Effects of nitric oxide-containing compounds on increases in cytosolic ionized Ca2+ and on aggregation of human platelets

Ivanova, Krassimira; Schaefer, Michael; Drummer, C.; Gerzer, R.

doi:10.1016/0922-4106(93)90057-g

Cited by 45 publications

(30 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2022 The effect of nitrovasodilators on platelet reactivity also is associated with an attenuation of agonist-induced elevations of intracellular calcium. 16 Indeed, in the present study, calcium ionophore induced robust elevations of intracellular calcium in platelets from hypercholesterolemic rabbits, which were attenuated by dietary arginine. This effect of dietary arginine was antagonized by in vitro exposure of the platelets to L, nitro-arginine, an antagonist of NO synthase.…”

Section: Discussionmentioning

confidence: 94%

L-arginine attenuates platelet reactivity in hypercholesterolemic rabbits.

Tsao

Theilmeier

Singer

et al. 1994

Arterioscler Thromb

114

View full text Add to dashboard Cite

Platelets are capable of producing nitric oxide (NO) through the L-arginine-NO synthase pathway. Acute exposure to supraphysiological concentrations of L-arginine in vitro increases the production of NO by platelets and is associated with an increase in platelet cyclic GMP (cGMP) levels and a reduction in platelet aggregation. The purpose of this study was to determine if chronic oral administration of L-arginine decreases platelet aggregation in hypercholesterolemic animals and to determine if this effect is mediated by the metabolism of L-arginine to NO. Male New Zealand White rabbits were fed normal chow (Con), a 1% cholesterol diet (Choi), or a 1% cholesterol diet supplemented with a sixfold enrichment of dietary L-arginine (Arg) or L-methionine (Met). After 10 weeks, cholesterol levels were equally increased in Choi and Arg animals, whereas plasma arginine levels were A therogenesis is thought to be initiated as a re-/\ sponse to injury of the endothelium. 1 This -Z. A. alteration of endothelial function favors platelet adherence and aggregation to the luminal surface, with the subsequent release of platelet-derived growth factors and vasoactive substances that contribute to the process of atherogenesis.One of the earliest alterations of the endothelium that has been observed in hypercholesterolemic animals and humans is decreased activity of endothelium-derived relaxing factor (EDRF). 24 EDRF is nitric oxide (NO) or a nitroso-containing compound derived from the metabolism of L-arginine by NO synthase. 58 This nitrovasodilator also inhibits platelet adhesion 9 and aggregation via the stimulation of intracellular guanylate cyclase to increase intracellular levels of cyclic GMP (cGMP). 1011 NO synthase and guanylate cyclase are also active in platelets, and platelet-derived NO autoregulates aggregation. 12 -13 A reduction in the activity of NO synthase by hypercholesterolemia could therefore lead to increased platelet-vessel wall interaction and enhanced atherogenesis.Recent studies in this laboratory have shown that chronic oral supplementation of the EDRF precursor L-arginine significantly improved NO-dependent vasodilation in hypercholesterolemic animals; this effect was associated with a striking reduction in intimal lesions. 14 To determine if this antiatherogenic effect of L-arginine Received August 13, 1993; revision accepted July 15, 1994 is associated with decreased platelet reactivity and enhancement of platelet-derived NO activity, we tested the hypothesis that (1) dietary L-arginine reduces platelet aggregation and (2) this effect is mediated by the metabolism of L-arginine to NO. Methods AnimalsMale New Zealand White rabbits received one of the following dietary interventions for 10 weeks: normal rabbit chow (Con), rabbit chow enriched with 1% cholesterol (Choi) (ICN Biomedical), or a 1% cholesterol chow supplemented with L-arginine (Arg) added to the drinking water throughout the course of the study. Supplementation with 2.25% L-arginine HO in the drinking water results in a sixfold e...

show abstract

Section: Discussionmentioning

confidence: 94%

L-arginine attenuates platelet reactivity in hypercholesterolemic rabbits.

Tsao

Theilmeier

Singer

et al. 1994

Arterioscler Thromb

114

View full text Add to dashboard Cite

show abstract

“…This effect was time-and concentration-dependent and, unlike that on cGMP concentrations, could largely be reversed by increasing concentrations of SNAP. ODQ had no effect on the plateletinhibitory actions of PGI2, which acts by elevating cAMP concentrations (25), or of 8-pCPT-cGMP, which mimics the actions of cGMP (26,27 (33,34). In our experiments, high concentrations of SNAP (100 ,uM) reversed the effect of ODQ on platelet aggregation, but they only partially restored cGMP concentrations, suggesting either that a relatively small increase in cGMP is enough to inhibit platelet aggregation or that the platelet-inhibitory action of supramaximal concentrations of NO may indeed include some cGMPindependent actions.…”

Section: Discussionmentioning

confidence: 99%

cGMP mediates the vascular and platelet actions of nitric oxide: confirmation using an inhibitor of the soluble guanylyl cyclase.

Moro

Russell

Cellek

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

429

246

View full text Add to dashboard Cite

The L-arginine:nitric oxide (NO) pathway is believed to exert many of its physiological effects via stimulation of the soluble guanylyl cyclase (SGC); however, the lack of a selective inhibitor of this enzyme has prevented conclusive demonstration of this mechanism of action. We have found that the compound LH- [1,2,4]oxadiazolo [4,3,-a]quinoxalin-1-one (ODQ) inhibits the elevation of cGMP induced by the NO donor S-nitroso-DL-penicillamine in human platelets and rat vascular smooth muscle (ICso = 10-60 nM and <10 nM, respectively) and that this is accompanied by prevention of the platelet inhibitory and vasodilator actions of NO donors. ODQ also inhibited the antiaggregatory action of NO generated by the platelets but did not affect the action of prostacyclin or that of a cGMP mimetic. In addition, ODQ inhibited the vasodilator actions of endogenously released NO and of NO generated after induction of NO synthase in vascular preparations. It did not, however, affect the increase in vascular smooth muscle cGMP or the dilatation induced by atrial natriuretic factor. ODQ had no effect on NO synthase activity, nor did it react with NO. It did, however, potently (IC50 10 nM) inhibit the activity of the SGC in cytosol obtained from crude extract of rat aortic smooth muscle. Thus ODQ prevents the actions of NO on platelets and vascular smooth muscle through its potent inhibitory effect on the SGC.Nitric oxide (NO), S-nitrosothiols, and other NO donors (1) activate the soluble guanylyl cyclase (SGC) by binding to the heme moiety of the enzyme (2). This results in increased cGMP concentrations that are associated with relaxation in vascular tissue (for review, see ref.3). In addition, these compounds increase cGMP in platelets, and this is thought to be the mechanism by which they inhibit platelet function (4,5).Studies attempting to investigate the role of SGC in the mediation of the physiological actions of NO have been hampered by the lack of a potent and selective inhibitor of this enzyme. Methylene blue has been used as such; however, this compound also inhibits prostacyclin (PGI2) production (6, 7), generates superoxide anions (8-10), and directly inhibits NO synthase (11). Furthermore, LY 83583 (6-anilino-5,8-quinolinedione), which inhibits elevation of cGMP concentrations in a number of tissues (12, 13), probably does so by generating superoxide anions (14).1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) has been shown to inhibit N-methyl-D-aspartate-induced increases in cGMP concentrations in rat brain slices and to inhibit the activity of SGC purified from bovine lung (15). We have now used this compound to characterize the role of SGC in the actions of NO in platelets and vascular tissue.MATERIALS AND METHODS Washed Platelet Suspensions. Human blood was collected, and PGI2-washed platelet (WP) suspensions were prepared as described (16).Platelet cGMP Concentrations. WPs (2-2.5 X 108/ml) were incubated without stirring in a platelet-ionized calcium lumiaggregometer (Chronolog) for 20 min at 37°C in th...

show abstract

“…Blood was drawn from the cubital vein into citric acid solution (6:1 vol/vol), and platelet suspensions were prepared according to Bassenge et al (9). Platelets were counted microscopically, and adjusted to a final concentration of 120,000 cells/ l. Thrombin-induced platelet aggregation was monitored in a two-channel aggregometer Elri-840 (ELRI, Milano, Italy) with the peak increase in light transmission obtained within 5 min after stimulation (21). All parameters were measured at an external Ca 2 ϩ concentration of 1 mM after equilibration of platelets with a buffer for 20 min.…”

Section: Methodsmentioning

confidence: 99%

Dietary supplement with vitamin C prevents nitrate tolerance.

Bassenge¹,

Fink²,

Skatchkov³

et al. 1998

J. Clin. Invest.

129

View full text Add to dashboard Cite

Enhanced formation of superoxide radicals has been proposed to play a major role in the development of nitrate tolerance in humans. We tested the effects of vitamin C (Vit-C) supplementation on glyceroltrinitrate (GTN)-induced hemodynamic effects during 3-d nonintermittent transdermal administration of GTN (0.4 mg/h) in nine healthy subjects. Tolerance development was monitored by changes in arterial pressure, dicrotic digital pulse pressure, and heart rate. Studies with GTN, Vit-C, or GTN/Vit-C were successively carried out at random in three different series in the same subjects. GTN treatment caused an immediate rise in arterial conductivity (a/b ratio of dicrotic pulse), but within 2 d of initiating GTN, the a/b ratio progressively decreased and reached basal levels. In addition, there was a progressive loss of the orthostatic decrease in blood pressure. However, coadministration of Vit-C and GTN fully maintained the GTN-induced changes in the orthostatic blood pressure, and the rise of a/b ratio was augmented by 310% for the duration of the test period. Changes in vascular tolerance in GTN-treated subjects were paralleled by upregulation of the activity of isolated platelets, which was also reversed by

show abstract

Effects of nitric oxide-containing compounds on increases in cytosolic ionized Ca2+ and on aggregation of human platelets

Cited by 45 publications

References 26 publications

L-arginine attenuates platelet reactivity in hypercholesterolemic rabbits.

L-arginine attenuates platelet reactivity in hypercholesterolemic rabbits.

cGMP mediates the vascular and platelet actions of nitric oxide: confirmation using an inhibitor of the soluble guanylyl cyclase.

Dietary supplement with vitamin C prevents nitrate tolerance.

Contact Info

Product

Resources

About