Protective effect of adrenergic blocking agents against kidney hemorrhagic necrosis of choline deficiency

Summary

A disturbed renal circulation due to an imbalance between vasoconstrictor catecholamines and a vasodilator such as acetylcholine, caused by a decrease in acetylcholine, has been postulated as the basic mechanism of hemorrhagic degeneration of the kidneys in choline deficiency. In previous works from our laboratory we have shown a marked increased in the levels of renal catecholamines in choline-deficient rats in comparison to choline supplemented animals, while the content of acetylcholine remained unchanged. Since the changes in tissue catecholamines occurred before there were kidney lesions, we have suggested that an autonomic imbalance, due to an excess of catecholamines, plays an important role in the pathogenesis of renal injury in choline-deficient rats. A series of experiments were then planned to explore this theory further by administering adrenergic blocking agents (alpha-methyldopa and reserpine) attempting to prevent the development of the renal injury in choline deficiency. Young male Wistar rats from our outbred colony were allocated into two experiments. In experiment I the animals were divided at random in 4 groups: group CS-I, was fed a cholinesupplemented diet; group CSD-I, was fed a choline-supplemented diet and treated with alpha-methyldopa; group CD-I, was fed a choline-deficient diet; and group CDD-I, was fed a choline deficient diet and treated with alpha-methyldopa. Groups CSD-I and CDD-I received daily intraperitoneal injections of alpha-methyldopa (300 mg/kg of body weight). In experiment II the animals were divided at random in 4 groups: group CS-II, was fed a choline-supplemented diet; group CSR-II, was fed a choline-supplemented diet and treated with reserpine; group CD-II, was fed a choline-deficient diet; and group CDR-II, was fed a choline-deficient diet and treated with reserpine. The appropriate groups received daily intraperitoneal injections of reserpine (0.4 mg/kg of body weight).

The kidneys of all surviving rats were studied grossly and histologically, and the levels of noradrenaline and adrenaline determined. All animals from controls groups (CS-I, CSD-I, CS-II and CSR-II) showed essentially normal kidneys on gross and light microscopic examination. On the other hand, while CD-I and CD-II rats showed severe hemorrhagic degeneration of the kidneys, the renal lesions of animals given alpha-methyldopa (CDD-I) and reserpine (CDR-II) were significantly less pronounced. The total content of noradrenaline and adrenaline in the kidneys of CDD-I and CD-I rats were not statistically different, although the CDD-I animals tended to have lower levels of catecholamines. The content of noradrenaline and adrenaline of rats from group CD-I was significantly higher than the corresponding values in CS-I rats. Besides, the total content of renal noradrenaline of CDD-I animals was found to be unaltered when compared to CS-I rats, while their content of adrenaline was found to be higher than the corresponding value in CS-I group. The noradrenaline levels of CS-I and CSD-I rats were similar, but the latter group had a higher renal adrenaline content than the former. The total content of noradrenaline and adrenaline of the group CDR-II was lower than that of the group CD-II and did not differ than that of the group CS-II. Besides, the total content of noradrenaline in the kidneys of CSR-II animals was lower than that of the CS-II animals, while the content of adrenaline did not differ in these groups.

The findings of the present investigation, besides confirming our previous observations, clearly show that alpha-methyldopa and reserpine afforded a protective effect against the renal injury of choline deficiency, thus giving strong additional support to the theory that the kidney hemorrhagic necrosis of choline deficiency in young rats is in all probability due to an autonomic imbalance.