NOSH-aspirin (NBS-1120), a novel nitric oxide- and hydrogen sulfide-releasing hybrid has enhanced chemo-preventive properties compared to aspirin, is gastrointestinal safe with all the classic therapeutic indications

We analysed the induction of tolerance to nitrates both in the vasculature (in vivo) and platelets (ex vivo). Simultaneously, we tested mechanisms underlying the induction of tolerance and interventions to prevent or overcome this phenomenon. For this purpose nitroglycerin (GTN 1.5 μg/kg per min i.v.), alone or in combination with ascorbate (55 μg/kg per min i.v.) as antioxidant, was infused continuously for a period of 5 days into chronically instrumented dogs. Along with haemodynamic parameters, ex vivo platelet function was continuously monitored. Following the start of GTN infusions there was a maximal coronary dilator response (245±15 μm) and, as an index of venodilation, a fall of left ventricular end-diastolic pressure (by 2.3±0.4 mmHg). Both responses declined progressively and disappeared during the infusion period. However, in combination with ascorbate as antioxidant the dilator responses were maintained fully throughout the infusion period. With GTN alone there was a progressive, unexpected upregulation of platelet activity demonstrated by enhanced thrombin-stimulated intracellular Ca2+ levels and increases in the microviscosity of platelet membranes (indicating enhanced receptor expression) associated with a progressive impairment in basal, unstimulated cGMP levels. These changes could also be prevented completely by i.v. co-administration of ascorbate. From these results it is concluded that vascular tolerance is closely reflected by simultaneous changes in platelet function and further, that both can be prevented completely by appropriate antioxidants such as ascorbate.

Tolerance to nitrates and simultaneous upregulation of platelet activity prevented by enhancing antioxidant state

Patients with CKD display a significantly higher risk of cardiovascular and thromboembolic complications, with around half of patients with advanced CKD ultimately dying of cardiovascular disease. Paradoxically, these patients also have a higher risk of hemorrhages, greatly complicating patient therapy. Platelets are central to hemostasis, and altered platelet function resulting in either platelet hyper- or hyporeactivity may contribute to thrombotic or hemorrhagic complications. Different molecular changes have been identified that may underlie altered platelet activity and hemostasis in CKD. In this study, we summarize the knowledge on CKD-induced aberrations in hemostasis, with a special focus on platelet abnormalities. We also discuss how prominent alterations in vascular integrity, coagulation, and red blood cell count in CKD may contribute to altered hemostasis in these patients who are high risk. Furthermore, with patients with CKD commonly receiving antiplatelet therapy to prevent secondary atherothrombotic complications, we discuss antiplatelet treatment strategies and their risk versus benefit in terms of thrombosis prevention, bleeding, and clinical outcome depending on CKD stage. This reveals a careful consideration of benefits versus risks of antiplatelet therapy in patients with CKD, balancing thrombotic versus bleeding risk. Nonetheless, despite antiplatelet therapy, patients with CKD remain at high cardiovascular risk. Thus, deep insights into altered platelet activity in CKD and underlying mechanisms are important for the optimization and development of current and novel antiplatelet treatment strategies, specifically tailored to these patients who are high risk. Ultimately, this review underlines the importance of a closer investigation of altered platelet function, hemostasis, and antiplatelet therapy in patients with CKD. 

Platelet Abnormalities in CKD and Their Implications for Antiplatelet Therapy

This study determines the release of nitric oxide (NO) from the coronary circulation of Langendorff hearts of rabbits, subsequent to administration of glyceryl trinitrate (GTN) and SIN-1. NO was measured on-line in the coronary effluent by the oxyhaemoglobin technique. Infusion of either GTN (10–40 moles/l) or SIN-1 (0.1–2.3 μmoles/l) into the coronary inflow resulted in a concentration-dependent NO release into the coronary effluent and a decrease in the coronary vascular resistance. NO generation from SIN-1 was identical with and without passage of the coronary circulation whereas NO generation from GTN was only detected after passage of the coronary vascular bed. NO generation by both substances was in the same range as endogenous NO release by two endothelium-dependent vasodilators, bradykinin (0.05 μmoles/l) and substance P (0.05 μmoles/l). Oxyhaemoglobin used for the assay of NO, inhibited the relaxation by SIN-1, but did not reduce vessel relaxations induced by GTN or iloprost, a stable prostacyclin analogue. Removal of the coronary endothelium by trypsin or pretreatment with L-NG-Monomethyl-arginine (30 μmoles/l) did neither affect NO release from GTN and SIN-1 nor the vasodilatory effect of both substances. These data are the first to directly demonstrate endothelium-independent NO release from organic nitrates during passage of an intact organ circulation. They additionally suggest a subendothelial site of metabolic NO formation from GTN.

On-line measurement of nitric oxide release from organic nitrates in the intact coronary circulation

Aims Cardiovascular side effects caused by non-steroidal anti-inflammatory drugs (NSAIDs), which all inhibit cyclooxygenase (COX)-2, have prevented development of new drugs that target prostaglandins to treat inflammation and cancer. Microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors have efficacy in the NSAID arena but their cardiovascular safety is not known. Our previous work identified asymmetric dimethylarginine (ADMA), an inhibitor of endothelial nitric oxide synthase, as a potential biomarker of cardiovascular toxicity associated with blockade of COX-2. Here, we have used pharmacological tools and genetically modified mice to delineate mPGES-1 and COX-2 in the regulation of ADMA. Methods and results Inhibition of COX-2 but not mPGES-1 deletion resulted in increased plasma ADMA levels. mPGES-1 deletion but not COX-2 inhibition resulted in increased plasma prostacyclin levels. These differences were explained by distinct compartmentalization of COX-2 and mPGES-1 in the kidney. Data from prostanoid synthase/receptor knockout mice showed that the COX-2/ADMA axis is controlled by prostacyclin receptors (IP and PPARβ/δ) and the inhibitory PGE2 receptor EP4, but not other PGE2 receptors. Conclusion These data demonstrate that inhibition of mPGES-1 spares the renal COX-2/ADMA pathway and define mechanistically how COX-2 regulates ADMA.

/pdf/mechanistic-definition-of-the-cardiovascular-mpges-1-cox-2-5266qnml51.pdf

Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis.

Since more than 20 years, aspirin is an approved and established first-line antiplatelet medication in cardiovascular prevention. This is partially due to ist unique mode of action which is not shared with any other antiplatelet agent as well by the reliability of its pharmacological efficacy: inhibition of platelet COX-1 and subsequent thromboxane formation in almost every patient. Aspirin acts synergistic with ADP-antagonists in dual antiplatelet therapy of acute coronary syndroms (ACS) and percutaneous coronary interventions (PCI) and is also approved for long-term secondary prevention. Patients with atrial fibrillation are an exception and benefit more from anticoagulants. After the introduction of the new oral anticoagulants (NOACs), i.e. direct inhibitors of factor Xa or thrombin formation, there is a renewed discussion about the role of antiplatelet agents, specifically if additional dual antiplatelet treatment is still necessary for an optimum clinical effect or whether one component, such as aspirin might be skipped in favor of other classes of oral antiplatelet agents, such as ADP-antagonists. The available data are insufficient to recommend this because of a low number of studies and a still uncertain benefit/risk (bleeding) ratio. More research on aspirin as a chemopreventive appears also to be necessary and is going on, in particular in individuals at high-risk for vascular thrombotic diseases (diabetics, preeclampsia, venous thrombembolism).

Why we should not skip aspirin in cardiovascular prevention

Organische nitrate und thrombozytenfunktion

Die Entwicklung neuer Antiplattchensubstanzen und Antithrombotika hat in den vergangenen Jahren erhebliche Fortschritte gemacht und wird aller Voraussicht nach in kurzer Zeit zur Einfuhrung neuer Praparate fuhren. Im Bereich der Antiplattchensubstanzen steht mit dem ADP-Antagonisten Clopidogrel seit einigen Jahren erstmals eine Substanz zur Verfugung, die eine therapeutische Alternative zu Azetylsalizylsaure, insbesondere bei der oralen Langzeit- Medikation darstellt. Prasugrel ist eine Weiterentwicklung der ADP-Antagonisten und befindet sich zurzeit in fortgeschrittenen Phasen der klinischen Entwicklung. Auf dem Gebiet der Antithrombotika ist ebenfalls das Interesse an oral wirksamen Substanzen hoch. Nach (Xi)Melagatran befinden sich, neben weiteren Thrombininhibitoren (z. B. Dabigatran) vor allem Inhibitoren von Faktor Xa (z. B. Rivoroxaban) in der klinischen Entwicklung. Es ist davon auszugehen, dass zumindest einige dieser Substanzen auch klinisch eingefuhrt werden und mit groser Wahrscheinlichkeit das therapeutische Spektrum der Antithrombotika erheblich bereichern werden.

[Haemostasis and antithrombotic drugs: pharmacology and novel therapeutic approaches].

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Why we should not skip aspirin in cardiovascular prevention

Organische nitrate und thrombozytenfunktion

[Haemostasis and antithrombotic drugs: pharmacology and novel therapeutic approaches].