2007 - 04

Br J Pharmacol. 2007 Apr;150(7):873-82. Epub 2007 Mar 12.

Nitropravastatin stimulates reparative neovascularisation and improves recovery from limb Ischaemia in type-1 diabetic mice.

Emanueli C, Monopoli A, Kraenkel N, Meloni M, Gadau S, Campesi I, Ongini E, Madeddu P. Bristol Heart Institute, University of Bristol, Bristol, UK.

BACKGROUND AND PURPOSE: Mature endothelial cells and their progenitors are dysfunctional in diabetes, resulting in deficient neovascularisation following arterial occlusion. This study aimed to evaluate the therapeutic activity of a nitric oxide (NO) releasing statin in the setting of experimental diabetes and peripheral ischaemia. EXPERIMENTAL APPROACH: The effects of NCX 6550, an NO-releasing pravastatin derivative, on angiogenesis in ischaemic limbs was studied in normoglycaemic mice or mice made diabetic by treatment with streptozotocin (STZ). Control mice received an equimolar dosage of the parent statin compound, pravastatin. The therapeutic action of NCX 6550 was also tested in mice lacking the gene for endothelial nitric oxide synthase (eNOS). KEY RESULTS: In normoglycaemic or STZ-diabetic CD1 mice, only NCX 6550 stimulated skeletal muscle revascularisation. In addition, NCX 6550 induced greater improvement in limb reperfusion and salvage, than pravastatin. The number of circulating endothelial progenitor cells was decreased in STZ-diabetic mice, this defect being prevented by NCX 6550 and, to a lesser extent by pravastatin. Invitro, high glucose concentrations reduced the migratory capacity of endothelial progenitor EPCs, which was partly reversed by preincubation with pravastatin and completely reversed by NCX 6550. The postischaemic recovery of eNOS knockout mice was severely impaired as a consequence of depressed angiogenesis and this recovery was improved by treatment with NCX 6550, but not with pravastatin. CONCLUSIONS AND IMPLICATIONS: These findings indicate that incorporation of a bioactive NO moiety improves the therapeutic profile of statins for the treatment of peripheral vascular disease.



Eur J Pharmacol. 2007 Apr 30;561(1-3):220-5. Epub 2007 Feb 1.

Effect of aspirin, paracetamol and their nitric oxide donating derivatives on exudate cytokine and PGE2 production in zymosan-induced air pouch inflammation in rats.

Mamuk S, Melli M. Ankara University, School of Medicine, Department of Pharmacology and Clinical Pharmacology, Morfoloji Binasi, Sihhiye 06100, Ankara, Turkey.

Effects of different doses of aspirin, compared to equimolar doses of nitric oxide (NO)-donating aspirin (NCX 4016), and of a single dose of paracetamol, compared to an equimolar dose of NO-donating paracetamol (NCX 701) were investigated in acute zymosan-induced air pouch inflammation in rats. Treatments were administered by orogastric route, and interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and prostaglandin E(2) (PGE(2)) levels in the exudates were analysed 4 h after zymosan injection by enzyme immunoassay (EIA). Aspirin, at 10, 30 and 100 mg/kg doses, increased IL-1beta levels in exudates, however, only the highest dose lead to a significant increase when compared to control, whereas a significant increase in TNF-alpha level was observed at all doses tested. NCX 4016, at equimolar doses for aspirin, i.e., 18.6, 55.8 and 186 mg/kg, respectively, did not cause any changes in exudate IL-1beta or TNF-alpha levels. These effects were significantly different, when aspirin was compared with the corresponding NCX 4016 group. Nevertheless, the ability of aspirin and NCX 4016 to inhibit PGE(2) synthesis in the exudate where comparable. Although paracetamol significantly increased exudate TNF-alpha level compared to the control group and NCX 701 group, neither paracetamol, nor NCX701 treatments changed the levels of exudate IL-1beta significantly. As expected, paracetamol and NCX 701 showed poor PGE(2) inhibition. At high doses, aspirin and NCX 4016 decreased the number of polymorphonuclear leukocytes in the exudate. However, this inhibition was not significantly different from the control group. Paracetamol and NO-paracetamol did not cause any change in the number of polymorphonuclear leukocytes in exudate. These results indicated that aspirin and NCX 4016 possessed different effects on cytokine production or release, despite the fact that both drugs inhibited the synthesis of PGE(2) in a similar way. Unlike paracetamol, which increased exudate TNF-alpha level, NCX 701 had no effect on TNF-alpha level in the exudates.



J Thromb Thrombolysis. 2007 Apr;23(2):129-33. Epub 2007 Jan 13.

Tissue factor and nitric oxide: a controversial relationship!

Dusse LM, Cooper AJ, Lwaleed BA. University of Southampton, Southampton, UK.

Tissue factor (TF) is the primary physiological initiator of blood coagulation. TF has a high-affinity for factor (F) VII resulting in the formation of (TF:FVII:FVIIa) bimolecular complex which, in the presence of Ca(2+), increases the enzymatic activity of FVIIa towards its natural substrates, FIX and FX, generating their active forms FIXa and FXa, respectively. This eventually leads to thrombin generation and a fibrin clot formation. Up-regulation of TF in injured blood vessels and atherosclerotic plaque can lead to undesirable vascular thrombosis. Nitric oxide (NO) is a free radical synthesized from L-arginine and molecular oxygen by nitric oxide synthases (NOS). NO participates in diverse physiological and pathophysiological process as an intra or extracellular messenger. A relationship between TF and NO has been proposed. Thus, models of TF regulation by NO has been studied in different cells and experimental animal models, but the results have been conflicting. The premise that NO donors can prevent TF expression in vivo has provided the foundation for a broad field of pharmacotherapeutics in vascular medicine. A new class of drugs combining a statin (inhibitors of coenzyme A reductase) with an NO-donating moiety has been described. The resulting drug, nitrostatin, has been suggested to increase the antithrombotic effects of native statin. However, it is questionable if NO release from these drugs had any significant role on TF inhibition. In summary, care must be taken in drawing conclusions about the relationship between NO and TF. Interpretation of NO studies must take several factors into consideration, including NO bioavailability, its half-life and inactivation, as well as the cell type and experimental model used.