European journal of pharmacology
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Although bradykinin (BK) antagonists have antinociceptive effects, they have not been evaluated for anti-inflammatory activity. When administered with carrageenan into the rat hindpaw, NPC567 significantly blocked carrageenan-induced hyperalgesia, hyperthermia and edema. In addition, NPC567 did not alter the in vitro release of immunoreactive BK by plasma kallikrein. These results indicate that the antinociceptive activity of NPC567, a BK antagonist, may be related to its overall anti-inflammatory activity and that is mechanism of action does not include inhibition of plasma kallikrein.
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Prolonged treatment of cultured rat heart muscle cells containing beta 1- and non-muscle cells containing beta 2-adrenoceptors with beta-adrenoceptor antagonists devoid of intrinsic sympathomimetic activity had no effect on beta-adrenoceptor density. In contrast, antagonists with intrinsic sympathomimetic activity decreased beta-adrenoceptor density and response (adenylate cyclase stimulation) in both heart muscle (beta 1) and non-muscle cells (beta 2) by a maximum of about 50%. An even larger down-regulation of beta-adrenoceptors and loss of receptor-stimulated adenylate cyclase activity was induced by the full endogenous agonist, noradrenaline, with the beta-adrenoceptors of heart muscle cells (beta 1) being much more sensitive to the beta 1-selective noradrenaline than the heart non-muscle cell beta 2-adrenoceptors. ⋯ The data presented indicate that the beta-adrenoceptor antagonists with intrinsic sympathomimetic activity, but not those without, upon prolonged treatment decrease the density and responsiveness of both beta 1- and beta 2-adrenoceptors in cultured rat heart cells. This suggests that the intrinsic sympathomimetic activity of these agents is not a subtype-selective component. Furthermore, the agonist and antagonist activity of these agents apparently depends on the concomitant presence of an endogenous full agonist and an its own affinity and that of the partial agonist for the beta-adrenoceptor subtype.