Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

[3H]Prostaglandin D2 binding to rabbit platelets was increased by about 150% in the presence of beta-adrenoceptor agonist, isoproterenol. The isoproterenol-induced potentiation of the [3H]prostaglandin D2 binding gave a bell-shaped dose-response relationship (maximum response at 3 X 10(-8) M) in a stereospecific manner. Similar and moderate potentiation was obtained with terbutaline. On the other hand, beta-adrenoceptor antagonists such as alprenolol, propranolol and butoxamine (beta 2-specific) had no potentiating effect on [3H]prostaglandin D2 binding; rather, they abolished the isoproterenol-induced increase of [3H]prostaglandin D2 binding. The beta 1-specific antagonist, metoprolol, did not have any effect. Rabbit platelets were found to possess one [3H]prostaglandin D2 binding site (Kd = 6 X 10(-7) M, Bmax = 787 fmol/mg protein). In the presence of isoproterenol at 3 X 10(-8) M, Bmax was increased with unaltering Kd value. Isoproterenol did not increase [3H]prostaglandin E1, [3H]prostaglandin E2 and [3H]prostaglandin F2 alpha bindings to platelets. The potential effect of isoproterenol was mimicked by forskolin, theophylline, dibutyryl cyclic AMP, prostaglandin E1 and prostaglandin I2, but it was abolished by 2', 5'-dideoxyadenosine, an inhibitor of adenylate cyclase, indicating that elevated level of cyclic AMP may be available for the induction of the increase of [3H]prostaglandin D2 binding. Prostaglandin D2-induced cyclic AMP synthesis and antiaggregation activity were also augmented in the presence of isoproterenol. These results suggest a beta 2-adrenoceptor-mediated cyclic AMP-dependent mechanism for the regulation of prostaglandin D2 receptor binding in rabbit platelets.
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PMID:Beta 2-adrenergic regulation of prostaglandin D2 receptor in rabbit platelets. 288 Jun 8

The actions of the novel metabolically stable and selective prostaglandin D2 receptor agonist ZK 118.182 ((5Z,13E)-(9R,11R,15S)-9-chloro-15-cyclohexyl-15- hydroxy-16,17,18,19,20-pentanor-3-oxa-5,13-prostadienoic acid) were studied in human platelets and polymorphonuclear neutrophils in vitro and compared to the naturally occurring agonist prostaglandin D2. ZK 118.182 inhibited collagen and ADP induced platelet aggregation more potently than prostaglandin D2 (IC50: 15 nM versus 60 nM) but was less effective than the stable prostacyclin mimetic iloprost (IC50: 3 nM). The same rank order of potencies was observed for the inhibition of collagen-induced platelet ATP secretion. A dose-dependent activation of adenylate cyclase could be demonstrated by ZK 118.182 which was comparable to that of prostaglandin D2 with respect to the concentration needed for half maximal stimulation (ED50) maximal cAMP level achievable. ZK 118.182 also dose dependently reduced the formyl-methionyl-leucyl-phenylalanine (FMLP) or platelet-activating factor (PAF) induced activation of polymorphonuclear neutrophils. Both, the oxygen burst resulting in the generation of superoxide anions and the degranulation of polymorphonuclear neutrophils accompanied by release of the lysosomal enzyme beta-glucuronidase, were significantly and dose dependently inhibited. ZK 118.182 was more potent than prostaglandin D2 in inhibiting polymorphonuclear neutrophil activation in all tests performed. In summary, ZK 118.182 is a prostaglandin D2 mimetic exerting potent inhibitory effects on human platelets and polymorphonuclear neutrophils.
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PMID:Inhibition of human platelets and polymorphonuclear neutrophils by the potent and metabolically stable prostaglandin D2 analog ZK 118.182. 752 76