Skip to main content
SpringerLink
Log in

Actions of the novel thromboxane A2 antagonists, ONO-1270 and ONO-3708, on smooth muscle cells of the guinea-pig basilar artery

  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Summary

The effects of the novel thromboxane A2 (TXA2) antagonists. ONO-1270 and ONO-3708, on the electrical and mechanical responses evoked by various agents, and in particular 9, 11-epithio-11, 12-methano-thromboxane A2 (STA2), were investigated in the guinea-pig artery. STA2 (up to 0.3 μM), and ONO-1270 and ONO-3708 (up to 1.0 μM) dit not modify the membrane potential in smooth muscle cells. Perivascular nerve stimulation induced an excitatory junction potential (e.j.p.), and with frequencies over 0.25 Hz, depression of e.j.ps occurred. STA2 (0.1 μM) and both ONO-1270 and ONO-3708 had no effect on these electrical events. STA2 (over 0.1 μM) produced phasic and tonic contractile responses, in a concentration dependent manner. Both ONO-1270 and ONO-3708 competitively inhibited the phasic contraction induced by STA2 as estimated from parallel shifts in the dose-response curve, and from the Lineweaver-Burk and Schild plots (the PA2 values were 8.22 for ONO-1270 and 8.70 for ONO-3708), but both agents inhibited non-competitively the PGF2α -induced contraction. ONO-1270 and ONO-3708 (up to 0.1 μM) had no effect on contractions induced by K+ and caffeine, but did slightly inhibited contractions induced by 5-hydroxytryptamine (5-HT). Following application of indomethacin, neither agent modified the 5-HT-induced contraction. In Ca2+-free solution, 10 nM STA2 produced a phasic but not a tonic contractile response. ONO-1270 and ONO-3708 (over 1 nM) inhibited this phasic contractile response. We conclude that ONO-1270 and ONO-3708 possess the properties of potent and selective antagonists for the TXA2 (STA2)-receptor in smooth muscle cells of the guinea-pig basilar artery.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abe Y, Tomita T (1968) Cable properties of smooth muscle. J Physiol 196:87–100

    Google Scholar 

  • Armstrong RA, Jones RL, Peesapati V, Will SG, Wilson NH (1985) Competitive antagonism at thromboxane receptors in human platelets. Br J Pharmacol 84:595–607

    Google Scholar 

  • Arunlakshana O, Schild HO (1959) Some quantitative uses of drug antagonist. Br J Pharmacol 14:48–58

    Google Scholar 

  • Berridge MJ, Irvine FF (1984) Inositol trisphosphate, a novel second messenger in cellular signal transduction. Nature 312:315–321

    Google Scholar 

  • Bolton T (1979) Mechanisms of actions of transmitters and other substances on smooth muscles. Physiol Rev 59:606–718

    Google Scholar 

  • Burk SE, Lefer, AM, Nicolaou KC, Smith, GM, Brayansmith J (1983) Responsiveness of platelets and coronary arteries from different species to synthetic thromboxane and prostaglandin peroxide analogues. Br J Pharmacol 78:287–292

    Google Scholar 

  • Coleman RA, Humphrey PPA, Kennedy J, Levy GP, Lumley P (1981) Comparison of the actions of U-46, 619, a prostaglandin H2 analogue, with those of prostaglandin H2 and thromboxane A2 on some isolated smooth muscle preparations. Br J Pharmacol 73:773–778

    Google Scholar 

  • Ellis EF, Neis AS, Oates JA (1977) Cerebral arterial smooth muscle contraction by thromboxane A2. Stroke 8:480–483

    Google Scholar 

  • Greenberg R, Steinbacher TE, Harris DN, Haslanger MF (1984) Thromboxane receptor antagonist properties of SQ 27427 in the anesthetized guinea pig. Eur J Pharmacol 103:19–24

    Google Scholar 

  • Hagen AA, Gerber JN, Sweeley CC, White RP, Robertson JT (1977) Levels and disappearance of prostaglandin F2α in cerebral spinal fluid: A clinical and experimental study. Stroke 8:672–675

    Google Scholar 

  • Hagen AA, White RP, Robertson JT (1979) Synthesis of prostaglandins and thromboxane B2 by cerebral arteries. Stroke 10:306–309

    Google Scholar 

  • Halushka PV, Knapp DR, Blair IA, Macdermol J (1984) Iodination of the W-side chain of a thromboxane-receptor antagonist for radioligand binding. Biochem Soc Trans 12: 690P

  • Hamberg M, Svensson J, Samuelsson B (1975) A new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci USA 72:2994–2998

    Google Scholar 

  • Harris DN Greenberg R, Phillips MB, Michel IM, Goldenberg JH, Haslanger MF, Steinbacher TE (1984) Effects of SQ 27427, a thromboxane A2 receptor antagonist, in the human platelet and isolated smooth muscle. Eur J Pharmacol 103:9–18

    Google Scholar 

  • Hashimoto T, Hirata M, Itoh T, Kanmura Y, Kuriyama H (1986) Inositol 1,4,5-triphosphate activates pharmacomechanical coupling in smooth muscle of the rabbit mesenteric artery. J Physiol 370:605–618

    Google Scholar 

  • Ito Y, Tajima K (1981) Actions of indomethacin and prostaglandins on neuro-effector transmission in the dog trachea. J Physiol 319:379–392

    Google Scholar 

  • Ito T, Ogawa K, Sakai K, Watanabe J, Satake T, Kayama N, Hiraku S, Naito J (1983) Effects of a selective inhibitor of thromboxane synthetase (OKY-1581) in human. Adv Prostagladin Thromboxane Leukotriene Res 11:245–251

    Google Scholar 

  • Itoh T, Kuriyama H, Suzuki H (1981) Excitation-contraction coupling in smooth muscle cells of the guinea-pig mesenteric artery. J Physiol 321:513–535

    Google Scholar 

  • Jones RL, Wilson NH, Armstrong RA, Peesapati V, Smith GM (1983) Effects of thomboxane antagonist EP 045 on platelet aggregation. Adv Prostaglandin Thromboxane Leukotriene Res, 11:345–350

    Google Scholar 

  • Katsura M, Miyamoto T, Hamanaka N, Kondo K, Terada T, Ohgaki Y, Kawasaki A, Tsuboshima M (1983) In vitro and in vivo effects of new powerful thromboxane antagonists (3-alkylamino pinane derivatives) Adv Prostaglandin Thromboxane Leukotriene Res 11:351–357

    Google Scholar 

  • Kawahara Y, Yamanishi J, Furuta Y, Kaibuchi K, Takai Y, Fukuzaki H (1983) Elevation of cytoplasmic free calcium concentration by stable thromboxane A2 analogue in human platelets. Biochem Biophys Res Commun 117:663–669

    Google Scholar 

  • Kennedy I, Coleman RA, Humphery PPA, Levy GP, Lumley P (1982) Studies on the characterization of prostanoid receptors, a proposed classification. Prostaglandins 24:667–690

    Google Scholar 

  • Kuriyama H, Ito Y, Suzuki H, Kitamura K, Itoh T (1982) Factors modifying contraction-relaxation cycle in vascular smooth muscles. Am J Physiol 243:H641-H662

    Google Scholar 

  • Le Breton GC, Venton DL, Enke SE, Halushka PV (1979) 13-Azaprostanoic acid: A specific antagonist of the human blood platelet thromboxane/endoperoxide receptor. Proc Natl Acad Sci USA 76:4097–4101

    Google Scholar 

  • Lefer AM, Smith EF, Araki H, Smith JB, Aharony D, Claremon DA, Magolda RL, Nicolaou KC (1980) Dissociation of vasoconstrictor and platelet aggregatory activities of thromboxane by carbocyclic thromboxane A2, a stable analogue of thromboxane A2. Proc Natl Acad Sci USA 77:1706–1710

    Google Scholar 

  • Makita Y (1983) Effects of prostaglandin I2 and carbocyclic thromboxane A2 on smooth muscle cells and neuromuscular transmission in the guinea-pig mesenteric artery. Br J Pharmacol 78:517–527

    Google Scholar 

  • Makita T, Kanmura T, Itoh T, Suzuki H, Kuriyama H (1983) Effects of nifedipine derivatives on smooth muscle cell and neuromuscular transmission in the rabbit mesenteric artery. Naunyn-Schmiedeberg's Arch Pharmacol 324:302–312

    Google Scholar 

  • Ogletree ML, Harris DN, Greenberg R, Haslanger MF, Nakane M (1985) Pharmacological actions of SQ29, 548, a novel selective thromboxane antagonist. J Pharmacol Exp Ther 234:435–441

    Google Scholar 

  • Pickard JD, Walker V (1984) Current concepts of the role of prostaglandins and other eicosanoids in acute cerebrovascular disease. In: Mackenze ET, Seylaz J, Bes A (eds) Neurotransmitters and the cerebral circulation, LERS, vol 2. Raven Press, New York, pp 191–218

    Google Scholar 

  • Randal MJ, Parry MJ, Hawkeswood E, Cross PE, Dickinson RP (1981) UK-37248 a novel selective thromboxane synthetase inhibitor with platelet anti-aggregatory and antithrombotic activity. Thromb Res 23:145–162

    Google Scholar 

  • Sasaguri T, Hirata M, Kuriyama H (1985) Dependence on Ca2+ of the activities of phosphatidylinositol 4,5-bisphosphate phosphatase and inositol 1,4,5-trisphosphate phosphatase in smooth muscles of the porcine coronary artery. Biochem J 231:497–503

    Google Scholar 

  • Sasaki T, Wakai S, Asano T, Takakura K, Sano K (1982) Prevention of cerebral vasospasm after SAH with a thromboxane synthetase inhibitor, OKY-1581. J Neurosurg 57:74–82

    Google Scholar 

  • Suematsu A, Hirata M, Hashimoto K, Kuriyama H (1984) Inositol 1,4,5-trisphosphate releases Ca2+ from intracellular store sites in skinned single cells of the porcine coronary artery. Biochem Biophysic Res Comm 120:481–485

    Google Scholar 

  • Tani E, Maeda Y, Fukumori T, Nakano M, Kochi N, Morimura T, Yokota M, Matsumoto T (1984) Effect of selective inhibitors of thromboxane A2 synthetase on cerebral vasospasm after early surgery. J Neurosurg 61:24–29

    Google Scholar 

  • Towart R, Perzborn E (1981) Nimodipine inhibits carbocylic thromboxane-induced contractions of cerebral arteries. Eur J Pharmacol 69:213–215

    Google Scholar 

  • Wolfe LS (1982) Eicosanoids: prostaglandins, thromboxanes, leukotrienes, and other derivatives of Carbon-20 unsaturated fatty acid. J Neurochem 38:1–14

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, Kyushu University, 812, Fukuoka, Japan

    Masahiko Fujioka, Tetsuhiko Nagao & Hirosi Kuriyama

Authors
  1. Masahiko Fujioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tetsuhiko Nagao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hirosi Kuriyama
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fujioka, M., Nagao, T. & Kuriyama, H. Actions of the novel thromboxane A2 antagonists, ONO-1270 and ONO-3708, on smooth muscle cells of the guinea-pig basilar artery. Naunyn-Schmiedeberg's Arch. Pharmacol. 334, 468–474 (1986). https://doi.org/10.1007/BF00569388

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00569388

Key words

Search

Navigation