Organic Nitrates: Direct Antiplatelet Effects and Synergism with Prostacyclin

Abstract

SummaryIsosorbide dinitrate inhibits platelet function in vivo at concentrations about 10 times lower than in vitro (10-7 -10-6 vs. 10-6 -10-5 M). We investigated two possible reasons for this difference. Isosorbide dinitrate and its in vivo longer-lived metabolites, isosorbide-2- and isosorbide-5-mononitrate were incubated for 5 min with human platelet-rich plasma or washed platelets; irreversible aggregation was induced with threshold doses of ADP, adrenaline, collagen, arachidonic acid and thrombin, and thromboxane (TX) B2 production was measured by radioimmunoassay. Moreover, the concentration of exogenous prostacyclin required to inhibit platelet aggregation by 50% (IC50) after preincubation with isosorbide dinitrate or vehicle was determined. At 10-7 M, only isosorbide-2-mononitrate inhibited aggregation (-12%, p >0.05) and TX production (-36%, p >0.01) by ADP. At 10-6 M isosorbide-2-mononitrate inhibited aggregation by adrenaline more than the dinitrate (-41% vs. -25%, p >0.05). In addition, at supra-threshold doses of all the aggregating agents, isosorbide dinitrate decreased IC50 of prostacyclin from 2.7 ± 1.2 to 0.36 ± 0.2 nM. Generation of a platelet-active metabolite and synergism with prostacyclin are new properties of isosorbide dinitrate that may account for antiplatelet effects in vivo.

cGMP inhibits IP3‐induced Ca2+ release in intact rat megakaryocytes via cGMP‐ and cAMP‐dependent protein kinases

“…Although it is usually assumed that cGMP‐mediated inhibition of [Ca 2+ ] i mobilization occurs predominantly via the activation of cGMP‐PK (Butt et al 1992; Geiger et al 1992; for review see Walter et al 1993; Lincoln et al 1996), it has also been reported that at least in part cGMP exerts its inhibitory effect via inhibition of cAMP breakdown due to inhibition of PDE III (Maurice & Haslam, 1990; for review see Beavo, 1995). Studies have shown that cGMP‐elevating agents potentiate the elevation of cAMP by prostaglandins when both cAMP and cGMP elevating agents are present at low concentrations (Radomski et al 1987; De Caterina et al 1988; Maurice & Haslam, 1990; Bowen & Haslam, 1991). Furthermore, the nitrovasodilators (SNP and SIN‐1) cause increases in platelet cAMP level even in the absence of adenylate cyclase activators and this effect is due to the inhibition of PDE III (Maurice & Haslam, 1990), the major phosphodiesterase isozyme present in platelets and vascular smooth muscles (for review see Beavo, 1995).…”

Impairment of Platelet Behaviour by Isosorbide Dinitrate - Rebuttal

“…Moreover, synergism with iloprost on nitrate inhibition of whole blood aggregation, another independent hypothesis, can be evaluated only by assessment of shifts in the dose-response curves of either drugs, and it is not clear if really such was the case in the authors' setting. The second part of Dutrillaux' letter appears interesting for two reasons: on one hand, it shows a previously unreported effect of ISDN on platelet aggregation induced by A 23187, an agonist not used in our previous study (1). Because of the relatively high concentrations of isosorbide dinitrate (500 pM) used in this experiment, this finding does not necessarily con tradict our observations on the greater sensitivity of ADP-induced aggregation to demonstrate the antiplatelet effects of nitrates.…”

Propriedades anti-aterogênicas do fator relaxante derivado do endotélio (óxido nítrico)

“…Estudos posteriores demonstraram que o FRDE-NO atua também sobre vários processos implicados na patogênese da aterosclerose e da trombose, como a adesão e agregação plaquetária, a formação de radicais livres de oxigênio (RLO 2 ), a ativação de polimorfonucleares (PMNs), a oxidação das lipoproteínas, a mitogênese e proliferação de células de músculo liso vascular, e a proliferação da íntima, entre outros (quadro II). [60][61][62][63] , mas também com concentrações próxi-mas às terapêuticas 64 . Em outros estudos, realizados in vivo e ex vivo, esta atividade antiagregante dos nitratos foi obtida com a aplicação de doses terapêuticas.…”