Inhibition of ADP-Induced Human Platelet Aggregation by Guanidine Thiols--a New Class of Guanylate Cyclase Activators and NO-Synthase Substrates

N. N. Belushkina¹ and I. S. Severina^1,2

¹Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Pogodinskaya ul. 10, Moscow, 119832 Russia; fax: (7-095) 245-08-57.

²To whom correspondence should be addressed.

Submitted June 18, 1996; revision submitted June 26, 1996.

Antiaggregatory properties of guanidine thiol derivatives with regard to their effect on human platelet guanylate cyclase activity were studied. Guanidine thiols contain in the same molecule both guanidine and thiol groups which act, respectively, as donor and acceptor of nitric oxide (NO). Three synthesized guanidine thiol derivatives--mercaptoethylguanidine (MEG), mercaptoethylguanidine disulfide (MEG disulfide), and S-methyl mercaptoethylguanidine (mercaptoethylguanidine methylated sulfhydryl group, S-methyl MEG)--were examined. All tested compounds appeared to be substrates of NO-synthase and human platelet guanylate cyclase activators. The stimulatory effects of MEG and MEG disulfide on guanylate cyclase activity were, respectively, 2- and 4-fold higher than that of L-arginine. Stimulation of the enzyme by S-methyl MEG is of the same order as that by L-arginine. In line with the intensity of guanylate cyclase activation were the antiaggregatory properties of the tested compounds. Increase in intensity of guanylate cyclase activation in the series compounds--S-methyl MEG < MEG < MEG disulfide--reveals complete correlation with the increasing ability of these compounds to inhibit ADP-induced platelets aggregation and to accelerate their spontaneous disaggregation. The mechanism of directed enhancement of the antiaggregatory properties of the tested compounds depending on their chemical structure and the intensity of guanylate cyclase activation is discussed.

KEY WORDS: guanylate cyclase, platelets, aggregation, guanidine thiols.

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