In this study, we investigated the carcinogenic response of transgenic mice carrying the human prototype c-Ha-ras gene, namely Tg rasH2/CB6F1 mice, to various genotoxic carcinogens and compared it with that of control non-transgenic CB6F1 mice (non-Tg mice). The present studies were conducted as the first step in the evaluation of the Tg rasH2/CB6F1 mouse as a model for the rapid carcinogenicity testing system. Short-term (< or = 6 months) rapid carcinogenicity tests of various genotoxic carcinogens, 4-nitroquinoline-1-oxide, cyclophosphamide, N,N-diethylnitrosamine, N-methyl-N-nitrosourea, N-methyl-N'-nitro-N-nitrosoguanidine and methylazoxymethanol, revealed that Tg rasH2/CB6F1 mice are more susceptible to these genotoxic carcinogens than control non-Tg mice. Tg rasH2/CB6F1 mice developed tumors more rapidly compared with non-Tg mice. Malignant tumors were observed only in the carcinogen-treated Tg rasH2/CB6F1 mice, but not in non-Tg mice treated with the same carcinogens. Each carcinogen induced tumors in corresponding target tissues of the Tg rasH2/CB6F1 mice. Only a very few lung adenomas but no other tumors were seen as spontaneous tumors during the 6 months of carcinogenicity tests. These results demonstrate that more rapid onset and higher incidence of more malignant tumors can be expected with high probability after treatment with various genotoxic carcinogens in the Tg rasH2/CB6F1 mice than in control non-Tg mice. The Tg rasH2/CB6F1 mouse seems to be a promising candidate as an animal model for the development of a rapid carcinogenicity testing system.

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Nitric oxide (NO) inhibits platelet adhesion and aggregation in vitro. In vivo, chronic inhibition of NO synthesis induces nephrosclerosis and hypertension. Although the pathophysiological mechanism of this glomerular injury has not been clarified, sympathetic nerve activation, a potent procoagulant stimulus elicited by NO inhibition, may play a role. To investigate the role of renal sympathetic nerves in the development of renal injury induced by N^G-nitro-L-arginine methyl ester (L-NAME), a specific NO synthesis inhibitor, we examined renal histological changes in four groups of Sprague-Dawley rats: (1) sham operated, vehicle treated; (2) sham operated, L-NAME treated; (3) denervated, vehicle treated, and (4) denervated, L-NAME treated. Following renal denervation or sham operation, L-NAME was administered orally for 4 weeks. Chronic NO inhibition induced platelet aggregation and erythrocyte stasis in the glomerular capillary lumen accompanied by electron-microscopic glomerular injury. Renal denervation abrogated platelet aggregation and glomerular injury in L-NAME-treated animals. Thus, chronic NO synthesis inhibition induced intraglomerular platelet aggregation and glomerular injury, which was attenuated by renal nerve denervation. These results suggest that intrinsic NO may have an antithrombotic effect in the glomeruli and may play a protective role in the progression of glomerular injury possibly mediated by renal sympathetic nerves.

The effect of acute denervation of the kidney on renal sodium and water excretion, and hemodynamics including intrarenal blood flow, was studied in anesthetized dogs. The intrarenal blood flow was measured by the radioactive microsphere method. In all experiments denervation natriuresis and diuresis were observed without significant change in glomerular filtration rate, renal blood flow and distribution of intrarenal blood flow. There was, however, an associated increase in potassium excretion. We suggest that denervation natriuresis and diuresis may be caused by the elimination of a direct nervous control of sodium and water reabsorption.

The effects of acute denervation of the kidney on renal tubular sodium and water excretion were studied in anesthetized, hypophysectomized, and cortisone-treated mongrel dogs during stable water diuresis produced by the infusion of 2.5% dextrose. In all experiments, denervation natriuresis, and diuresis were observed without significant change in glomerular filtration rate (GRF) and renal plasma flow (RPF). Fractional sodium delivery to the distal nephron (CNa + CH2O/100 ml GFR) and fractional free water clearance (CH23/100 ml GFR) was significantly greater in the denervated kidney compared with the innervated kidney (9.6+/-1.2 vs. 6.7+/-0.9% and 8.8+/-1.2 vs. 6.5+/-0.8%, respectively). Distal tubular sodium reabsorption (CH2O/(CNa + CH2O)) was not significantly different. We conclude that renal denervation primarily affects the proximal tubule as manifested by a decrease in the reabsorption of sodium and water. A small effect of denervation on the distal nephron is not completely ruled out.