Arterial occlusions and the role of NO

Cardiovascular diseases (CVDs) are the leading cause of death globally, taking an estimated 17.9 million lives each year1. CVDs caused by arterial occlusion are a group of disorders of the heart and blood vessels and include acute myocardial infarction (AMI) and stroke (ischemic) accounting for more than four out of five CVD deaths. Acute occlusion can also occur in extremities, acute limb ischemia (ALI), kidneys (renal arteries) or in arteries of the small intestine.

These conditions are all vascular emergencies where blood supply is critically reduced causing ischemia (lack of tissue oxygenation) to avoid permanent tissue damage, and prompt intervention are needed. Arterial occlusions in CVD have similar aetiologies, which are:  

  1. Thrombosis: Platelet aggregation and fibrin formation creating a blood clot.

  2. Embolism: A blood clot, often formed in the heart, travels to the brain or other organs.

  3. Local vasoconstriction in the affected organ due to endothelial dysfunction and activation of platelets with release of vasoconstrictors e.g., thromboxane, serotonin. Endothelial dysfunction causes diminished endogenous local NO-production which is further enhanced by increased breakdown of the produced NO caused by the ischemic and inflammatory condition. These factors lead to vasospasm which further reduce the blood supply to the threatened organ.

Ischemia-Reperfusion injury (IRI) – Even if an arterial occlusion could be removed and blood flow to affected tissues restored, a paradoxical exacerbation of cellular dysfunction and death, following restoration of blood flow to previously ischemic tissues can occur (IRI). The optimal treatment of arterial occlusion should thus not only reestablish blood supply, but also reduce IRI.

Role of platelets and inflammation in Thrombosis: Uncontrolled activation of platelets is a key pathological event in acute thrombosis, vessel occlusion, and ischemic tissue damage. The basis of platelets’ contribution to thrombus formation relies on fibrinogen bridges between adjacent activated platelets, leading to formation of a large, multi-platelet aggregate.

A thrombotic event is directly linked to an inflammatory reaction. It is also well-known that activation of platelets leads to increased binding to all types of leukocytes. The precise role of platelet/leukocyte binding is still not completely understood, but both activations, priming (increased responsiveness towards other activators), and down-regulation of platelet as well as leukocyte functions have been described.

The role of nitric oxide in arterial occlusion. Patients over 70 years, and those with hypertension, diabetes, and obesity have reduced endogenous NO production2. Also, inflammation is an important part of atherosclerosis development, closely associated with arterial occlusion.

Anti-thrombotic and anti-inflammatory properties of NO. Evidence from animal models shows that platelet‐derived NO contributes to the regulation of thrombus formation. In humans, conditions with defective platelet NO-production are associated with an enhanced risk of CVD. NO prevents thrombosis through all aspects of platelet activation, and NO insufficiency may lead to platelet hyperreactivity and to arterial thrombosis. Several studies of patients suffering ischemic stroke, myocardial infarction, coronary syndrome, and atrial fibrillation show patient platelets have impaired production of NO or NO-induced cGMP formation and enhanced reactivity. This platelet hyperreactivity may be reduced by the administration of NO donors.

Current treatments for acute arterial occlusion. Acute arterial occlusion is a medical emergency depending on the period that an organ will tolerate ischemia, which is a few minutes in the brain and roughly 4-6 hours in a limb. Symptoms of arterial occlusion include pain and loss of function. The longer these symptoms are present, the less likely it is to salvage the organ. Dissolving or removing a blood clot to revascularize tissue is crucial.  Dissolving of blood clots can be done by using systemic or local (catheter-directed via femoral or radial artery) antithrombotic therapy. Mechanical removal of blood clots can be performed surgically (arterial by-pass) or endovascularly with inflatable balloons to open up the occlusion and then applying stents. The technique that will provide the most rapid restoration of arterial flow with the least risk to the patient should be selected.

Today’s treatments are insufficient. Despite the advances in treatment during the last decades, current treatments are not sufficient: Removal of the blood clot with directed catheter guided local thrombolytic agents or mechanical removal are complicated and time consuming, and not all hospitals are able to perform these techniques. Even when attempts to mechanically remove thrombi are done, often part of the thrombi is loosened and travels further downstream, obliterating smaller vessels. Antithrombotic agents do not always work and require some time to reach their full effect. The quickest methods, systemically used antithrombotic agents, have an inherent risk of bleeding as a side effect and are thus even contra indicated in some patients.

Nitric Oxide (NO) – a potential first aid treatment for acute occlusion of arteries. As a treatment, NO is administered through NO donors, which are molecules with the ability to release NO when applied to the body and have been in use since the mid-19th century to treat heart disease, the most well-known being nitroglycerin. Well-known problems with currently available NO donors are tolerance development and the risk of side effects attributed to the release of NO throughout the entire circulatory system. As NO has important functions in several biological systems, third generation of NO donors (NO donors enabling targeted delivery of NO) can have beneficial effects in several diseases and organ systems. 

Arterial occlusion by thrombus/emboli and local vasoconstriction would optimally be treated with a NO donor specifically targeted to the site of ischemia to avoid systemic side effects. However, today there are no such intravenous NO-donors in clinical use.

Since the discovery that nitroglycerin and related compounds operate through the release of NO, considerable resources have been invested in attempts to develop new and better NO donors. However, it has now been more than 30 years since the groundbreaking discoveries relating to NO were made, and no progress in developing improved NO donors with higher specificity and fewer side effects has been achieved. However, with Supernitro this has been changed, unlike previously known NO donors, Supernitro releases NO with an ultra-fast half-life due to very rapid decomposition after infusion to the circulatory system. Due to this, when given intravenously in a wide dose range, the majority of the NO is released and exerts its effects primarily in the circulation of the lung and thus has only minor effects in systemic circulation. Supernitro, given as an intravenous treatment, has lung selective action since the lung is the first major organ to receive the drug. However, other organs like the heart, brain or extremities can be targeted with Supernitro by direct arterial infusions to locally release NO without systemic effects using the same pharmacodynamic principle. Furthermore, Supernitro does not seem to induce tolerance or methemoglobinemia (in the effective dose rage), problems associated with established NO therapies (i.e., inhaled NO and/or nitroglycerin infusions), which are thus other beneficial properties of PDNO compared to other organic nitrates.

Attgeno intends to further investigate the potential of Supernitro in various conditions with arterial occlusions.

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