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Comparison of cardiac and hemodynamic effects of plateletactivating factor-acether and leukotriene D4 in anesthetized dogs

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Summary

In anesthetized dogs, platelet-activating factor-acether (PAF; 0.2–1.6 μg/kg) and leukotriene (LT) D4 (0.5, 1, and 3 μg/kg) were injected into the left circumflex (LCX) coronary artery. Cardiac and systemic hemodynamics, and the ECG were continuously recorded.PAF reduced cardiac performance and affected hemodynamics in a dose-dependent manner: At 7±3s, LCX flow initially increased by 40%–172% followed by a reduction of 43%–100%, and coronary diameter (measured with ultrasonic techniques) decreased by 4%–10%. Total and late coronary resistance increased. Left ventricular (LV) systolic pressure fell by 22%–48% and LV filling pressure decreased by 5 mm Hg after 0.8 μg/kg PAF. The LVdP/dtmax diminished by 38%–47%. Peak blood pressure reduction (35%) occurred 60s after PAF application and lasted for 1.4 min. Heart rate decreased by 10%–17% at peak PAF actions.

LTD 4 reduced LCX flow by 38%–87%, and coronary diameter by 5%–12%, returning to control value within 3.4 min. Blood pressure, LV pressure, and LVdP/dtmax decreased while heart rate and LV filling pressure increased. ST segments and R-wave voltage of the ECG in lead II elevated after either compound although the effects were more pronounced after LTD4.

Indomethacin (5 mg/kg i.v.) pretreatment did not affect LTD4 actions on cardiohemodynamics, but the putative leukotriene antagonist FPL 55712 (1 mg/kg i.v.) blocked LTD4 actions on the heart and circulation. PAF influences on LCX flow were modified by indomethacin: initial flow rose by 250%, and coronary diameter fell by 12%, followed by sustained flow and diameter reduction during the second phase on PAF action. FPL 55712 did not affect the early flow increase after PAF but attenuated the later flow reduction, which was blocked by indomethacin.

Thus, PAF and LTD4 may have effects on canine conduit arterics besides their effects on the coronary resistance vessels. The circulatory derangement after PAF may be aggravated by additional eicosanoid release. PAF and LTD4 may be involved in coronary blood flow variations and negative inotropy accompanying anaphylactic disease state.

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References

  1. Benveniste J, Henson PM, Cochrane CG (1972) Leukocyte-dependent histamine release from rabbit platelets. The role of IgE, basophils, and a platelet-activating factor. J Exp Med 136:1356–1377

    PubMed  Google Scholar 

  2. Benveniste J, Roubin R, Chignard M, Jouvin-Marche E, Le Couedic JP (1982) Release of platelet-activating factor (PAF-acether) and 2-lyso PAF-acether from three cell types. Agents Actions 12:711–713

    PubMed  Google Scholar 

  3. Mencia-Huerta JM, Benveniste J (1979) Platelet-activating factor and macrophages. I. Evidence for the release from rat and mouse peritoncal macrophages and not from mastocytes. Eur J Immunol 9:409–415

    PubMed  Google Scholar 

  4. Demopoulos CA, Pinckard RN, Hanahan DJ (1979) Platelet-activating factor. Evidence for 1-0-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine as the active component (a new class of lipid chemical mediators). J Biol Chem 254:9355–9358

    PubMed  Google Scholar 

  5. McManus LM, Hanahan DJ, Pinckard RN (1981) Human platelet stimulation by acetyl glyceryl ether phosphorylcholine. J Clin Invest 67:903–906

    PubMed  Google Scholar 

  6. Lotner GZ, Lynch JM, Betz SJ, Henson PM (1980) Human neutrophil derived platelet activating factor. J Immunol 124:676–684

    PubMed  Google Scholar 

  7. Chignard M, Le Couedic JP, Tence M, Vargaftig BB, Benveniste J (1979) The role of platelet-activating factor in platelet aggregation. Nature 279:799–800

    PubMed  Google Scholar 

  8. Vargaftig BB, Lefort J, Chignard M, Benveniste J (1980) Platelet-activating factor induces a platelet-dependent bronchoconstriction unrelated to the formation of prostaglandin derivatives. Eur J Pharmacol 65:185–192

    PubMed  Google Scholar 

  9. Benveniste J, Chignard M (1985) A role for PAF-acether (platelet-activating factor) in platelet-dependent vascular diseases. Circulation 72:713–717

    PubMed  Google Scholar 

  10. McManus LM, Pinckard RN, Fitzpatrick FA, O'Rourke RA, Crawford MH, Hanahan DJ (1981) Acetyl glyceryl ether phosphorylcholine. Intravascular alterations following intravenous infusion into the baboon. Lab Invest 45:303–307

    PubMed  Google Scholar 

  11. Hanahan DJ, Demopoulos CA, Liehr J, Pinckard RN (1980) Identification of platelet activating factor isolated from rabbit basophils as acetyl glyceryl ether phosphorylcholine. J Biol Chem 255:5514–5516

    PubMed  Google Scholar 

  12. Voelkel NF, Worthen S, Reeves JT, Henson PM, Murphy RC (1982) Nonimmunological production of leukotrienes induced by platelet-activating factor. Science 218:286–288

    PubMed  Google Scholar 

  13. Lefer AM, Müller HF, Smith JB (1984) Pathophysiological mechanisms of sudden death induced by platelet activating factor. Br J Pharmac 83:125–130

    Google Scholar 

  14. Feuerstein G, Boyd LM, Ezra D, Goldstein RE (1984) Effect of platelet-activating factor on coronary circulation of the domestic pig. Am J Physiol 246:H466-H471

    PubMed  Google Scholar 

  15. Lewis RA, Austen KF, Drazen JM, Clark DA, Marfat A, Corey EJ (1980) Slow reacting substances of anaphylaxis: identification of leukotrienes C-1 and D from human and rat sources. Proc Natl Acad Sci USA 77:3710–3714

    PubMed  Google Scholar 

  16. Feuerstein G (1984) Leukotrienes and the cardiovascular system. Prostaglandins 27:781–802

    PubMed  Google Scholar 

  17. Fiedler VB, Mardin M, Abram TS (1984) Leukotriene D4-induced vasoconstriction of coronary arteries in anaesthetized dogs. Eur Heart J 5:253–260

    PubMed  Google Scholar 

  18. Fiedler VB, Mardin M, Gardiner PJ, Abram TS (1985) Leukotrienes on porcine hemodynamics and prostanoid release. Int J Cardiol 8:451–463

    PubMed  Google Scholar 

  19. Ertl G, Fiedler VB, Bauer B, Schwarzenberger P, Kochsiek K (1986) The effects of nifedipine and indomethacin on leukotriene C4- and D4-induced coronary constriction at normal and reduced coronary perfusion in dogs. J Cardiovasc Pharmacol 8:1078–1085

    PubMed  Google Scholar 

  20. Vane JR (1971) Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature New Biol 231:232–235

    PubMed  Google Scholar 

  21. Augstein J, Farmer JB, Lee TB, Sheard P, Tattersall ML (1973) Selective inhibitor of slow reacting substance of anaphylaxis. Nature New Biol 245:215–217

    PubMed  Google Scholar 

  22. Holtz J, Held W, Sommer O, Kühne G, Bassenge E (1982) Ergonovine-induced constrictions of epicardial coronary arteries in conscious dogs: α-adrenoceptors are not involved. Basic Res Cardiol 77:278–291

    PubMed  Google Scholar 

  23. Vatner SF, Hintze TH, Macho P (1982) Regulations of large coronary arteries by β-adrenergic mechanisms in the conscious dog. Circ Res 51:56–66

    PubMed  Google Scholar 

  24. Michelassi F, Landa L, Hill RD, Lowenstein E, Watkins WD, Petkau AJ, Zapol WM (1982) Leukotriene D4: a potent coronary artery vasoconstrictor associated with impaired ventricular contractions. Science 217:841–843

    PubMed  Google Scholar 

  25. Bessin P, Bonnet J, Apffel D, Soulard C, Desgroux L, Pelas I, Benveniste J (1983) Acute circulatory collapse caused by platelet-activating factor (PAF-acether) in dogs. Eur J Pharmacol 86:403–413

    PubMed  Google Scholar 

  26. Apprill P, Schmitz JM, Campbell WB, Tilton G, Ashton J, Raheja S, Buja LM, Willerson JT (1985) Cyclic blood flow variations induced by platelet-activating factor in stenosed canine coronary arteries despite inhibition of thromboxane synthetase, serotonin receptors, and α-adrenergic receptors. Circulation 72:397–405

    PubMed  Google Scholar 

  27. Smith KA, Prewitt RL, Byers LW, Muirhead EE (1981) Analogs of phosphatidylcholine: α-adrenergic antagonists from the renal medulla. Hypertension 3:460–470

    PubMed  Google Scholar 

  28. Muirhead EE, Byers LW, Desiderio D, Smith KA, Prewitt RL, Brooks B (1981) Alkyl ether analogs of phosphatidylcholine are orally active in hypertensive rabbits. Hypertension 3 Suppl I:I107-I111

    PubMed  Google Scholar 

  29. McIntyre TM, Zimmerman GA, Satoh K, Prescott SM (1985) Cultured endothelial cells synthesize both platelet-activating factor and prostacyclin in response to histamine, bradykinin, and adenosine triphosphate. J Clin Invest 76:271–280

    PubMed  Google Scholar 

  30. Bonnet J, Thibaudeau D, Bessin P (1983) Dependency of the PAF-acether induced bronchospasm on the lipoxygenase pathway in the guinea-pig. Prostaglandins 26:457–466

    PubMed  Google Scholar 

  31. Greenwald JE, Bianchine JR, Wong LK (1979) The production of the arachidonate metabolite HETE in vascular tissue. Nature 281:588–589

    PubMed  Google Scholar 

  32. Piper PJ, Letts LG, Galton SA (1983) Generation of a leukotriene-like substance from porcine vascular and other tissues. Prostaglandins 25:591–599

    PubMed  Google Scholar 

  33. Chacos N, Falck JR, Wixtrom C, Capdevila (1982) Novel epoxides formed during the liver cytochrome P-450 oxidation of arachidonic acid. Biochem Biophys Res Commun 104:916–922

    PubMed  Google Scholar 

  34. Furchgott RF (1983) Role of endothelium in response of vascular smooth muscle. Circ Res 53:557–573

    PubMed  Google Scholar 

  35. Tomoike H, Ootsubo H, Sakai K, Kikuchi Y, Nakamura M (1981) Continuous measurement of coronary artery diameter in situ. Am J Physiol 240:H73-H79

    PubMed  Google Scholar 

  36. Gow BS, Schonfeld D, Patel DJ (1974) The dynamic clastic properties of the canine left circumflex coronary artery. J Biomechanics 7:389–395

    Google Scholar 

  37. Gould KL, Lipscomb K, Hamilton GW (1974) Physiologic basis for assessing critical coronary stenosis. Am J Cardiol 33:87–94

    PubMed  Google Scholar 

  38. Burke JA, Levi R, Guo ZG, Corey EJ (1982) Leukotrienes C4, D4 and E4: effects on human and guinea-pig cardiac preparationsin vitro. J Pharmacol Exp Ther 221:235–241

    PubMed  Google Scholar 

  39. Hattori Y, Levi R (1984) Negative inotropic effect of leukotrienes: leukotrienes C4 and D4 inhibit calcium-dependent contractile responses in potassium-depolarized guinea-pig myocardium. J Pharmacol Exp Ther 230:646–651

    PubMed  Google Scholar 

  40. David D, Naito M, Michelson E, Watanabe Y, Chen CC, Morganroth J, Shaffenburg M, Blenko T (1982) Intramyocardial conduction: a major determinant of R-wave amplitude during acute myocardial ischemia. Circulation 65:161–167

    PubMed  Google Scholar 

  41. Hellstrom HR (1984) Leukotriene-induced coronary spasm. Am J Cardiol 53:653 (Letter to the Editor)

    PubMed  Google Scholar 

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Author notes

  1. V. B. Fiedler

    Present address: Department of Pharmacology, Bayer AG, P.O. Box 101709, D-5600, Wuppertal 1 (Elberfeld), FRG

Authors and Affiliations

  1. Stoke Court Research Department, Miles Laboratories Ltd., Slough, UK

    V. B. Fiedler & M. Mardin

  2. Department of Pharmacology, Bayer AG, P.O. Box 101709, D-5600, Wuppertal 1 (Elberfeld), FRG

    T. S. Abram

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  2. M. Mardin
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  3. T. S. Abram
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Fiedler, V.B., Mardin, M. & Abram, T.S. Comparison of cardiac and hemodynamic effects of plateletactivating factor-acether and leukotriene D4 in anesthetized dogs. Basic Res Cardiol 82, 197–208 (1987). https://doi.org/10.1007/BF01907067

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  • DOI: https://doi.org/10.1007/BF01907067

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