Evidence for a Direct Effect on Vascular Permeability of Platelet-Activating Factor Induced Hemoconcentration in the Guinea Pig

Summary

The ability of synthetic platelet-activating factor (PAF) given intravenously to produce loss (extravasation) of protein rich plasma (resulting in hemoconcentration) has been examined using guinea pigs. Hemoconcentration induced by PAF was not prevented by prior administration of inhibitors of thromboxane synthetase (7-(3-pyridyl)heptanoic acid, UK-37,248-01), PGI₂, aspirin, indomethacin or antiserum induced thrombocytopenia. Calcium channel blockers (nifedipine, verapamil, diethyl-amino octyltrimethoxybenzoate, diltiazem), antihistamines (pyrilamine, cimetidine, diphenhydramine), or the elevator of cAMP IBMX were ineffective in blocking PAF-induced hemoconcentration. In contrast, CV-3988, reported to be a specific antagonist to PAF, was 98% inhibitory of PAF extravasation when given i. a. at 3.5 mg/kg. The ED₅₀ was 0.14 mg/kg I. A. and 15 mg/kg p.o. against 75 ng/kg PAF. These data suggest that PAF-induced hemoconcentration involves receptor mediated alterations of vascular permeability that are inhibited by a specific PAF antagonist.

Keywords

Platelet-activating factor - Guinea pig - Extravasation - Endothelial permeability - Thromboxane inhibitors - Calcium channel blockers - Antihistamines

• References

• 1 Bjork J, Lindbom L, Gerdin B, Smedegard G, Arfors KE, Benveniste J. PAF-acether (platelet activating factor) increases microvascular permeability and affects endothelium-granulocyte interaction in microvascular beds. Acta Physiol Scand 1983; 119: 305-311
• 2 Humphrey DM, Hanahan DJ, Pinckard RN. Induction of leukocytic infiltrates in rabbit skin by acetyl glyceryl ether phosphorylcholine. Lab Invest 1982; 47: 227-229
• 3 Wedmore CV, Williams TJ. Platelet-activating factor (PAF), a secretory product of polymorphonuclear leukocytes, increases vascular permeability in rabbit skin. Br J Pharmacol 1981; 74: 916P-921P
• 4 McManus LM, Hanahan DJ, Demopoulos CA, Pinckard RN. Pathobiology of the intravenous infusion of acetyl glyceryl ether phosphorylcholine (AGEPC), a synthetic platelet activating factor (PAF), in the rabbit. J Immunol 1980; 124: 2919-2936
• 5 McManus LM, Pinckard RN, Fitzpatrick FA, O’Rourke RA, Crawford MH, Hanahan DJ. Acetyl glyceryl ether phosphorylcholine. Intravascular alterations following intravenous infusion into the baboon. Lab Invest 1981; 45: 303-309
• 6 Humphrey DM, McManus LM, Hanahan DJ, Pinckard RN. Morphological basis of increased vascular permeability induced by acetyl glyceryl ether phosphorylcholine. Lab Invest 1984; 50: 16-24
• 7 Mojarad M, Hamasaki Y, Said SI. Platelet-activating factor increases pulmonary microvascular permeability and induces pulmonary edema. Bull Eur Physiopathol Respir 1983; 19: 253-261
• 8 Bessin P, Bonnet J, Apffel D, Soulard C, Desgroux L, Pelas I, Benveniste J. Acute circulatory collapse caused by platelet-activating factor (PAF-acether) in dogs. Eur J Pharmacol 1984; 86: 403-408
• 9 Heffner JE, Shoemaker SA, Canham EM, Patel M, McMurtry IF, Morris HG, Repine JE. Platelet-induced pulmonary hypertension and edema. A mechanism involving acetyl glyceryl ether phosphorylcholine and thromboxane A2 Chest 1983; 83: 78-85
• 10 Humphrey DM, McManus LM, Satouchi K, Hanahan DJ, Pinckard RN. Vasoactive properties of acetyl glyceryl ether phosphorylcholine and analogues. Lab Invest 1982; 46: 422-431
• 11 Morley J, Page CP, Paul W. Inflammatory actions of platelet activating factor (PAF-acether) in guinea pig skin. Br J Pharmacol 1983; 80: 503-511
• 12 Pirotzky E, Page CP, Roubin R, Pfister A, Paul W, Bonnet J, Benveniste J. PAF-acether-induced plasma exudation is independent of platelets and neutrophils in rat skin. Microcirc Endo Lymphol 1984; 1: 107-114
• 13 Handley DA, Van Valen RG, Melden MK, Saunders RN. Evaluation of dose and route effects of platelet activating factor-induced extravasation in the guinea pig. Thromb Haemostas 1984; 52: 34-36
• 14 Tanouchi T, Kawamura M, Ohyama I, Kajiwara I, Iguchi Y, Okada T, Miyamoto T, Taniguchi K, Hayashi M, Iizuka K, Nakazawa M. Highly selective inhibitors of thromboxane synthetase. 2. Pyridine derivatives. J Med Chem 1981; 24: 1149-1156
• 15 Terashita Z, Taushima S, Yoshioka Y, Nomura H, Inada Y, Nishikawa K. CV-3988 - A specific antagonist of platelet-activating factor (PAF). Life Sci 1983; 32: 1975-1981
• 16 Heymans F, Michel E, Borrel M-C, Wichrowski B, Godfroid J-J, Convert O, Coeffier E, Tence M, Benveniste J. New total synthesis and high resolution ¹H-NMR spectrum of platelet-activating factor, its enantiomer and racemic mixtures. Biochim Biophys Acta 1981; 666: 230-241
• 17 O’Flaherty JT, Wykle RL, Miller CH, Lewis JC, Waite M, Bass DA, McCall CE, DeChatelet LR. 1-0-alkyl-sn-glyceryl-3-phosphoryl-choline: A novel class of neutrophil stimulants. Am J Pathol 1981; 103: 70-81
• 18 Cazenave J, Benveniste JH, Mustard JF. Aggregation of rabbit platelets by platelet-activating factor is independent of the release reaction of the arachidonate pathway and inhibited by membrane-active drugs. Lab Invest 1979; 41: 275-282
• 19 Valone FH. Isolation of a platelet membrane protein which binds the platelet-activating factor 1-0-hexadecyl-2-acetyl-sn-glycero-3-phos-phorylcholine. Immunol 1984; 52: 169-174
• 20 Blank ML, Cress EA, Whittle T, Snyder F. In vivo metabolism of a new class of biologically active phospholipids: 1-alkyl-2-acetyl-src-glycero-3-phosphocholine, a platelet-activating hypotensive phospholipid. Life Sci 1981; 29: 769-775
• 21 Lartigue-Mattei C, Godeneche D, Chabard J-L, Berger J-A. Pharmacokinetic study of PAF-acether. Preliminary results after intravenous administration of a 3H-labelled product to the rabbit. Agents Actions 1982; 15: 703-704
• 22 Camussi G, Tetta C, Bussolino F. Inhibitory effect of prostacyclin (PGI₂) on neutropenia induced by intravenous injection of platelet-activating factor (PAF) in the rabbit. Prostaglandins 1983; 25: 343-349
• 23 Bussolino F, Camussi G. Effect of prostacyclin on platelet-activating factor induced rabbit platelet aggregation. Prostaglandins 1980; 20: 781-785
• 24 Bjork J, Smedegard G. Acute microvascular effects of PAF-acether, as studied by intravital microscopy. Eur J Pharmacol 1983; 96: 87-91
• 25 Westwick J, Marks G, Powling MJ, Kakkar VV. Diltiazem, the cardiac channel calcium antagonist, is a potent, selective and competitive inhibitor of platelet activating factor on human platelets. J Pharmacologie 1983; 14: 62-68
• 26 Myers A, Ramey E, Ramwell P. Glucocorticoid protection against PAF-acether toxicity in mice. Br J Pharmacol 1983; 79: 595-598
• 27 Vargaftig BB, Chignard M, Lefort J, Benveniste J. Platelet-tissue interaction: role of platelet-activating factor (PAF-acether). Agents Actions 1980; 10: 502-505
• 28 Shaw JO, Pinckard RN, Ferrigni KS, McManus LM, Hanahan DJ. Activation of human neutrophils with 1-0 hexadecyl/octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (platelet-activating factor). J Immunol 1981; 127: 1250-1261
• 29 Chilton FH, O’Flaherty JT, Walsh CE, Thomas MJ, Wykle RL, DeChalete LR, Waite M. Platelet-activating factor: stimulation of the lipoxygenase pathway in polymorphonuclear leukocytes by 1-0-alkyl-2-0-acetyl-sn-glycerol-3-phosphocholine. J Biol Chem 1982; 257: 5402-5409
• 30 Kamitani T, Katamoto M, Tatsumi M, Katsata K, Ono T, Kikuchi H, Kumada S. Mechanism(s) of the hypotensive effect of synthetic 1-0-octadecyl-2-0-acetyl-glycero-3-phosphorylcholine. Eur J Pharmacol 1984; 98: 357-364
• 31 Tanaka S, Kasuya Y, Masuda Y, Shigenobu K. Studies of the hypotensive effects of platelet activating factor (PAF, l-0-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine) in rats, guinea pigs, rabbits and dogs. J Pharm Dyn 1983; 6: 866-874
• 32 Stimler NP, O’Flaherty JT. Spasmogenic properties of platelet-activating factor. Evidence for a direct mechanism in the contractile response of pulmonary tissues. Am J Pathol 1983; 113: 75-83
• 33 Apprill P, Schmitz J, Campbell W, Buja LM, Ashton J, Willerson J. Platelet activating factor causes cyclic flow variations despite thromboxane synthetase inhibition and pharmacologic antagonism of alpha2 adrenergic receptors and serotonin receptors. Fed Proc 1984; 43: 51
• 34 Terashita Z-I, Imura Y, Nishikawa K, Sumida S. Is platelet activating factor (PAF) a mediator of endotoxin shock?. Eur J Pharmacol 1985; 109: 257-261