sq-29548 and picotamide

We evaluated the capacity of anti-aggregating agents to influence thromboxane A(2) and prostacyclin formation, arachidonic acid-endoperoxide redirection, platelet aggregation and vessel tone, in isolated rabbit aorta incubated with homologous platelets. Picotamide (N,N'bis(3-pyridinylmethyl)-4-methoxy-isophthalamide), the only dual thromboxane A(2)-synthase inhibitor/receptor antagonist in clinical use, inhibited arachidonic acid-induced platelet aggregation with low potency, increased 180-fold by aorta presence. It inhibited thromboxane A(2) formation in platelets and, in aorta presence, increased prostacyclin formation. Ozagrel (OKY-046, (E)-3-(4-(1-imidazolylmethyl)phenyl)-2-propenoic acid), a pure thromboxane A(2)-synthase inhibitor, behaved similarly to picotamide, although the aorta caused a higher (600-fold) shift. The potency of the antagonist SQ 29,548 (1S-(1 alpha,2 beta(5Z),3 beta,4 alpha))-7-(3((2-((phenylamino)carbonyl)hydrazino)methyl)-7-oxabicyclo(2.2.1)hept-2-yl)-5-heptenoic acid) was unaffected by aorta. In coincubation experiments, arachidonic acid-challenge increased thromboxane A(2)-dependent vessel tone; picotamide increased prostacyclin and reduced thromboxane A(2) formation and vasoconstriction. Ozagrel mimicked picotamide; aspirin (acetylsalicylic acid) reduced aorta contractility, thromboxane A(2) and prostacyclin formation. SQ 29,548 reduced vasoconstriction without affecting eicosanoids. We demonstrate the importance of redirection of eicosanoids in the mechanism of action of thromboxane A(2) inhibitors/antagonists within platelet-vascular wall interactions. These findings bear relevance in the development of novel anti-thrombotic drugs.

Topics: Animals; Aorta, Thoracic; Arachidonic Acid; Aspirin; Blood Platelets; Bridged Bicyclo Compounds, Heterocyclic; Cell Communication; Dinoprost; Endothelium, Vascular; Fatty Acids, Unsaturated; Hydrazines; In Vitro Techniques; Male; Methacrylates; Muscle Tonus; Muscle, Smooth, Vascular; Phthalic Acids; Platelet Activation; Platelet Aggregation Inhibitors; Rabbits; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase

Two currently available edible oils-olive and canola-and two oil blends of plant origin having different n-3/n-6 polyunsaturated fatty acid (PUFA) ratios were evaluated for their ability to modify vascular dysfunction in the spontaneously hypertensive rat (SHR). Synthetic diets supplemented with test oils (5% w/w) were fed for 12 weeks, and segments of thoracic aorta used to assess vascular function. Vessels from the SHR displayed a spontaneous constrictor response after the inhibition of endothelial cell nitric oxide (NO) with N(omega)-nitro-L-arginine (NOLA). Dietary alpha -linoleate enrichment led to a reduction (P<0.05) in this abnormality with a dietary n-3/n-6 PUFA ratio of 1.0 (blend-1) yielding the best outcome. Relaxation to acetylcholine (ACh) was unaffected by dietary lipid supplementation. NOLA treated rings also displayed contractions to ACh that were abolished by indomethacin, thromboxane antagonists SQ29548, picotamide and flavonoids kaempferol and quercetin. In contrast, alpha-tocopherol, rutin and the lipoxygenase inhibitor esculetin resulted in only partial (30-55%) inhibition, and were ineffective against the NOLA-induced contraction suggesting the operation of different biochemical mechanisms in mediating the spontaneous and Ach-induced contractions. Results implicate plant-based oils and antioxidants as potential modulators of vascular function.

Topics: Acetylcholine; alpha-Tocopherol; Animals; Antioxidants; Aorta; Bridged Bicyclo Compounds, Heterocyclic; Cardiovascular Agents; Diet; Dose-Response Relationship, Drug; Endothelium, Vascular; Fatty Acids, Unsaturated; Flavonoids; Hydrazines; Hypertension; Indomethacin; Kaempferols; Lipid Metabolism; Nitric Oxide; Phthalic Acids; Plant Oils; Platelet Aggregation Inhibitors; Quercetin; Rats; Rats, Inbred SHR; Rutin; Umbelliferones

The aim of the present study was twofold: 1) to assess whether inhibition of thromboxane A2 (TxA2) synthase exerts more potent antiplatelet effects when applied concomitantly with TxA2 and prostaglandin (PG)H2 receptor blockade and 2) whether these effects are mediated through redirection of PG endoperoxides toward the synthesis of antiplatelet PGs, such as PGI2 and PGE2. Thus, cyclic flow variations (CFVs), due to recurrent platelet aggregation, were initiated in the stenotic, endothelially injured carotid arteries of 39 rabbits. After 30 min of CFVs, the animals received: 1) SQ29548 (up to 0.6 mg/kg bolus + 0.2 mg kg-1 hr-1, n = 13), a TxA2/PGH2 receptor antagonist; 2) dazoxiben (up to 15 mg/kg bolus + 5 mg kg-1 hr-1, n = 13), a TxA2 synthase inhibitor and 3) picotamide (up to 20 mg/kg bolus + 20 mg kg-1 hr-1, n = 13), a drug with simultaneous TxA2 synthase and receptor blocking properties. CFVs were abolished in 6, 7, and 12 animals treated with SQ29548, dazoxiben, and picotamide, respectively (P < .01 for picotamide versus SQ29548 and dazoxiben). The animals in which CFVs were not abolished by SQ29548 or dazoxiben received the other drug at the same dose. CFVs were abolished by dazoxiben in five of seven rabbits that initially did not respond to SQ29548 and by SQ29548 in five of six animals that did not respond to dazoxiben. All animals that responded to the combination of SQ29548 and dazoxiben, as well as those that responded to picotamide, received increasing intravenous infusions of epinephrine to restore CFVs.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aspirin; Bridged Bicyclo Compounds, Heterocyclic; Drug Synergism; Epinephrine; Fatty Acids, Unsaturated; Female; Hydrazines; Imidazoles; Male; Phthalic Acids; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandins; Rabbits; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane-A Synthase