title: Advantages of a selective beta-isoform phosphoinositide 3-kinase antagonist, an anti-thrombotic agent devoid of other cardiovascular actions in the rat.
abstract: Phosphoinositide 3-kinase (PI3K) beta has been shown to play a critical role in shear-induced arterial thrombosis. The anti-thrombotic effects of a beta isoform selective PI3K inhibitor, TGX221, were compared to the effects of non-selective PI3K inhibitors (LY294002 and wortmannin) and a PI3K delta inhibitor (IC87114) in the rat. TGX221 (2.5 mg/kg i.v.) abolished cyclic flow reductions in a Folts-like carotid artery stenosis preparation of thrombosis while not changing bleeding time, heart rate, blood pressure or carotid vascular conductance. In contrast, the PI3K non-selective isoform inhibitor, wortmannin (5 mg/kg i.v.) was as effective in abolishing cyclic flow reductions, but caused marked hypotension and carotid vasodilatation. In isolated mesenteric arteries, wortmannin was the most potent relaxant of K+-precontracted vessels (pEC(50)=6.6), while LY294002 and TGX221 were 40-60 fold less potent and IC87114 was without effect. These findings suggest that of the subclass of PI3K isoforms, the beta isoform is critical for the selective development of arterial thrombosis in vivo. The multiple actions of wortmannin are consistent with inhibition of the PI3K-C2alpha and beta isoforms and possibly other actions. Thus, a selective inhibitor of the beta isoform of PI3K offers advantages as a potential therapeutic target for the treatment of thrombosis without unwanted extension of bleeding time or adverse cardiovascular sequelae.
authors.affiliation: Cardiovascular Therapeutics Unit, Department of Pharmacology, University of Melbourne, Victoria 3010, Australia.
authors.forename: Sharelle A
authors.initials: SA
authors.lastname: Sturgeon
authors.forename: Catherine
authors.initials: C
authors.lastname: Jones
authors.forename: James A
authors.initials: JA
authors.lastname: Angus
authors.forename: Christine E
authors.initials: CE
authors.lastname: Wright
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001760:Bleeding Time; D001794:Blood Pressure / Q000187:drug effects; D002317:Cardiovascular Agents; D017984:Enoxaparin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology*; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D013312:Stress, Physiological / Q000097:blood; D013379:Substrate Specificity; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D000925:Anticoagulants; D002317:Cardiovascular Agents; D017984:Enoxaparin; D004791:Enzyme Inhibitors; D005343:Fibrinolytic Agents; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011744:Pyrimidinones; C504718:TGX 221