Prevention by NCX 4016, a nitric oxide-donating aspirin, but not by aspirin, of the acute endothelial dysfunction induced by exercise in patients with intermittent claudication

Abstract

Ischemia/reperfusion damage evokes systemic inflammation and endothelial dysfunction in patients with intermittent claudication. We compared the effects of aspirin with those of a nitric oxide-donating aspirin in preventing the acute, systemic endothelial dysfunction provoked by exercise-induced ischemia of the lower limbs in patients with intermittent claudication. In a prospective, randomized, single-blind, parallel-groups trial among 44 patients with intermittent claudication we compared four weeks of aspirin (100 mg o.d.) with NCX 4016 (800 mg b.i.d.). Primary end point was the exercise-induced changes in brachial flow-mediated vasodilation (FMD) at day 28; secondary end points were effort-induced changes of markers of neutrophil (plasma elastase) and endothelial (soluble VCAM-1) activation. Baseline FMD was comparable in the two groups, both on day 1 (pre-treatment: aspirin = 3.1 +/- 0.5%, nitroaspirin = 3.9 +/- 0.7%, p = NS), and on day 28 (aspirin = 3.4 +/- 0.7%, NCX 4016 = 3.2 +/- 0.6%, p = NS). Maximal treadmill exercise induced an acute worsening of FMD in both groups at baseline (aspirin = -1.15%, nitroaspirin = -1.76%); after four weeks treatment, the impairment of FMD induced by exercise was still present in the aspirintreated group (-1.46%) while it was abolished in the NCX 4016-treated group (+0.79%, p = 0.038 vs. aspirin). Similarly, exercise induced an increase of plasma elastase and of sVCAM-1 which were not affected by aspirin while they were suppressed by NCX 4016. Maximal treadmill exercise induces a systemic arterial endothelial dysfunction in patients with intermittent claudication. A nitric oxide-donating aspirin, but not aspirin, prevents effort-induced endothelial dysfunction.

Hyperglycemia-Induced Platelet Activation in Type 2 Diabetes Is Resistant to Aspirin but Not to a Nitric Oxide–Donating Agent

“…The observation that despite incomplete suppression of platelet COX-1, NCX 4016 inhibited several parameters of ex vivo and in vivo platelet activation in diabetic individuals suggests that the antiplatelet activity exerted was largely due to the released NO. Indeed, NCX 4016, but not aspirin, enhanced plasma levels of NOx, demonstrating the delivery of NO in vivo (12). Considering that NCX 4016 in vitro inhibits platelet COX-1 irreversibly and with a potency similar to that of aspirin (18), the lower inhibition we found in vivo suggests that only a minor fraction of NCX 4016 is absorbed as such after oral administration (13).…”

“…Plasma levels of NO degradation products, nitrites plus nitrates, were measured by the Griess reagent method (12). …”

“…NCX 4016 was shown to display a wide range of antiplatelet activities in vitro and in vivo (11) and to release biologically relevant amounts of NO after oral administration to humans (12,13). …”

Protective role of nitric oxide donors on endothelium in ischemia-reperfusion injury: a meta-analysis of randomized controlled trials

“…A total of 510 articles were found from the search and after removing duplicates ( N = 99), 411 articles were screened based on the title and abstract, and 383 articles were excluded based on the exclusion criteria. A total of seven articles were selected for further screening, and their complete manuscripts were reviewed, of which two articles were excluded because one of them could not be found in usable full text and the other [ 25 ] contained confounding factors (aspirin) in addition to NO, resulting in the inclusion of five studies in the systematic review. We also referred to the references of these five articles and found two more that met the eligibility criteria for the review, which totaled up to seven articles [ 26 – 32 ], of which four articles included two independent clinical studies, thereby increasing the final number of included studies in the meta-analysis to 11.…”

Gaseous Mediators as a Key Molecular Targets for the Development of Gastrointestinal-Safe Anti-Inflammatory Pharmacology

“…Importantly, NCX-4016 has also shown protective effects in a human trial conducted among patients with intermittent claudication, pathology in which physical effort induces endothelial dysfunction in ischemia/reperfusion-dependent mechanisms. NCX-4016 administered orally for four weeks, significantly prevented from the exercise-induced endothelial damage, in contrast to the standard aspirin treatment, which was devoid of such effect ( Gresele et al, 2007 ). On the other hand, another human trial revealed that NCX-4016 markedly reversed insulin resistance and enhanced vascular response to insulin in obese insulin-resistant men ( Gresele and Momi, 2006 ).…”