Pharmacological studies on the mechanism of pressure inhibition of human platelet aggregation.
Platelet shape change and aggregation in response to adenosine diphosphate (ADP), epinephrine, collagen, thrombin, ristocetin, and phorbol myristate acetate (PMA) were studied photometrically at 1 ATA air and 35 ATA helium (He). Pressure inhibited aggregation in response to all agents except PMA. Dose response curves were constructed for ADP and epinephrine at 1 ATA and 35 ATA in the presence of acetylsalicyclic acid (ASA) 2.5 . 10(-4) M, which prevents aggregation due to released ADP and other granular constituents thus allowing study of the effect of the added stimulus alone. Pressure inhibited aggregation and yielded a shallower dose response curve. Pharmacologically, this would be interpreted as non-competitive blockade or reduced availability of receptors. All of the agonist agents inhibited by pressure are dependent upon extracellular Ca2+ for their function. All unmask other receptors (integrins) for adhesive proteins, principally fibrinogen. These integrins incorporate Ca2+ to become active. In contrast, PMA-induced aggregation, and shape change, are independent of extracellular Ca2+ and were unaffected by pressure. It is proposed that pressure may distort Ca2(+)-dependent surface glycoprotein receptors in a manner that reduces ligand affinity and hence inhibits platelet aggregation. The possibility that other calcium-mediated cell processes are affected by pressure cannot be discounted.
Philp
R B
RB
Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada.
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000328:Adult; D002118:Calcium / Q000302:isolation & purification / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D006023:Glycoproteins / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D016023:Integrins / Q000032:analysis / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; D011312:Pressure; D011971:Receptors, Immunologic / Q000187:drug effects* / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D006023:Glycoproteins; D016023:Integrins; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; D011971:Receptors, Immunologic; C032193:glycoprotein receptor GPIb-IX; D000255:Adenosine Triphosphate; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D004837:Epinephrine