TiPS-March 1991[Vol.121

87

20 Si& E. and Baur, R. (1988) koc. Natl Acad. Sri. USA 85,6192-61% 21 Moran, 0. and Dascal, N. (1989) Mol. BrainRcs. 5, 193-202 22 Harrison, N. L. and Lambert, N. A. ~m%E6C. (1990)NcWophnrfIracolog!j (1989) J. Physiol.bndon) 4l2,17P 23 Gyenes, M., Farrant, M. and Farb, D. H. 18 &skr, F. M. t-tnl. (1989) BrairrRes.499, (1988) Mol. Pharmacol.34,7l9-723 24 Chen, Q. X., Steker, A., Kay, A. R. and w-38 19 SkJaer, A., Kay, A. R. and Wong, Wong, R. K. S. (1990) J. Physiol.fLotrdortJ R. K. S. (1988) Science 241,339341 4m,207-221

15 Huganir, R. L. and Greengard, P. (1987) TrendsPhamrrcof.sci. a, 472477 16 Cash, D. J. and Subbardo, K. (1987) Biockafstry 26,7x&7562 17 Pa&t, K. D., Hoffer,6. J. and Bickford-

ModWon of platelet aggregation by an L-arginine-nitric oxide pathway The demonstration of the synthesis of nitric oxide from the

amino acid L-arglnine by vascular endothell~ cells has led to the elucidation of the importance of the L-arginlnenitrlc oxide pathway as a regulator of cell function in a number of tissues’. Nitric oxide not only mediates the control of vascular tone and blood pressure, but is also a neurotransmltter or neuromodulator in the central and peripheral nervous systems. These effects are mediated via activation of the soluble guanylyl cyclase, leading to elevation of intracellular levels of CCMP. Present evidence indicates that in all these cases nitric oxide is acting primarily as a mechanism for cell to cell communication. In these systems nitric oxide is formed by an enzyme that is soluble, constitutive, NADPH- and Caz+-dependent and is released in response to receptor or mechanical stimulation. Nitric oxide is also formed in other cells, including macrophages”, by an enzyme that is not constitutive but is inducible by cytokines, is Ca’+independent and requires NADPH and tetrahydrobiopterin. Nitric oxide released by macrophages acts as a cytotoxic molecule for bacteria, Parasites and tumour cells’. It has recently been shown that platelets produce nitric oxide from L-arginine by a Ca*+-dependent mechanism and that this pathway plays a ptory role in platelet function” . Previous studies had shown that platelet aggregation is inhibited by nitric oxide through activation of the soluble guanylyl cyclasa and elevation of intraplatelet cCMP’“*‘l. However, it has long been known that agents that induce

platelet aggregation,

such as collagen, also cause a transient rise in intraplatelet ISMP”*~. Furthermore, L-ar@nine was also known to inhibit platelet aggregation” by a mechanism unknown at that time. Recent studies have shown that the platelet aggregation induced by collagen was inhibited by Larginine, which concomitantly potentiated the rise in cGMPs. This enhancement of the rise in cGMP levels was observed only in stimulated but not in resting platelets. Furthermore, N”-monomethyl+arginine (L-NMMA), an inhibitor of the formation of nitric oxide from L-argininers*r6, potentiated the collagen-induced aggre gatlon and prevented the concomitant rise in CGMP. L-NMMA itself also prevented the effects of L-arginine on platelet aggregation and on the increase in cCMP levelss. All these data are consistent with the activation of an Larginin+nitric oxide pathway in platelets during aggregation.

25 fknovic. J.. Strasser, R, Caron, M. and Lefkowitr, R. (1986) Proc.Natf Acad. Sri. USA 83,2797-2801

HB: K(2-(mothylamino]-ethyl)-Sisoquinoionesulfonamide IBEX:isobutylmethylxanthine PICII? protein kinase inhibitor peptide WE N-(6aminohexyl)-k-lnaphthalenesulfonamidehydtochloride

,i;;;;c~~h~~$$; T; conclusion. The antiaggregating effect of L-arginine was potentiated by a subthreshold concentration of prostacyclin and by the selective CGMP phosphodiesterase inhibitor zprinast (M&B2294@, agents known to potentiate

the

antiaggregating

effect of nitric oxideriJ7. In addition, other inhibitors of nitric oxide synthase, such as l@nitroL-arginine and N-iminoethyl-Lomithine, similarly; potentiated platelet aggregation . Nitric oxide synthase in platelet cytosol is NADPH- and Ca*+dependent, like that in endothelium and brain’s*‘9, and shows a profile of inhibition by L-arginine analogues similar to that of the endothelial enzymdo. It is likely that the rise in intraplatelet Ca*’ levels that follows platelet stimulation by aggregating agents leads to activation of the Ca*‘-dependent nitric oxide synthase which acts as a local downregulatory mechanism. The t-arginine-nitric oxide pathway is activated t-y several aggregating agents, and the

TiPS - March 2992 [Vol. 221

8s potency of r.-argiaccording to the proaggregatov agent used. It is most active against collagen and arachidonic acid and less active against ADP, thrombin and calcimycin (~23187). This is also the rank

antiaggregatov

nine

varies

order for the inhibitory effects of nitric oxide on these agents”. The

relatively low efficacy of L-arf$nine and nitric oxide as inhibitors of thrombin- or calcimycin-induced aggregation may reflect the fact that these compounds activate multiple pathways of aggregation”, while the formation of &MP may preferentially inhibit only the phospholipase AZ-controlled pathway of platelet aggregationz2. The existence in platelets of the t-arginine-nitric oxide pathway

indicates that platelet function could be modulated by nitric oxide synthesized by a constitutive nitric oxide synthase in both platelets and in !he vascular endothelium”. In pathological conditions, platelet aggregation may also be modified as a result of the expression of an inducible nitric oxide synthase and subsequent release of nitric oxide from macrophagesz4, vascular endothelium= and the vascular smooth muscle laye?425. Whether pharmacological

regulation

offers an alternative antithrombotic strategy remains to be estab-

lished. Finally, the formation of nitric oxide from r.-arginine in piatelets further illustrates the widespread distibution of this pathway and the biological relevance of nitric oxide as the endogenous stimulator of the soluble guanylyl cyclase. The demonstration of the existence of the L-arginine-nitric oxide pathway in platelets playing an autoregulatory role suggests that rises in cCMP observed in some other cells may also be mediated by nitric oxide released by the same cell as a mechanism of

autocrine regulation. MAREK W. RADOMSKI, M. ]. PALMER AND

SALVADOR

COUrk

MDNCADA

Rtsturch .&bomkwics, Bfrkrnh~lm BR3 36s. UK.

7% Wkome

tiibba, J. B., Jr, Taintor, R. R., Vavrin.2. and Rachlin, E. M. (19%) Bkhtm. Biophys. Rer. Commun. 157,874 3 Matietta, M. A., Yoon. P. S., lyengar. R., Leaf, C. D. and Wishnok, J. 5. (19BB) Biochemistry 27, 87&??711 4 Stuehr, D., Cross, 5.. Sakuma, 1.. Levi, R. and Nathan, C. (19B9) J. Exp. Med. 169, loll-1020 5 Billiar, T. R. et al. (1989) J. Exp. Med. 169, 1467-1472 6 Amber, 1. 1.. Hibba, J. 8.. Jr, Taintor. R. R. and Vavrin, Z. (1988) J. Leukocyte Biol. 43,187-192 7 Hibbs, J. B., Jr et PI. (1990) in Nitric Oxide from L-Agininr: A Biorcgrdatory System (Moncada, S. and H&a, E. A., eds), PP. lB9-223, Eiaevier 8 Radomski, M. W., Palmer, R. M. J. and Moncada, S. (1990) Pmr. Nat/ Acad. Sci. USA B7,5193-5197 9 Radomski, M. W., Palmer, R. M. J. and Moncada, S. (1990) Br. J. Pharmocol. 101, 325-328 10 Mellion, 8. T. et al. (1981) Blood 57, 946-955 11 Radomski, M. W., Palmer, R. M. J. and Moncads, S. (1987) Br. I. Pharmncol. 92, IL&187 12 Haslam, R., Davidaon, M. M., Davies, T., Lynham, J. A. and McUcna&an, M. D. (1978) Adv. Cyclic Nucleofide Res. 9,533-552 13 Steer, 1. M. and Salzmann, E. N. (lsa0)

Adv.Cyclic Nuclevti~ Res. 12.71-92 14 Caren, R. and Co&o, 1. (1977) Proc.Sot. Exp. Biol. Med. 143.1067-1@71 1.5 Hibbs, J. 8.. Vavrin, Z. and Taintor, R. R. (19B7)1. Immune/. 138, -565 16 Palmer, R M. J., Reea, D. D., Aahton, D. S. and Moncada, S. (19&Q B&hem. Biophys.Rcs. Commur. 153,X!%-1256 17 Radomaki, M. W., Palmer, R. hi. J. and Moncada, S. (19B7) Br. 1. Pharmacol.92, 63%646 18 Palmer, R. M. J. and Moncada, S. (IsaS) Biochcm. Biophys. Rcs. Commun. 158, 34B-352 19 Knowtea, R. C., Palacioa, hi., Pakner, R. M. J. and Moneada, S. (19B9) Pwc. N4tl And. Sci. USA B6,5159-5162 2O Reea, D. D.. Palmer, R M. J.. Schulz, R. Hodaon, H. F. and Moncada, S. (1990) Br. 1. Phmmrcol. 101,746952 21 S&s, W. (19B9) Physfot. ReV. 69,58_17B 22 Sane, D. C., Bielawaka, A., Greenberg. C. S. and Hammun, Y. A. (19B9) Bio165. them. Biophys. Res. Commm. 708-714 23 R4domski,M. W., Palmer, R. M. J. and Moncada, S. (1990) Proc. Natf Acad. Sri. USA B7,1OM3-la%&7 24 Knowlea, R. C., Salter, hi., Bmoka, S. 1. and Monc4d4,S. (19Xt) B&chew. Biophys. Res. Cornmtm. 172,1fM2-lMB 25 Rees, D. D., Cekk, S., PM, R M. J. and Monad4, S. (1990) B&cheat. Biophys. Rea.Common.173.S41-547

Chemical warfare: a rdtion

statement

by the

InternationalUnionoi Toxicology

of

nitric oxide synthesis in platelets is possible, and whether this

RICHARD

2

f,ongky

References 1 MonKada. j., Palmer. R. M. I. and Higgs. E. A. (19B9)Bi&rr. Pha;cnncol. 38,17O9-1715

We live in a world that is increasingly dangerous and threatening. The ongoing war in the Middle East, as well as numerous wars in recent history, have caused concern that there may be an increasing danger of chemical warfare. As toxicohrgists, we present a unified position against such warfare - as an international scientific union of 28 national and multinational toxicological societies worldwide. Chemical warfare may cause death and suffering, without relief, to large populations. Although sophisticated chemical warfare may not cause immediate harm, i.e. there may be no apparent signs of initial suffering, it can produce long term damage that can affect en&e populations. The public, always keenly aware of the potential for chemical catastrophe in the industrial sector, is now also extremely alarmed at the prospect of chemical warfare.

In the event of chemical war fare, antidotes and anhlpniste to toxicity are extremely difffcult to use when extensive populations are exposed. It is encouraging that in the Second World War, those countries that axuld have utilizedchemfcalwarfarewereresponsible enough not to do so. With these points in mind, IUTOX reafffrrns unwaveringly that toxicology must remain a science for the we&being of humanity and that the improvement in the quality of life must be the criterion for the responsible use of chemicals. We, therefore, emphatically condemn any kind of chemical warfare. We encourage all toxic& ogiets to: (1) abstain front fnitiatives that may harm human befngs; and (2) disseminate awamneaa of the danger that such activities involve. ??Next month’s issue includes a review on Toxicology of mustard gas’ by Uri Wormser.

Modulation of platelet aggregation by an L-arginine-nitric oxide pathway.

TiPS-March 1991[Vol.121 87 20 Si& E. and Baur, R. (1988) koc. Natl Acad. Sri. USA 85,6192-61% 21 Moran, 0. and Dascal, N. (1989) Mol. BrainRcs. 5, 1...
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