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1 The effects of sulphasalazine (SZP) and PhCL28A on macroscopic lesion formation and ex vivo prostaglandin inactivation were studied in the ethanol (ETOH) and phenylbutazone (PBT) models of gastric ulcers in the rat. Prostaglandin 'synthesis' during homogenisation of the stomachs was also studied in the latter model. 2 Both PhCL28A and SZP when injected i.p. prevented the formation of ETOH-and PBT-induced gastric ulcers with ED,5 values of 13 and 41 mg kg-' (vs ETOH) and 3 and 32 mg kg-' (vs PBT) for PhCL28A and SZP respectively. However, neither compound was active orally in the dose ranges used (up to 30 mg kg-' for PhCL28A and I00 mg kg-' for SZP). 3 Irrespective of the route of administration, SZP (100mgkg-') and PhCL28A (30mgkg-') produced slight but statistically significant decreases in ex vivo prostaglandin inactivation by 100,000 g cytosolic supernatants prepared from stomachs not receiving ulcerogen. When tested in vitro, PhCL28A (ICm, = 230 nM) was approximatively 480 times more potent than SZP (ICy, = 110 M) against rat stomach cytosolic prostaglandin inactivation.4 Both ETOH (50%, 5 ml kg-', orally) and PBT (200 mg kg-', orally) significantly decreased ex vivo gastric cytosolic prostaglandin inactivation. PhCL28A (30mg kg-', orally or i.p.) decreased prostaglandin inactivation still further after ulcerogen treatment except when given i.p. before ETOH treatment. SZP (100mg kg-') had a similar effect when given orally before PBT treatment. 5When the prostaglandin content of the stomach homogenates was used as a measure of ex vivo prostaglandin synthesis in the PBT experiments, PhCL28A 30 mg kg-' orally (but not i.p.) produced an 88% increase in prostaglandin E2 (PGE2) levels, but had no effect on 6-keto-PGF,, or thromboxane B2 formation during homogenization. SZP (100mg kg' i.p. or orally) was without effect. 6 We conclude from these results that the anti gastric ulcer activity of SZP and PhCL28A is independent of prostaglandin inactivation and endogenous prostaglandin formation is probably not involved.

The effects of long term D-penicillamine treatment on adjuvant arthritis in the rat were determined in order to establish a possible approach to the laboratory evaluation of anti-rheumatic drugs. Oral pretreatment (1-3 months) followed by continued through-treatment on a daily basis (100 mg/kg p.o.) failed to modify the parameters tested: viz. (a) body weight changes; (b) primary paw lesions; (c) secondary hind paw lesions; (d) secondary forepaw, ear and tail lesions; (e) the number of 'responders'. Autopsy showed no macroscopic abnormalities in the lungs, heart, thymus, liver, spleen, adrenal glands, kidneys and gastro-intestinal tract. These results are discussed in relation to previous findings whereby rat adjuvant arthritis, in addition to other experimental immune reactions, has been suggested as an indicator for D-penicillamine activity.

Noninsulin-dependent mellitus is characterized by the coexistence of defective insulin secretion with insulin resistance in peripheral tissues. Therapeutic objectives are, therefore, to normalize glucose-induced insulin secretion and to restore normal glucose transport into insulin-sensitive tissues. In the present study we evaluate the effects of acute and subchronic administration (2 or 10 days) of the alpha 2-adrenoceptor antagonist SL 84.0418 on glucose tolerance in nondiabetic control rats and type I and type II diabetic rats and the level of the insulin-sensitive glucose transporter GLUT-4, which is exclusively expressed in white and brown adipose tissues, heart, and skeletal muscles. Glucose tolerance and insulin secretion were markedly impaired in type II diabetic rats (neonatal injection of streptozotocin) and were totally corrected by an acute i.p. injection of SL 84.0418. As a consequence of the chronic restoration of insulin secretion, GLUT-4 messenger RNA (mRNA) levels, initially decreased by 67% in white adipose tissue of type II diabetic rats, were normalized by subchronic (10 days), but not acute (2 days), treatment with SL 84.0418. The same results were obtained in brown adipose tissues of type II diabetic rats, whereas no modification of GLUT-4 mRNA levels remained very low in brown adipose tissues of type I diabetic rats (adult injection of streptozotocin) after acute or subchronic administration of SL 84.0418, suggesting that this drug acted by the restoration of insulin secretion. This study reports a decrease in GLUT-4 levels in insulin-sensitive tissues in this model of type II diabetes as well as its regulation after subchronic normalization of insulin secretion. We suggest a direct role for the alpha 2-adrenoceptor antagonist SL 84.0418 in pancreatic beta-cells that allows normalization of glucose tolerance.

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