No abstract

1 The interaction between the cannabinoid agonists, WIN 55,212-2 or CP 55,940 with the CB 1 receptor-selective antagonists, SR141716A or LY320135 was investigated using the rat electricallystimulated vas deferens bioassay. 2 Tissues were stimulated by single-®eld pulses (150 V, 0.5 ms) delivered every 30 mins. In the presence of nifedipine (3 mM), agonists elicited a concentration-dependent inhibition of the contractile response, with pEC 50 values of 7.93 and 6.84 for WIN 55,212-2 and CP 55,940, respectively. 3 SR141716A and LY320135 caused parallel dextral displacements of the agonist concentrationresponse curves. However, the shift of the agonist curves by either antagonist was accompanied by a concentration-dependent enhancement of basal (agonist-independent) tissue contraction. 4 Addition of the amidase inhibitor, phenylmethylsulphonyl¯uoride (200 mM), resulted in a signi®cant reduction of the basal twitch response, an eect consistent with the presence of tonic receptor activation mediated by the endogenous cannabinoid, anandamide. 5 In light of these ®ndings, we propose a theoretical model of competitive agonist-antagonist interaction in the presence of endogenous agonist tone that was used to derive an optimized analytical approach for the determination of antagonist potency estimates under conditions of tonic receptor activation. 6 This approach yielded pK B estimates for SR141716A and LY320135 that were in good agreement with their activity at cannabinoid CB 1 receptors. 7 It is concluded that the rat vas deferens contains prejunctional cannabinoid CB 1 receptors that are under tonic activation from endogenous substances; under these conditions our analytical approach is preferable to the standard methods for the determination of antagonist potency.

Several hypolipidemic drugs, plasticizers, and other chemicals induce hepatic peroxisome proliferation and hepatocellular carcinomas in rodents. These agents induce and promote hepatocarcinogenesis by unknown mechanisms, since most studies have not found them to be genotoxic. Peroxisome proliferators increase the expression of several genes, including those for the enzymes of the peroxisomal beta-oxidation pathway and the cytochrome P-450 4A family, which metabolize lipids, including eicosanoids and their precursor fatty acids. The peroxisome proliferators ciprofibrate and perfluorodecanoic acid (PFDA) were therefore examined for their ability to alter hepatic eicosanoid concentrations. Rats received injections of 3 or 10 mg PFDA/kg body weight every 14 days or were fed 0.01% ciprofibrate for 10 days, 24 days, 6 weeks, 26 weeks, or 54 weeks. The activity of the peroxisomal enzyme fatty acyl CoA oxidase was significantly increased by both ciprofibrate and PFDA at all times. Hepatic concentrations of prostaglandins E2 and F2a (PGE2, PGF2a), thromboxane B2 (TXB2), and leukotriene C4 (LTC4) were measured by immunoassay. Concentrations of PGE2, PGF2a, and TXB2 were decreased in livers of rats receiving ciprofibrate or PFDA compared to livers of control rats, with ciprofibrate exerting a greater effect than PFDA at the doses used. Hepatic LTC4 concentrations were significantly increased by ciprofibrate at 10 days and PFDA at 54 weeks, and significantly decreased by PFDA at 26 weeks. These alterations in eicosanoid concentrations may be important in the natural history of peroxisome proliferator-induced hepatocarcinogenesis.

No abstract

The purpose of this study was to determine if increasing dietary fat, either as saturated fat or polyunsaturated fat, would alter initiation of hepatocarcinogenesis by diethylnitrosamine (DEN) or 2-acetylaminofluorene (AAF). Rats were fed one of three purified diets: a low-fat (LF) diet (containing 5% of calories as safflower oil), a high saturated fat (HSF) diet (containing 48% of calories as palm oil) and a high polyunsaturated fat (HPUF) diet (containing 48% of calories as safflower oil). Four weeks later, all rats were subjected to partial hepatectomy (PH). Rats were then divided into four groups and received no carcinogen, DEN (10 mg/kg, p.o., 24 h after PH) or AAF (25 or 100 mg/kg, p.o., 12 h after PH). Five days later, all rats were fed an unrefined diet, and 9 weeks later, all rats were fed phenobarbital in the diet for 26 weeks as a tumor promoter. In rats initiated with DEN, the number of gamma-glutamyl transpeptidase-positive and ATPase-negative foci was higher in the rats fed the HPUF diet, but not the HSF diet, as compared to rats fed the LF diet. The incidence of neoplastic nodules, the mean focal volume and the volume fraction, however, were not significantly altered by dietary fat in DEN-injected rats. The dietary fat content of the diet did not affect the induction of altered hepatic foci or neoplastic nodules in rats initiated with AAF or receiving no initiation. This study shows that initiation of hepatocarcinogenesis can be influenced by dietary fat, but that the effect may be carcinogen-specific.