European journal of pharmacology
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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.
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Flupirtine is a novel analgesic recently introduced with therapy. The present study assessed the role of opioid mechanisms in flupirtine-induced antinociception, localized its site of action along the neuraxis and evaluated its relative potency. Analgesic and general behavioral effects of flupirtine (0.3-10 mg/kg i.v.) were compared to those of the opioid analgesic pentazocine (0.3-5 mg/kg i.v.) in chronic spinal dogs. ⋯ Both drugs constricted pupils and lowered body temperature. In drug interaction studies, a relatively high dose (1 mg/kg i.v.) of the opioid antagonist naltrexone antagonized the effects of pentazocine but not those of flupirtine. It is concluded that flupirtine-induced antinociception is not opiate-receptor mediated, that its antinociceptive actions occur primarily at supraspinal sites and that its potency is less than that of pentazocine in the dog.
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[Thi5,8,D-Phe7]bradykinin caused hind-paw edema and degranulation of isolated peritoneal mast cells in a dose-dependent manner. Pretreatment with diphenhydramine/methysergide or compound 48/80 completely suppressed the edematous response caused by [Thi5,8,D-Phe7]bradykinin, whereas bradykinin-induced hind-paw swelling was only partially inhibited by diphenhydramine and methysergide pretreatment; the residual response was significantly further depressed by [Thi5,8,D-Phe7]bradykinin. Neither the bradykinin- nor [Thi5,8,D-Phe7]bradykinin-induced edematous response was significantly affected by aspirin or BW755C. ⋯ These results suggest that the edematous response elicited by [Thi5,8,D-Phe7]bradykinin was mainly due to the actions of mediators released by the degranulation of mast cells. Unlike bradykinin, [Thi5,8,D-Phe7]bradykinin was devoid of a direct exudation-promoting effect but exerted an antagonistic effect on the direct effect of kinin. If the influence of mast cells degranulation could be minimized, [Thi5,8,D-Phe7]bradykinin could be used as a tool to evaluate the role of kinin in the edematous response in inflammation.
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The hypotensive effects of anaritide (Wy-47,663), a 26 amino acid atrial natriuretic factor, were examined in conscious, monocrotaline-induced chronic pulmonary hypertensive rats. Anaritide (0.25-8 micrograms/kg per min i.v.) decreased systemic arterial pressure at 2-8 micrograms/kg per min by as much as -15.6 +/- 0.4 mm Hg. The pulmonary hypotensive response to anaritide was not different from vehicle treatment. We conclude that anaritide is more effective in decreasing systemic than pulmonary arterial pressures in monocrotaline-induced pulmonary hypertensive rats.
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Comparative Study
Pro-inflammatory effects of bradykinin, sigma-cyclo[Lys1,Gly6]bradykinin and sigma-cyclo-kallidin in the rat.
A comparison of the effects of bradykinin (BK), sigma-cyclo-BK and sigma-cyclo-kallidin (sigma-cyclo-KD) to induce oedema, hyperalgesia and blood flow in the rat paw was made. BK produced dose-dependent increases in oedema and blood flow and a reduction in the nociceptive pressure threshold. Sigma-Cyclo-BK and sigma-cyclo-KD were more potent than BK at inducing oedema and increasing blood flow but had no effect on nociceptive pressure threshold at the doses used. The relative lack of hyperalgesic activity of sigma-cyclo-BK and sigma-cyclo-KD compared with BK raises the possibility of differences between kinin receptors mediating permeability and blood flow changes and those involved in nociception in this model.