Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1995 May;115(1):210–216. doi: 10.1111/j.1476-5381.1995.tb16341.x

Intrinsic activity of the non-prostanoid thromboxane A2 receptor antagonist, daltroban (BM 13,505), in human platelets in vitro and in the rat vasculature in vivo

Frédéric Bertolino, Jean-Pierre Valentin, Myriam Maffre, Françoise Grelac, Anne-Marie Bessac, Jacques Maclouf, André Delhon, Sylviane Lévy-Toledano, Jean-François Patoiseau, Francis C Colpaert, Gareth W John
PMCID: PMC1908744  PMID: 7647979

Abstract

1 We evaluated the effects of daltroban on (i) human platelet shape change and aggregation in vitro, and (ii) mean systemic and pulmonary arterial pressures (MAP and MPAP, respectively) as well as haematocrit, in anaesthetized, open-chest Sprague-Dawley rats, compared with those of a chemically distinct prostanoid thromboxane A2 (TxA2) receptor antagonist, SQ 29,548, and agonist, U-46619.

2 In human platelets in vitro, daltroban (10 nM—100 μM; n = 6 per group) concentration-dependently induced shape change, attaining at 50 μM, a maximum amplitude of 0.83±0.09 mV representing 46.4±4.8% of that evoked by U-46619 (1.78±0.20 mV at 0.2 μM; n = 9); and inhibited U-46619-induced platelet aggregation with an IC50 of 77 (41–161)nM. SQ 29,548 (10 nM—100 μM; n = 6 per group) failed to evoke any platelet shape change, but potently inhibited U-46619-induced platelet aggregation with an IC50<10 nM.

3 In anaesthetized rats in vivo, daltroban (10–2500 μg kg-1, i.v. infused over 2 min; n = 4–8 per group) produced a bell-shaped dose-response curve for MPAP and haematocrit, and evoked maximal increases of 12.7±2.1 mmHg and 5.8±1.5% at 80 μg kg-1 (n = 6) and 630 μg kg-1 (n = 8), respectively (both P<0.05) with ED50S of 20 (16–29) and 217 (129–331) μg kg-1, respectively. By comparison, U-46619 (0.16–20 μg kg-1, i.v.), induced dose-dependent increases in MPAP and haematocrit (25.4±1.0 mmHg and 16.1±2.9% at the highest dose; n = 12, both P<0.01), with ED50S of 1.8 (1.3–2.5) and 3.9 (3.5–5.4) μg kg-1, respectively. Daltroban dose-dependently increased MAP with a maximum amplitude of 42.2±4.4 mmHg at a dose of 80 μg kg-1 [ED50 = 94 (64–125) μg kg-1], similar to that induced by U-46619 (41.3±9.6 mmHg) at a dose of 0.63 μg kg-1 [ED50 = 0.22 (0.13–0.24) μg kg-1]. SQ 29,548 (10–2500 μg kg-1, i.v.; n = 4 per group) failed to modify significantly any of these parameters.

4 Our results clearly demonstrate that daltroban, in a similar manner to the TxA2 analogue, U-46619, but unlike the TxA2 receptor antagonist, SQ 29,548, exhibits significant intrinsic activity in human platelets in vitro and in the rat vasculature in vivo, possibly through TxA2 receptor activation.

Keywords: Arterial pressure, daltroban, human platelet aggregation, shape change, pulmonary hypertension, thromboxane A2, TxA2/PGH2 receptors

Full text

PDF
210

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barlow R. B. Problems associated with the partiality of a partial agonist. Trends Pharmacol Sci. 1994 Sep;15(9):320–322. doi: 10.1016/0165-6147(94)90021-3. [DOI] [PubMed] [Google Scholar]
  2. Bertolino F., Valentin J. P., Maffre M., Bessac A. M., John G. W. TxA2 receptor activation elicits organ-specific increases in microvascular permeability in the rat. Am J Physiol. 1995 Feb;268(2 Pt 2):R366–R374. doi: 10.1152/ajpregu.1995.268.2.R366. [DOI] [PubMed] [Google Scholar]
  3. Bertolino F., Valentin J. P., Maffre M., Jover B., Bessac A. M., John G. W. Prevention of thromboxane A2 receptor-mediated pulmonary hypertension by a nonpeptide angiotensin II type 1 receptor antagonist. J Pharmacol Exp Ther. 1994 Feb;268(2):747–752. [PubMed] [Google Scholar]
  4. Brittain R. T., Boutal L., Carter M. C., Coleman R. A., Collington E. W., Geisow H. P., Hallett P., Hornby E. J., Humphrey P. P., Jack D. AH23848: a thromboxane receptor-blocking drug that can clarify the pathophysiologic role of thromboxane A2. Circulation. 1985 Dec;72(6):1208–1218. doi: 10.1161/01.cir.72.6.1208. [DOI] [PubMed] [Google Scholar]
  5. Darius H., Smith J. B., Lefer A. M. Beneficial effects of a new potent and specific thromboxane receptor antagonist (SQ-29,548) in vitro and in vivo. J Pharmacol Exp Ther. 1985 Nov;235(2):274–281. [PubMed] [Google Scholar]
  6. Davies R., Slater J. D., Forsling M. L., Payne N. The response of arginine vasopressin and plasma renin to postural change in normal man, with observations on syncope. Clin Sci Mol Med. 1976 Sep;51(3):267–274. doi: 10.1042/cs0510267. [DOI] [PubMed] [Google Scholar]
  7. Dorn G. W., 2nd, DeJesus A. Human platelet aggregation and shape change are coupled to separate thromboxane A2-prostaglandin H2 receptors. Am J Physiol. 1991 Feb;260(2 Pt 2):H327–H334. doi: 10.1152/ajpheart.1991.260.2.H327. [DOI] [PubMed] [Google Scholar]
  8. Dorn G. W., 2nd Distinct platelet thromboxane A2/prostaglandin H2 receptor subtypes. A radioligand binding study of human platelets. J Clin Invest. 1989 Dec;84(6):1883–1891. doi: 10.1172/JCI114375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Farrukh I. S., Michael J. R., Summer W. R., Adkinson N. F., Jr, Gurtner G. H. Thromboxane-induced pulmonary vasoconstriction: involvement of calcium. J Appl Physiol (1985) 1985 Jan;58(1):34–44. doi: 10.1152/jappl.1985.58.1.34. [DOI] [PubMed] [Google Scholar]
  10. Furci L., Fitzgerald D. J., Fitzgerald G. A. Heterogeneity of prostaglandin H2/thromboxane A2 receptors: distinct subtypes mediate vascular smooth muscle contraction and platelet aggregation. J Pharmacol Exp Ther. 1991 Jul 1;258(1):74–81. [PubMed] [Google Scholar]
  11. Hall S. E. Thromboxane A2 receptor antagonists. Med Res Rev. 1991 Sep;11(5):503–579. doi: 10.1002/med.2610110504. [DOI] [PubMed] [Google Scholar]
  12. Hanasaki K., Nagasaki T., Arita H. Characterization of platelet thromboxane A2/prostaglandin H2 receptor by a novel thromboxane receptor antagonist, [3H]S-145. Biochem Pharmacol. 1989 Jun 15;38(12):2007–2017. doi: 10.1016/0006-2952(89)90501-7. [DOI] [PubMed] [Google Scholar]
  13. Hui S. G., Ogle C. W. Thromboxane-mimetic U46619 causes depressor responses in anaesthetized rats. J Pharm Pharmacol. 1991 Aug;43(8):592–593. doi: 10.1111/j.2042-7158.1991.tb03543.x. [DOI] [PubMed] [Google Scholar]
  14. Janssens W. J., Deckmyn H., Gresele P., Vermylen J. BM 13.177 selectively inhibits endoperoxide analogue induced vascular contractions. Arch Int Pharmacodyn Ther. 1985 Jul;276(1):28–34. [PubMed] [Google Scholar]
  15. Kakushi H., Shike T., Hayasaki Y., Arita H., Uchida K. [Effect of (+)-S-145 calcium salt dihydrate, an orally active antagonist of the thromboxane A2/prostaglandin endoperoxide receptor, on platelet aggregation]. Nihon Yakurigaku Zasshi. 1991 Aug;98(2):113–120. doi: 10.1254/fpj.98.2_113. [DOI] [PubMed] [Google Scholar]
  16. Liel N., Mais D. E., Halushka P. V. Desensitization of platelet thromboxane A2/prostaglandin H2 receptors by the mimetic U46619. J Pharmacol Exp Ther. 1988 Dec;247(3):1133–1138. [PubMed] [Google Scholar]
  17. Lyons D., Fowler G., Petrie J. C., Webster J. The haemodynamic effects of GR 32191, a thromboxane A2 receptor antagonist, in patients with renal artery stenosis and hypertension. Br J Clin Pharmacol. 1993 Sep;36(3):271–273. doi: 10.1111/j.1365-2125.1993.tb04229.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lévy-Toledano S., Bredoux R., Rendu F., Jeanneau C., Savariau E., Dassin E. Isolement et fonctions des plaquettes I. A partir de plasma riche en plaquettes. Comparaison de deux méthodes: filtration sur gel et centrifugation sur gradient d'albumine. II. Nouvelle méthode à partir de sang total: centrifugation sur gradients de métrizamide. Nouv Rev Fr Hematol. 1976;16(3):367–380. [PubMed] [Google Scholar]
  19. Miki I., Kase H., Ishii A. Differences in activities of thromboxane A2 receptor antagonists in smooth muscle cells. Eur J Pharmacol. 1992 Oct 1;227(2):199–204. doi: 10.1016/0922-4106(92)90128-i. [DOI] [PubMed] [Google Scholar]
  20. Murray R., FitzGerald G. A. Regulation of thromboxane receptor activation in human platelets. Proc Natl Acad Sci U S A. 1989 Jan;86(1):124–128. doi: 10.1073/pnas.86.1.124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Nakajima M., Ueda M. Actions of a novel thromboxane A2-receptor antagonist, S-145, on isolated monkey and cat arteries. J Cardiovasc Pharmacol. 1989 Sep;14(3):502–509. doi: 10.1097/00005344-198909000-00022. [DOI] [PubMed] [Google Scholar]
  22. Noguchi K., Ojiri Y., Chibana T., Matsuzaki T., Sakanashi M. Regional vascular responses to thromboxane A2 analogue and their blockade with vapiprost, a selective thromboxane receptor blocking drug, in anesthetized dogs. Jpn J Pharmacol. 1992 Dec;60(4):341–348. doi: 10.1254/jjp.60.341. [DOI] [PubMed] [Google Scholar]
  23. Nossaman B. D., McMahon T. J., Ragheb M. S., Ibrahim I. N., Babycos C. R., Hood J. S., Kadowitz P. J. Blockade of thromboxane/endoperoxide receptor-mediated responses in the pulmonary vascular bed of the cat by sulotroban. Eur J Pharmacol. 1992 Mar 17;213(1):1–7. doi: 10.1016/0014-2999(92)90225-s. [DOI] [PubMed] [Google Scholar]
  24. Ogletree M. L., Harris D. N., Greenberg R., Haslanger M. F., Nakane M. Pharmacological actions of SQ 29,548, a novel selective thromboxane antagonist. J Pharmacol Exp Ther. 1985 Aug;234(2):435–441. [PubMed] [Google Scholar]
  25. Ogletree M. L., Harris D. N., Schumacher W. A., Webb M. L., Misra R. N. Pharmacological profile of BMS 180,291: a potent, long-acting, orally active thromboxane A2/prostaglandin endoperoxide receptor antagonist. J Pharmacol Exp Ther. 1993 Feb;264(2):570–578. [PubMed] [Google Scholar]
  26. Otani K., Shima N., Doteuchi M. [Pharmacological actions of S-145, a novel thromboxane A2 antagonist, in various smooth muscles]. Nihon Yakurigaku Zasshi. 1989 Nov;94(5):319–328. doi: 10.1254/fpj.94.319. [DOI] [PubMed] [Google Scholar]
  27. Pliska V. Models to explain dose-response relationships that exhibit a downturn phase. Trends Pharmacol Sci. 1994 Jun;15(6):178–181. doi: 10.1016/0165-6147(94)90145-7. [DOI] [PubMed] [Google Scholar]
  28. Ritter J. M., Barrow S. E., Doktor H. S., Stratton P. D., Edwards J. S., Henry J. A., Gould S. Thromboxane A2 receptor antagonism and synthase inhibition in essential hypertension. Hypertension. 1993 Aug;22(2):197–203. doi: 10.1161/01.hyp.22.2.197. [DOI] [PubMed] [Google Scholar]
  29. Schumacher W. A., Steinbacher T. E., Youssef S., Ogletree M. L. Antiplatelet activity of the long-acting thromboxane receptor antagonist BMS 180,291 in monkeys. Prostaglandins. 1992 Nov;44(5):389–397. doi: 10.1016/0090-6980(92)90135-g. [DOI] [PubMed] [Google Scholar]
  30. Takahara K., Murray R., FitzGerald G. A., Fitzgerald D. J. The response to thromboxane A2 analogues in human platelets. Discrimination of two binding sites linked to distinct effector systems. J Biol Chem. 1990 Apr 25;265(12):6836–6844. [PubMed] [Google Scholar]
  31. Terres W., Kupper W., Hamm C. W., Bleifeld W. Resting myocardial ischemia after intravenous infusion of BM 13.177 (sulotroban), a thromboxane receptor antagonist. Thromb Res. 1987 Dec 1;48(5):577–583. doi: 10.1016/0049-3848(87)90389-6. [DOI] [PubMed] [Google Scholar]
  32. White G. M., Broska P. Vesicles and bulla in an infant. Bullous varicella (chicken pox complicated by bullous impetigo). Arch Dermatol. 1994 Jan;130(1):107–110. doi: 10.1001/archderm.130.1.107. [DOI] [PubMed] [Google Scholar]
  33. Yoshimura K., Tod M. L., Pier K. G., Rubin L. J. Role of venoconstriction in thromboxane-induced pulmonary hypertension and edema in lambs. J Appl Physiol (1985) 1989 Feb;66(2):929–935. doi: 10.1152/jappl.1989.66.2.929. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES