Characterization of a new compound, S35b, as a guanylate cyclase activator in human platelets.
The effects of S35b (4-methyl-3-phenyl sulfonylfuroxan), a new phenyl sulfonylfuroxan compound, were investigated on human platelets activated by different agonists. Platelet aggregation evoked by arachidonic acid (AA), collagen, ADP and thrombin was inhibited by the drug in a dose-dependent manner. S35b inhibited the AA-induced increase of cytosolic free Ca2+ ([Ca2+]i) and production of malondialdehyde. A primary action of the compound on cyclooxygenase is unlikely since: (1) U-46619 (15s-hydroxy-11,9-[epoxymethano]-prosta-5Z,13E-dienoic acid, a stable epoxymethano analog of prostaglandin H2) could not reverse the inhibitory effect of S35b on AA-induced aggregation and [Ca2+]i increase; (2) U-46619-induced aggregation and [Ca2+]i rise were inhibited by S35b; and (3) at high collagen concentrations platelet aggregation (which is unresponsive to aspirin under such conditions) was blocked by S35b as well. Thus the drug action is likely to be exerted at an early step of the platelet activation pathway. The elevation in the platelet cGMP level evoked by S35b in a time- and concentration-dependent manner can account for the inhibitory effect: increased cGMP levels could interfere, for instance, with G protein-phospholipase C coupling and subsequent phosphoinositide hydrolysis.
Dipartimento di Genetica, Biologia e Chimica Medica, University of Torino, Italy.
D
D
Ghigo
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R
Heller
R
R
Calvino
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P
Alessio
R
R
Fruttero
A
A
Gasco
A
A
Bosia
G
G
Pescarmona
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005663:Furans / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D010069:Oxadiazoles; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors / Q000494:pharmacology
D005663:Furans; D010069:Oxadiazoles; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D016718:Arachidonic Acid; C074047:4-methyl-3-(phenylsulfonyl)furoxan; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D006162:Guanylate Cyclase; D005978:Glutathione; D006152:Cyclic GMP; D002118:Calcium