan blue, first demonstrable at 24 hr, reaching a max by 72-96 hr after irradiation, and thereafter slowly returning to normal. Pretreatment of rats with the monoamine oxidase (MAO) inhibitor iproniazid (250 mg/kg before and 125 mg/kg 24 hr after irradiation) led to striking suppression of the accumulation of trypan blue in the intestine, most marked at 24 hr. Compound HP 1275 (1-methyl-2- phenoxyethylhydrazinium, 200 mg/kg) was the most effective MAO inhibitor tested in reducing intestinal capillary permeability after abdominal irradiation. Similarly, HP 1273 (2,4'-hydroxphenoxyethylhydrazinium) and pheniprazine each caused a marked reduction (68 and 50%, respectively) of the dye-leakage measured 48 hr after irradiation. To eliminate preirradiation anoxia in the mode of action of the MAO inhibitors, the effect of these compounds after irradiation was tested. It was shown that delaying the administration of the MAO inhibitors until completion of irradiation failed to prevent their characteristic effect on the increased capillary permeability in the intestine; these compounds still caused a 75% reduction of dye leakage. The effect of irradiation on the pressor amine content of the adrenalmore » glands was investigated in rats exposed to half-body irradiation of 1500 r and killed 1, 2 or 3 days later. After irradiation there was a progressive loss of pressor amines (adrenaline and noradrenaline) from the adrenal glands, their lowest concentration being reached 3 --4 days after irradiation. Adrenalectomy failed to prevent the action of MAO inhibitors. Injection of the adrenolytic drug dibenamine immediately before administration of the MAO inhibitor HP 1273 and exposure to x rays reversed the usual inhibitory action of HP 1273 on increased capillary permeability. Similarly, simultaneous treatment with dibenamine and HP 1275 caused no inhibition of increased capillary permeability in adrenalectomized rats. Treatment with dibenamine alone failed to affect the usual capillary permeability changes. On the other hand, BOL 148 (1 mg/kg before and a further 1 mg/kg 24 hr after irradiation) failed to modify the effect of the MAO inhibitor in reducing dye leakage assayed 48 hr after injury. In an attempt to reproduce the effect of the MAO inhibitors with the aid of pressor amines, rats were irradiated over the abdomen with 1000 r and then injected immediately with adrenaline (0.5 mg/kg). However, systematically administered adrenaline failed to cause any detectable reduction of vascular permeability in the intestine. Similarly, injections of 5-hydroxytryptamine (5- HT) and noradrenaline led to no significant suppression of dye staining in the intestine as measured 48 hr after irradiation. Pretreatment of rats with pyrogallol, an inhibitor of catechol-O-methyltransferase, an enzyme that inactivates monoamines by a pathway different from that of MAO, failed to diminish the increased capillary permeability 24 or 48 hr after abdominal irradiation with 1000 r. Pretreatment with cysteamine HCl, a radioprotectant SH compound (200 mg/kg immediately before and 100 mg/kg 24 hr after abdominal irradiation with 1000 r), failed to reduce the changes in intestinal vascular permeability assayed 48 hr later. To test the effect of the most successiul MAO inhibitor on mortality after x irradiation, rats pretreated with HP 1273 (100 mg/ kg subcutaneously) were exposed to 975-r whole-body irradiation. Pretreatment with MAO inhibitors accelerated death after whole-body irradiation. Since the peak mortality coincided with max release of 5-HT from the intestine, the animals may have died from the toxic effects of the released 5-HT rather than from the usual gastrointestinal lesions. This hypothesis is supported by the clinical picture preceding death in the animals pretreated with MAO inhibitors, i.e., a drop in body temperature and profound collapse with moderate gastrointestinal symptoms; the control animals« less