1 The adenosine A3 receptor agonist, N6-2-(4-aminophenyl)ethyladenosine (APNEA) induces hypotension in the anaesthetized rat

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A selective antagonist for the recently characterized 5-HT4 receptor is lacking. The only surmountable antagonist available, ICS 205-930, is a weak antagonist and is far more potent at 5-HT3-than at 5-HT4 receptors. In this paper, SDZ 205-557 (2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino) ethyl ester) is characterized as the first potent, selective and surmountable antagonist at 5-HT4 receptors in the isolated guinea pig ileum. SDZ 205-557 was investigated in the non-stimulated and in the field-stimulated guinea pig ileum longitudinal muscle preparation for its affinity for 5-HT4-, 5-HT3-, muscarine-, nicotine- and histamine H1 receptors. The affinity for 5-HT1-, 5-HT2-, alpha 1-, alpha 2- and opiate (mu) receptors was determined by binding assays. SDZ 205-557 was devoid of substantial affinity (pKD values below 5.6) for all receptors investigated except for 5-HT3- and 5-HT4 receptors. At these two receptors, SDZ 205-557 acted as an antagonist without measurable intrinsic activity. At the 5-HT4 receptors of the non-stimulated guinea pig ileum, responses to 5-HT and 5-methoxytryptamine were antagonized by SDZ 205-557 with identical pA2 values of 7.4. The effect of renzapride was also blocked with no significant change in the maximum response; Schild analysis, however, revealed that the interaction was not competitive with an "apparent" pA2 value of 7.6. A pA2 of 6.8 was obtained using zacopride as a contractile agent; this value differed significantly from 7.4, the value obtained for 5-HT and 5-methoxytryptamine.(ABSTRACT TRUNCATED AT 250 WORDS)

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Prostanoids are synthesized by resident macrophages upon stimulation with diacylglycerols. Oleoylacetylglycerol and dioctanoylglycerol induced prostaglandin E and thromboxane synthesis in a time- and concentration-dependent manner. Both diacylglycerols inhibited the lysophosphatide acyltransferase, which is the key enzyme in the reacylation of arachidonic acid. By this mechanism the pool of free arachidonic acid available for prostanoid synthesis is increased. Both diacylglycerols were able to inhibit the membrane-bound lysophosphatide acyltransferase by a direct interaction independent of protein kinase C. Thus lysophosphatide acyltransferase could be shown to be a new target of these diacylglycerols, known as activators of protein kinase C.