Anti-platelet and anti-thrombotic effects of OP-41483·α-CD, a prostacyclin analogue, in experimental animals

Katsube, Nobuo; Sakaguchi, Kimiko; Fujitani, Buichi; Aishita, Hideki

doi:10.1016/0952-3278(93)90028-u

Cited by 8 publications

(3 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus PGH should lead to systemic effects such as the decrease in platelet aggregability as observed in an experimental study in rabbits after PGH liberation due to endothelin-1 injection [19], In that study ADP-induccd platelet aggrega bility appeared to be reduced and platelet cAMP was found to be increased. Another experimental study in rabbits demonstrated systemic attenuation of ADP and collageninduced platelet aggregation and platelet ad hesiveness to de-endothelialized blood vessels using the PGH analog OP-41483.a-CD [20]. We have used 5 pg ml-1 of collagen for the measurement of platelet aggregability and, therefore, the changes in impedance may re flect the number of platelets rather than mi nor changes in their aggregability.…”

Section: Discussionmentioning

confidence: 99%

Effects of Prostacyclin Substitution on Systemic Procoagulant Turnover and Cardiorespiratory Variables in Experimental Hypercoagulability

Scherer

Schmidt²,

Kox

et al. 1997

Pathophysiol Haemos Thromb

View full text Add to dashboard Cite

Endotoxin infusion (lipopolysaccharide from Escherichia coli 120 μg kg^–1 i.v.) was titrated to produce hypercoagulability in rabbits and the effects of prostacyclin (PGI₂) treatment (continuous infusion of 6 ng kg^–1 min^–1 i.v.) on coagulation variables, cardiorespiratory variables, and fibrin deposition in the microcirculation of vital organs were studied. PGI₂ infusion did not influence the concentration of soluble fibrin, throm-belastographic variables, or systemic platelet aggregability. Fibrin deposition in the microcirculation of the liver and the lungs was reduced to 50% of that observed in untreated animals (p < 0.01). The antiplatelet properties of PGI₂ were unable to reduce experimental endotoxin-induced systemic procoagulant turnover but improved organ perfusion during the initial phase of disseminated intravascular coagulation.

show abstract

Section: Discussionmentioning

confidence: 99%

Effects of Prostacyclin Substitution on Systemic Procoagulant Turnover and Cardiorespiratory Variables in Experimental Hypercoagulability

Scherer

Schmidt²,

Kox

et al. 1997

Pathophysiol Haemos Thromb

View full text Add to dashboard Cite

show abstract

“…Prostaglandin I 2 (IP) receptor agonists have demonstrated their potent antiplatelet and antithrombotic effects in experimental animals [10,11]. In addition, IP‐receptor agonists have been shown to reduce ischemic injury effectively in the acute myocardial infarction and stroke models [12–14].…”

mentioning

confidence: 99%

TRA-418, a novel compound having both thromboxane A2 receptor antagonistic and prostaglandin I2 receptor agonistic activities: its antiplatelet effects in human and animal platelets

Yamada

Miyamoto

Isogaya

et al. 2003

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

To cite this article: Yamada N, Miyamoto M, Isogaya M, Suzuki M, Ikezawa S, Ohno M, Otake A, Umemura K. TRA-418, a novel compound having both thromboxane A 2 receptor antagonistic and prostaglandin I 2 receptor agonistic activities: its antiplatelet effects in human and animal platelets. Summary. TRA-418 is a novel compound that has been found in our screening for compounds having both thromboxane A 2 (TP) receptor antagonistic and prostaglandin I 2 (IP) receptor agonistic activities. In the binding assays, TRA-418 showed a 10-fold higher af®nity to TP-receptors than IP-receptors. TRA-418 inhibited platelet aggregation induced by the TP-receptor agonist, U-46619 and by arachidonic acid at concentrations lower than those required for inhibition of ADP-induced aggregations. Furthermore, TRA-418 inhibited not only platelet aggregation induced by ADP alone, but also that induced by ADP in the presence of the TP-receptor antagonist, SQ-29548. When the IC 50 values of TRA-418 for platelet aggregation were estimated in platelet preparations from monkeys, dogs, cats, and rats using ADP and arachidonic acid as the platelet stimulating agents, it was found that the values estimated in monkey platelets were quite similar to those estimated in human platelets. In ex vivo platelet aggregation in monkeys, TRA-418 exhibited signi®cant inhibitory effects on arachidonic acidinduced aggregation in platelet preparations from monkeys treated at 3 mg kg min À1 or higher doses, where neither a signi®cant decrease in blood pressure nor a signi®cant increase in heart rate was observed. These results are consistent with the fact that TRA-418 has a relatively potent TP-receptor antagonistic activity together with a relatively weak IP-receptor agonistic activity. Prostaglandin I 2 (IP) receptor agonists have demonstrated their potent antiplatelet and antithrombotic effects in experimental animals [10,11]. In addition, IP-receptor agonists have been shown to reduce ischemic injury effectively in the acute myocardial infarction and stroke models [12±14]. Despite these useful properties as antithrombotic agents, the clinical application of IP-receptor agonists have been limited to pulmonary hypertension or moderate thrombotic disease such as arterial sclerosis obstruction because of their potent vasodilating effects [15,16].In this connection, a number of in vitro studies have reported that remarkable synergistic effects on human platelet aggregation can be observed with concomitant use of an IP-receptor agonist and a TP-receptor antagonist [17±19]. This ®nding suggests a useful application of an IP-receptor agonist in combination with a TP-receptor antagonist in vivo. In fact, we have con®rmed that concomitant use of the IP-receptor agonist, beraprost, at a limited dose effectively potentiates the antithrombotic effects of aspirin and other TP-receptor antagonists without any severe hypotension [20]. These results prompted us to screen compounds having a relatively potent TP-receptor antagonistic activity together with a relatively weak IP-...

show abstract

“…To date, several potential mechanisms for inhibition of platelet aggregation have been suggested. These include inhibition of adenosine receptors and thromboxane synthase (Martinez et al, 1992;Vittori et al, 1996), increased cGMP (Bassenge and Stewart, 1988), increased NO-releasing compounds (Civelli et al, 1994), and synthesis of prostacyclin analogues (Katsube et al, 1993). Depletion of glutathione (GSH) in platelets has been correlated with inhibition of platelet aggregation by several compounds.…”

mentioning

confidence: 99%

Association of Quinone-Induced Platelet Anti-Aggregation with Cytotoxicity

Kim

Lee²,

Lee³

et al. 2001

Toxicological Sciences

View full text Add to dashboard Cite

Various anti-platelet drugs, including quinones, are being investigated as potential treatments for cardiovascular disease because of their ability to prevent excessive platelet aggregation. In the present investigation 3 naphthoquinones (2,3-dimethoxy-1,4-naphthoquinone [DMNQ], menadione, and 1,4-naphthoquinone [4-NQ]) were compared for their abilities to inhibit platelet aggregation, deplete glutathione (GSH) and protein thiols, and cause cytotoxicity. Platelet-rich plasma, isolated from Sprague-Dawley rats, was used for all experiments. The relative potency of the 3 quinones to inhibit platelet aggregation, deplete intracellular GSH and protein thiols, and cause cytotoxicity was 1,4-NQ > menadione >> DMNQ. Experiments using 2 thiol-modifying agents, dithiothreitol (DTT) and 1-chloro-2,4-dintrobenzene (CDNB), confirmed the key roles for GSH in quinone-induced platelet anti-aggregation and for protein thiols in quinone-induced cytotoxicity. Furthermore, the anti-aggregative effects of a group of 12 additional quinone derivatives were positively correlated with their ability to cause platelet cytotoxicity. Quinones that had a weak anti-aggregative effect did not induce cytotoxicity (measured as LDH leakage), whereas quinones that had a potent anti-aggregative effect resulted in significant LDH leakage (84-96%). In one instance, however, p-chloranil demonstrated a potent anti-aggregative effect, but did not induce significant LDH leakage. This can be explained by the inability of p-chloranil to deplete protein thiols, even though intracellular GSH levels decreased rapidly. These results suggest that quinones that deplete GSH in platelets demonstrate a marked anti-aggregative effect. If this anti-aggregative effect is subsequently followed by depletion of protein thiols, cytotoxicity results.

show abstract

Anti-platelet and anti-thrombotic effects of OP-41483·α-CD, a prostacyclin analogue, in experimental animals

Cited by 8 publications

References 23 publications

Effects of Prostacyclin Substitution on Systemic Procoagulant Turnover and Cardiorespiratory Variables in Experimental Hypercoagulability

Effects of Prostacyclin Substitution on Systemic Procoagulant Turnover and Cardiorespiratory Variables in Experimental Hypercoagulability

TRA-418, a novel compound having both thromboxane A2 receptor antagonistic and prostaglandin I2 receptor agonistic activities: its antiplatelet effects in human and animal platelets

Association of Quinone-Induced Platelet Anti-Aggregation with Cytotoxicity

Contact Info

Product

Resources

About