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The contribution of several vasoactive mediators such as histamine, serotonin, bradykinin, arachidonic acid metabolites and PAF to vascular permeability changes was determined in a rat model of acute endotoxemia. Lipopolysaccharide (10-40 mg/kg, i.v.) from E. coli 0127:B8 (LPS) elicited an increase in Evans blue extravasation in trachea, thymus, seminal vesicle and stomach, whereas other organs remained unaffected. LPS (25 mg/kg)-induced extravasation was not inhibited by intravenous pretreatment with histamine (H1) antagonist mepyramine (5 mg/kg) or bradykinin (B2) antagonist HOE-140 (0.1 mg/kg), whereas other standard drugs selectively inhibited leakage in particular tissues, e.g. the cyclooxygenase inhibitor indomethacin (5 mg/kg) in trachea (78%) and seminal vesicle (64%), the serotonin and H1 antagonists cyproheptadine (2 mg/kg) in trachea (88%) and stomach (56%) and the dual cyclooxygenase/lipoxygenase inhibitor phenidone (10 mg/kg) in seminal vesicle (87%). PAF antagonists lexipafant and UR-12460 (10 mg/kg), but not apafant, potently inhibited extravasation in trachea (59, 84%) and seminal vesicle (81, 78%) and in stomach only UR-12460 (52%), whereas all of them were ineffective in thymus. When extravasation was induced by PAF (4 micrograms/kg) a low dose (0.1 mg/kg) of the three PAF antagonists strongly reduced extravasation in thymus and seminal vesicle, whereas lexipafant and UR-12460 did so in trachea (82, 100%) and only lexipafant in stomach (100%). Mepyramine, cyproheptadine, HOE-140 and indomethacin did not inhibit the effect of PAF, whereas phenidone inhibited it by 58% in trachea. These results suggest that most of the LPS-induced increase in vascular permeability is mediated by secondary vasoactive mediators among which PAF plays a pivotal role, although their relative contribution may vary from tissue to tissue.

UR-7280 (3-tert-butyl-1-propyl-5-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-y l]methyl]-1H-pyrazole-4-carboxylic acid) is a new and potent angiotensin AT1-selective receptor antagonist. Binding studies in rat liver membranes showed that UR-7280 is an apparently competitive antagonist. However, in rabbit aorta this compound antagonized the angiotensin II-induced contractile response in an insurmountable way, causing a significant reduction of the maximal response. Additional binding studies evidenced that UR-7280 has a slowly reversible binding profile, consistent with its functional properties in rabbit aorta. The results obtained with a series of structural analogues of UR-7280 demonstrated a relationship between the size of the pyrazole 3-substituent and the surmountable or insurmountable mode of antagonism, indicating that this position may play a key role in the interaction between the antagonist and the angiotensin AT1 receptor.

In the present paper, we have studied the effect of lithium on cAMP levels induced by isoprenaline and norepinephrine in the presence of alpha- or beta-adrenoceptor antagonists. Our results show that low lithium concentrations, starting at 0.3 x 10(-3) M, have a significant inhibitory effect on cAMP content induced by isoprenaline in brain tissue pretreated with the alpha-adrenoceptor blocker phenoxybenzamine. On the other hand, the inhibitory effect of lithium on cAMP levels induced by norepinephrine when beta-adrenoceptors are blocked with propranolol, is observed at concentrations starting at 2.5 x 10(-3) M. These results show that in the presence of alpha blockade, low lithium concentrations which are within the therapeutic plasma range for treatment of manic patients, are able to act on an adenylate cyclase-cAMP system coupled to beta-adrenoceptors.

We studied the effects of lithium chloride, given i.p. in doses of 0.05, 1, 2, 4 and 8 mEq/kg twice daily for 14 days, on preparations of guinea pig myenteric plexus. The effects of lithium added to isolated myenteric plexus preparations derived from chronically treated animals showed that relatively low lithium concentrations produced a statistically significant decrease in the force of contraction, this effect being concentration-dependent. 3-Isobutyl-1-methylxanthine (IBMX) induced a statistically significant inhibition, between 30 and 50%, of the lithium effects. cAMP levels in animals treated chronically with lithium were studied, using an isotopic displacement technique. Our results show that only the highest dose of lithium (8 mEq/kg per day) significantly decreased basal levels of cAMP. In the presence of IBMX, low doses of lithium (1 mEq/kg per day) induced a very significant decrease in cAMP levels, but the inhibition remained constant, approximately 30-35%, at doses from 2 mEq/kg per day. In guinea pig myenteric plexus preparations from acutely treated animals, our results show a direct relationship between lithium concentration and inhibition of the cAMP accumulation induced by IBMX.

The effect of fosfosal, a non-acetylated salicylic acid derivative, on the content of prostaglandin E2 (PGE2) and the migration of polymorphonuclear leukocytes in inflammatory exudates induced by s.c. implantation of 0.5% carrageenan soaked sponges in rats has been determined. Fosfosal, which does not inhibit PG synthesis in vitro, is capable of reducing, in a dose-dependent manner, the PGE2 content of the exudates, with a maximum reduction of 50-60% at a total dose of 100 mg/kg i.p. Acetylsalicylic acid was slightly more potent (68% reduction, 2 x 50 mg/kg i.p.). Six hours after fosfosal administration, salicylic acid, the principal metabolite of fosfosal, accumulated in the exudates at concentrations of about 100 micrograms/ml. These concentrations were sufficient to inhibit PG synthetase activity in vitro. Neither fosfosal nor acetylsalicyclic acid affected polymorphonuclear leukocyte migration at doses which significantly reduced the concentrations of PGE2. Indomethacin, used as reference, reduced leukocyte migration by 28 and 45% at a dose of 1 and 10 mg/kg i.p. respectively. The results indicate that fosfosal, in spite of its lack of effect on PG biosynthesis in vitro, exerts an effect on the inflammatory locus in vivo which may account, at least in part, for its anti-inflammatory activity. Moreover, our results confirm that the inhibition of PG synthesis and leukocyte migration are mediated by different mechanisms.