Abstract
The present study was undertaken to characterize the antiplatelet and antithrombotic effects of BM-573 [N-tert-butyl-N′-[2-(4′-methylphenylamino)-5-nitrobenzenesulfonyl]urea], an original combined thromboxane receptor antagonist and thromboxane synthase inhibitor in rats, and to determine its effects on mice bleeding time. Intraperitoneal injection of a single dose of 5 mg/kg BM-573 to rats inhibited U-46619 (9,11-dideoxy-9,11-methanoepoxy-prostaglandin F2)-induced washed platelet aggregation 30 min and 1, 2, and 4 h after drug administration with a maximum antiplatelet effect observed after 1 and 2 h. In a rat model of thrombosis induced by ferric chloride application on the abdominal aorta, BM-573 significantly reduced the thrombus weight by 92.53, 80.20, 64.75, and 18.21% at doses of 5, 2, 0.5, and 0.2 mg/kg, respectively. Time to occlusion of abdominal aorta in the BM-573-treated group (41.50 ± 5.21 min) was significantly prolonged compared with the vehicle-treated rats (16.16 ± 0.79 min). Like furegrelate, seratrodast, and acetylsalicylic acid, BM-573 did not affect the tail bleeding time induced by tail transection in mice compared with vehicle-treated mice. Moreover, BM-573, a close derivative of the loop diuretic torasemide, failed to induce a significant increase in diuresis in rat and did not produce a decrease in blood glucose concentration as observed with the sulfonylurea glibenclamide. In conclusion, we have demonstrated that the nitrobenzenic sulfonylurea BM-573, an original combined thromboxane receptor antagonist and thromboxane synthase inhibitor, is a potent antithrombotic agent that does not affect bleeding time. Moreover, BM-573 lost the diuretic property of torasemide and has no impact on glycemia.
Footnotes
-
This work was supported by Fonds de la Recherche Scientifique Médicale Grant 3.4.505.01.F. Vincent Tchana-Sato is a Research Fellow of the Fonds National de la Recherche Scientifique (FNRS), and Laurence de Leval is a Research Associate of the FNRS.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
DOI: 10.1124/jpet.103.063610.
-
ABBREVIATIONS: COX, cyclooxygenase; TXA2, thromboxane A2; ASA, aspirin; PG, prostaglandin; PGH2, prostaglandin endoperoxide H2; TP, TXA2 receptor; PGI2, prostacyclin; BM-573, N-tert-butyl-N′-[2-(4′-methylphenylamino)-5-nitrobenzenesulfonyl]urea; U-46619, 9,11-dideoxy-9,11-methanoepoxy-prostaglandin F2; BT, bleeding time; HPLC, high-performance liquid chromatography; TTO, time to occlusion; TXRA, thromboxane receptor antagonist; TXSI, thromboxane synthase inhibitor; Z-335, [2-(4-chlorophenylsulfonylaminomethyl)indan-5-yl]acetate; BMS-180291, [(+)1S-(1α,2α,3α,4α)]-2-[[3-[4-[(n-pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid].
- Received November 28, 2003.
- Accepted January 16, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|