• 1. Sinakos Z, Caen JP. Platelet aggregation in mammalians (human, rat, rabbit, guinea-pig, horse, dog). A comparative study. Thromb Diath Haemorrh 1969; 17: 99111.

    • Search Google Scholar
    • Export Citation
  • 2. Kerry R, Scrutton MC, Wallis RB. Mammalian platelet adrenoceptors. Br J Pharmacol 1984; 81: 91102.

  • 3. Takano S, Kimura J, Ono T. Inhibition of aggregation of rabbit and human platelets induced by adrenaline and 5-hydroxytryptamine by KB-R7943, a Na(+)/Ca(2+) exchange inhibitor. Br J Pharmacol 2001; 132: 13831388.

    • Search Google Scholar
    • Export Citation
  • 4. Grant JA, Scrutton MC. Novel alpha2-adrenoreceptors primarily responsible for inducing human platelet aggregation. Nature 1979; 277: 659661.

    • Search Google Scholar
    • Export Citation
  • 5. Hsu CY, Knapp DR, Halushka PV. The effects of alpha adrenergic agents on human platelet aggregation. J Pharmacol Exp Ther 1979; 208: 366370.

    • Search Google Scholar
    • Export Citation
  • 6. Lasch P, Jakobs KH. Agonistic and antagonistic effects of various alpha-adrenergic agonists in human platelets. Naunyn Schmiedebergs Arch Pharmacol 1979; 306: 119125.

    • Search Google Scholar
    • Export Citation
  • 7. Pinthong D, Songsermsakul P, Rattanachamnong P, et al. The effects of imidazoline agents on the aggregation of human platelets. J Pharm Pharmacol 2004; 56: 213220.

    • Search Google Scholar
    • Export Citation
  • 8. Motulsky HJ, Shattil SJ, Insel PA. Characterization of alpha 2-adrenergic receptors on human platelets using [3H]yohimbine. Biochem Biophys Res Commun 1980; 97: 15621570.

    • Search Google Scholar
    • Export Citation
  • 9. Shattil SJ, McDonough M, Turnbull J, et al. Characterization of alpha-adrenergic receptors in human platelets using [3H]clonidine. Mol Pharmacol 1981; 19: 179183.

    • Search Google Scholar
    • Export Citation
  • 10. Motulsky HJ, Insel PA. [3H]Dihydroergocryptine binding to alpha-adrenergic receptors of human platelets. A reassessment using the selective radioligands [3H]prazosin, [3H]yohimbine, and [3H]rauwolscine. Biochem Pharmacol 1982; 31: 25912597.

    • Search Google Scholar
    • Export Citation
  • 11. Lanza F, Cazenave JP. Studies of α2-adrenergic receptors of intact and functional washed human platelets by binding of 3H-dihydroergocryptine and 3H-yohimbine–correlation of 3H-yohimbine binding with the potentiation by adrenaline of ADP-induced aggregation. Thromb Haemost 1985; 54: 402408.

    • Search Google Scholar
    • Export Citation
  • 12. Ardlie NG, McGuiness JA, Garrett JJ. Effect on human platelets of catecholamines at levels achieved in the circulation. Atherosclerosis 1985; 58: 251259.

    • Search Google Scholar
    • Export Citation
  • 13. Hjemdahl P, Chronos NA, Wilson DJ, et al. Epinephrine sensitizes human platelets in vivo and in vitro as studied by fibrinogen binding and P-selectin expression. Arterioscler Thromb 1994; 14: 7784.

    • Search Google Scholar
    • Export Citation
  • 14. Goto S, Ikeda Y, Murata M, et al. Epinephrine augments von Willebrand factor-dependent shear-induced platelet aggregation. Circulation 1992; 86: 18591863.

    • Search Google Scholar
    • Export Citation
  • 15. Mustonen P, Lassila R. Epinephrine augments platelet recruitment to immobilized collagen in flowing blood—evidence for a von Willebrand factor-mediated mechanism. Thromb Haemost 1996; 75: 175181.

    • Search Google Scholar
    • Export Citation
  • 16. Stump DC, Macfarlane DE. Clonidine and para-aminoclonidine, partial agonists for the alpha2-adrenergic receptor on intact human blood platelets. J Lab Clin Med 1983; 102: 779787.

    • Search Google Scholar
    • Export Citation
  • 17. Banga HS, Simons ER, Brass LF, et al. Activation of phospholipases A and C in human platelets exposed to epinephrine: role of glycoproteins IIb/IIIa and dual role of epinephrine. Proc Natl Acad Sci U S A 1986; 83: 91979201.

    • Search Google Scholar
    • Export Citation
  • 18. Clare KA, Scrutton MC, Thompson NT. Effects of alpha 2-adrenoceptor agonists and of related compounds on aggregation of, and on adenylate cyclase activity in, human platelets. Br J Pharmacol 1984; 82: 467476.

    • Search Google Scholar
    • Export Citation
  • 19. Dahmani S, Paris A, Jannier V, et al. Dexmedetomidine increases hippocampal phosphorylated extracellular signal-regulated protein kinase 1 and 2 content by an alpha 2-adrenoceptor-independent mechanism: evidence for the involvement of imidazoline I1 receptors. Anesthesiology 2008; 108: 457466.

    • Search Google Scholar
    • Export Citation
  • 20. Ferry N, Henry D, Battais E, et al. Critical assessment of the platelet adenylate cyclase system as a potential model for testing alpha 2 adrenergic activity. Biochem Pharmacol 1986; 35: 15111516.

    • Search Google Scholar
    • Export Citation
  • 21. Atlas D, Burstein Y. Isolation and partial purification of a clonidine-displacing endogenous brain substance. Eur J Biochem 1984; 144: 287293.

    • Search Google Scholar
    • Export Citation
  • 22. Meeley MP, Ernsberger PR, Granata AR, et al. An endogenous clonidine-displacing substance from bovine brain: receptor binding and hypotensive actions in the ventrolateral medulla. Life Sci 1986; 38: 11191126.

    • Search Google Scholar
    • Export Citation
  • 23. Michel MC, Regan JW, Gerhardt MA, et al. Nonadrenergic [3H] idazoxan binding sites are physically distinct from alpha 2-adrenergic receptors. Mol Pharmacol 1990; 37: 6568.

    • Search Google Scholar
    • Export Citation
  • 24. Zonnenchein R, Diamant S, Atlas D. Imidazoline receptors in rat liver cells: a novel receptor or a subtype of alpha 2-adrenoceptors? Eur J Pharmacol 1990; 190: 203215.

    • Search Google Scholar
    • Export Citation
  • 25. Piletz JE, Sletten K. Nonadrenergic imidazoline binding sites on human platelets. J Pharmacol Exp Ther 1993; 267: 14931502.

  • 26. Piletz JE, Zhu H, Chikkala DN. Comparison of ligand binding affinities at human I1-imidazoline binding sites and the high affinity state of alpha-2 adrenoceptor subtypes. J Pharmacol Exp Ther 1996; 279: 694702.

    • Search Google Scholar
    • Export Citation
  • 27. García-Sevilla JA, Zis AP, Hollingsworth PJ, et al. Platelet alpha 2-adrenergic receptors in major depressive disorder. Binding of tritiated clonidine before and after tricyclic antidepressant drug treatment. Arch Gen Psychiatry 1981; 38: 13271333.

    • Search Google Scholar
    • Export Citation
  • 28. Piletz JE, Halaris A, Nelson J, et al. Platelet I1-imidazoline binding sites are elevated in depression but not generalized anxiety disorder. J Psychiatr Res 1996; 30: 147168.

    • Search Google Scholar
    • Export Citation
  • 29. Piletz JE, Halaris AE, Chikkala D, et al. Platelet I1-imidazoline binding sites are decreased by two dissimilar antidepressant agents in depressed patients. J Psychiatr Res 1996; 30: 169184.

    • Search Google Scholar
    • Export Citation
  • 30. Bondy GS, Gentry PA. Characterization of the normal bovine platelet aggregation response. Comp Biochem Physiol C 1989; 92: 6772.

  • 31. Soloviev MV, Okazaki Y, Harasaki H. Whole blood platelet aggregation in humans and animals: a comparative study. J Surg Res 1999; 82: 180187.

    • Search Google Scholar
    • Export Citation
  • 32. Suzuki T, Goryo M, Inanami O, et al. Inhibition of collagen-induced platelet aggregation in Japanese black cattle with inherited platelet disorder, Chediak-Higashi syndrome. J Vet Med Sci 1996; 58: 647654.

    • Search Google Scholar
    • Export Citation
  • 33. Zucker-Franklin D, Benson KA, Myers KM. Absence of a surface-connected canalicular system in bovine platelets. Blood 1985; 65: 241244.

    • Search Google Scholar
    • Export Citation
  • 34. White JG. The secretory pathway of bovine platelets. Blood 1987; 69: 878885.

  • 35. Meyers KM, Lindner C, Grant B. Characterization of the equine platelet aggregation response. Am J Vet Res 1979; 40: 260264.

  • 36. Segura D, Monreal L, Espada Y, et al. Assessment of a platelet function analyser in horses: reference range and influence of a platelet aggregation inhibitor. Vet J 2005; 170: 108112.

    • Search Google Scholar
    • Export Citation
  • 37. Billah MM, Lapetina EG. Platelet-activating factor stimulates metabolism of phosphoinositides in horse platelets: possible relationship to Ca2+ mobilization during stimulation. Proc Natl Acad Sci U S A 1983; 80: 965968.

    • Search Google Scholar
    • Export Citation
  • 38. Siess W, Lapetina EG. Properties and distribution of phosphatidylinositol-specific phospholipase C in human and horse platelets. Biochim Biophys Acta 1983; 752: 329338.

    • Search Google Scholar
    • Export Citation
  • 39. England GC, Clarke KW. Alpha 2 adrenoceptor agonists in the horse—a review. Br Vet J 1996; 152: 641657.

  • 40. Paddleford RR, Harvey RC. Alpha 2 agonists and antagonists. Vet Clin North Am Small Anim Pract 1999; 29: 737745.

  • 41. Livingston A. Pain and analgesia in domestic animals. Handb Exp Pharmacol 2010;(199):159189.

  • 42. Hikasa Y, Abe M, Satoh T, et al. Effects of imidazoline and nonimidazoline alpha-adrenergic agents on canine platelet aggregation. Pharmacology 1999; 58: 171182.

    • Search Google Scholar
    • Export Citation
  • 43. Eglen RM, Hudson AL, Kendall DA, et al. ‘Seeing through a glass darkly’: casting light on imidazoline ‘I’ sites. Trends Pharmacol Sci 1998; 19: 381390.

    • Search Google Scholar
    • Export Citation
  • 44. Newman-Tancredi A, Nicolas JP, Audinot V, et al. Actions of alpha2 adrenoceptor ligands at alpha2A and 5-HT1A receptors: the antagonist, atipamezole, and the agonist, dexmedetomidine, are highly selective for alpha2A adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol 1998; 358: 197206.

    • Search Google Scholar
    • Export Citation
  • 45. MacLennan SJ, Luong LA, Jasper JR, et al. Characterization of alpha 2-adrenoceptors mediating contraction of dog saphenous vein: identity with the human alpha 2A subtype. Br J Pharmacol 1997; 121: 17211729.

    • Search Google Scholar
    • Export Citation
  • 46. Garcia-Villar R, Toutain PL, Alvinerie M, et al. The pharmacokinetics of xylazine hydrochloride: an interspecific study. J Vet Pharmacol Ther 1981; 4: 8792.

    • Search Google Scholar
    • Export Citation
  • 47. Ranheim B, Arnemo JM, Ryeng KA, et al. A pharmacokinetic study including some relevant clinical effect of medetomidine and atipamezole in lactating dairy cows. J Vet Pharmacol Ther 1999; 22: 368373.

    • Search Google Scholar
    • Export Citation
  • 48. Guard CL, Schwark WS. Influences of yohimbine on xylazine-induced depression of central nervous, gastrointestinal and cardiovascular function in the calf. Cornell Vet 1984; 74: 312321.

    • Search Google Scholar
    • Export Citation
  • 49. Ruckebusch Y, Toutain PL. Specific antagonism of xylazine effects on reticulo-rumen motor function in cattle. Vet Med Rev 1984; 1: 312.

    • Search Google Scholar
    • Export Citation
  • 50. Hikasa Y, Takase K, Emi S, Ogasawara S. Antagonistic effects of alpha-adrenoceptor blocking agents on reticuloruminal hypomotility induced by xylazine in cattle. Can J Vet Res 1988; 52: 411415.

    • Search Google Scholar
    • Export Citation

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Effects of imidazoline and nonimidazoline alpha-adrenergic agents, including xylazine, medetomidine, yohimbine, tolazoline, and atipamezole, on aggregation of bovine and equine platelets

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  • 1 Department of Veterinary Internal Medicine, Faculty of Agriculture, Tottori University, Koyama-Minami 4-101, Tottori 680-8553, Japan.
  • | 2 Department of Veterinary Internal Medicine, Faculty of Agriculture, Tottori University, Koyama-Minami 4-101, Tottori 680-8553, Japan.
  • | 3 Department of Veterinary Internal Medicine, Faculty of Agriculture, Tottori University, Koyama-Minami 4-101, Tottori 680-8553, Japan.
  • | 4 Department of Veterinary Internal Medicine, Faculty of Agriculture, Tottori University, Koyama-Minami 4-101, Tottori 680-8553, Japan.

Abstract

Objective—To investigate effects of various imidazoline and nonimidazoline α-adrenergic agents on aggregation and antiaggregation of bovine and equine platelets.

Sample—Blood samples obtained from 8 healthy adult cattle and 16 healthy adult Thoroughbreds.

Procedures—Aggregation and antiaggregation effects of various imidazoline and nonimidazoline α-adrenergic agents on bovine and equine platelets were determined via a turbidimetric method. Collagen and ADP were used to initiate aggregation.

Results—Adrenaline, noradrenaline, or α-adrenoceptor agents alone did not induce changes in aggregation of bovine or equine platelets or potentiate ADP- or collagen-induced platelet aggregation. Adrenaline and the α2-adrenoceptor agonist clonidine had an inhibitory effect on ADP- and collagen-induced aggregation of bovine platelets. The α2-adrenoceptor antagonists phentolamine and yohimbine also inhibited collagen-induced aggregation of bovine platelets. Noradrenaline, other α-adrenoceptor agonists (xylazine, oxymetazoline, and medetomidine), and α-adrenoceptor antagonists (atipamezole, idazoxan, tolazoline, and prazosin) were less effective or completely ineffective in inhibiting ADP- and collagen-induced aggregation of bovine platelets. The imidazoline α2-adrenoceptor agonist oxymetazoline submaximally inhibited collagen-induced aggregation of equine platelets, and the α2-adrenoceptor antagonist idazoxan, along with phentolamine and yohimbine, also inhibited collagen-induced aggregation of equine platelets. The imidazoline compound antazoline inhibited both ADP- and collagen-induced aggregation of equine platelets.

Conclusions and Clinical Relevance—Several drugs had effects on aggregation of platelets of cattle and horses, and effective doses of ADP and collagen also differed between species. The α2-adrenoceptor agonists (xylazine and medetomidine) and antagonists (tolazoline and atipamezole) may be used by bovine and equine practitioners without concern for adverse effects on platelet function and hemostasis.

Abstract

Objective—To investigate effects of various imidazoline and nonimidazoline α-adrenergic agents on aggregation and antiaggregation of bovine and equine platelets.

Sample—Blood samples obtained from 8 healthy adult cattle and 16 healthy adult Thoroughbreds.

Procedures—Aggregation and antiaggregation effects of various imidazoline and nonimidazoline α-adrenergic agents on bovine and equine platelets were determined via a turbidimetric method. Collagen and ADP were used to initiate aggregation.

Results—Adrenaline, noradrenaline, or α-adrenoceptor agents alone did not induce changes in aggregation of bovine or equine platelets or potentiate ADP- or collagen-induced platelet aggregation. Adrenaline and the α2-adrenoceptor agonist clonidine had an inhibitory effect on ADP- and collagen-induced aggregation of bovine platelets. The α2-adrenoceptor antagonists phentolamine and yohimbine also inhibited collagen-induced aggregation of bovine platelets. Noradrenaline, other α-adrenoceptor agonists (xylazine, oxymetazoline, and medetomidine), and α-adrenoceptor antagonists (atipamezole, idazoxan, tolazoline, and prazosin) were less effective or completely ineffective in inhibiting ADP- and collagen-induced aggregation of bovine platelets. The imidazoline α2-adrenoceptor agonist oxymetazoline submaximally inhibited collagen-induced aggregation of equine platelets, and the α2-adrenoceptor antagonist idazoxan, along with phentolamine and yohimbine, also inhibited collagen-induced aggregation of equine platelets. The imidazoline compound antazoline inhibited both ADP- and collagen-induced aggregation of equine platelets.

Conclusions and Clinical Relevance—Several drugs had effects on aggregation of platelets of cattle and horses, and effective doses of ADP and collagen also differed between species. The α2-adrenoceptor agonists (xylazine and medetomidine) and antagonists (tolazoline and atipamezole) may be used by bovine and equine practitioners without concern for adverse effects on platelet function and hemostasis.

Contributor Notes

Dr. Hikasa was supported by a Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (grant No. 18580316) and by a Tottori University President Discretion Grant.

Address correspondence to Dr. Hikasa (hikasa@muses.tottori-u.ac.jp).