Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anagrelide (BL-4162A, 6,7-dichloro-1,5-dihydroimidazo[2, 1-6] quinazolin-2[3H]one monohydrochloride hydrate) is a potent and broad spectrum inhibitor of platelet aggregation. Prior studies showed that anagrelide inhibited platelet cyclic AMP (cAMP) phosphodiesterase activity but did not appreciably elevate platelet cAMP levels. We examined the effects of anagrelide on washed human platelets and found that anagrelide caused significant elevation of cAMP levels. Anagrelide treatment also resulted in activation of the platelet cAMP-dependent protein kinase at anagrelide concentrations of 0.1 to 1 microgram/ml, which inhibited platelet aggregation but caused only small increases in platelet cAMP content. When whole platelets were incubated with radiolabeled phosphate, anagrelide increased phosphorylation of platelet proteins with relative molecular weights of 22, 26, 50 and 80 kilodaltons. The pattern of protein phosphorylation stimulated by anagrelide treatment was similar to that observed when the platelets were treated with forskolin. Anagrelide also inhibited the rise in intracellular Ca++ caused by thrombin, as measured using Fura-2-loaded platelets. The inhibition of increased intracellular Ca++ resulted from block of thrombin-induced mobilization of intracellular Ca++, as well as prevention of Ca++ influx through the plasma membrane. Anagrelide itself had no influence on inositol 1,4,5-trisphosphate-induced Caz5++ release from isolated platelet membrane vesicles. These studies suggest that anagrelide inhibits platelet phosphodiesterase activity in intact platelets resulting in an elevation in cAMP levels sufficient to activate the cAMP-dependent protein kinase and inhibit agonist-activated Ca++ fluxes.
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PMID:Effects of anagrelide on platelet cAMP levels, cAMP-dependent protein kinase and thrombin-induced Ca++ fluxes. 282 59

Induction of atherosclerosis in rabbits by feeding a cholesterol enriched diet reduced the platelet half-life in male rabbits from 37.0 +/- 4.1 hr to 30.1 +/- 3.9 hr (mean +/- S.D. p less than or equal to 0.01). Platelets from these animals exhibited increased sensitivity to arachidonic acid but decreased sensitivity to ADP. No significant change was found in aggregation to collagen or thrombin, or in the production of thomboxane B2 induced by collagen. The reduced platelet survival was dependent upon the recipient animal and not the platelet donor. Platelets from cholesterol-fed animals survived normally in normal animals, whereas platelets from normal animals in cholesterol-fed animals had a reduced platelet survival even compared to platelets from cholesterol-fed animals. This might suggest that some functional change had occurred in the cholesterol platelet in response to its altered environment. Anagrelide (1 mg/kg/day) normalised shortened platelet survival in both male and female rabbits fed the high cholesterol diet.
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PMID:Shortening of platelet survival by induced hypercholesterolaemia in rabbits and its prolongation by anagrelide. 664 89