Nitric Oxide Donor – An Overview

Nitric oxide (NO) is responsible for multiple physiological and pathological functions in the cardiovascular system. Pharmacological agents that release NO are effective instruments to assess NO’s critical function in cardiovascular physiology or therapy. These agents are divided into two categories: those that spontaneously release NO and one of its redox congeners, and those that need enzymatic metabolism to produce NO. 

The concentration of NO in vitro is directly measured by myoglobin and the nitrosation of haemoglobin. The donors of NO are shown to inhibit and stimulate the migration, proliferation, and differentiation of angiogenesis in vivo and endothelial cells in vitro. Furthermore, numerous routinely used cardiovascular medications benefit the patients by regulating the NO pathway. 

In this section, we cover these groups of drugs, describing their basic chemistry and pharmacology and providing an outline of their cardiovascular modes of action.

Overview of a Nitric Oxide Donor

Hypertension, heart failure, atherosclerosis, arterial thrombotic disorders, coronary heart disease, and stroke are all associated with dysfunction of the typically protective endothelium. NO deficiency can be caused by a total lack of NO synthesis, decreased bioavailability of bioactive NO, or increased NO inactivation. NO deficiency, regardless of its metabolic source, impairs NO-mediated signalling transduction of regular or protective physiological activities. Therefore, the restoration or augmentation of endogenous NO by exogenously supplied NO donors has laid the groundwork for a diverse field of cardiovascular medicine pharmacotherapeutics.

Nitrite and organic nitrate esters are a well-known family of NO-donating compounds that have been employed in cardiovascular therapy since the 19th century. These medicines have direct vasoactive actions and have been used for many years to treat ischemic heart disease, heart failure, and hypertension. However, the therapeutic half-life of typical nitrate preparations, systemic absorption with possibly severe hemodynamic effects, and drug tolerance restrict their use. 

Novel NO donors with selective effects, an extended half-life, and a decreased risk of drug tolerance have been created to circumvent these constraints. NO donors are pharmacologically-active compounds that release or are converted to NO or redox congeners. We examine our modern knowledge of NO-donating chemicals and cardiovascular medications that alter the bioactivity of endogenously generated NO in this article.

Effects of Nitric Oxide Donor

• Muscle Flexibility

NO is a robust vasodilator in all vascular beds and a profound relaxant in the majority of smooth muscle tissues. This action is caused by the activation of guanylyl cyclase and the production of cyclic guanosine monophosphate (cGMP). This cGMP, in turn, promotes the dephosphorylation and inactivation of myosin light chains, resulting in smooth muscle relaxation. NO has a physiological role in erectile tissue function, as smooth muscle relaxation is essential to generate the blood inflow that induces erection. NO also appears to have a role in the pathophysiology of hypotension in septic shock.

• Adhesion of Cells

NO inhibits cell adhesion, resulting in decreased platelet aggregation and neutrophil adherence to vascular endothelium. The latter impact is most likely related to endothelial cells’ lower production of adhesion molecules such as integrins.

• Inflammation

NO generation is caused by tissue damage, and NO appears to enhance inflammation both directly and indirectly through the activation of prostaglandin synthesis by cyclooxygenase 2 and the release of prostanoids.

• Chemistry of organic compounds

Nitrosylation is the process of adding a NO moiety to another molecule. The Traube reaction involves the addition of two equivalents of NO to an enolate to produce a diazeniumdiolate (also called nitroso hydroxylamine). The product can then undergo a retro-aldol reaction, resulting in a process similar to the haloform reaction. For example, NO interacts with acetone and an alkoxide to generate a diazeniumdiolate on each site, with methyl acetate being lost as a byproduct.

• Traube response

This reaction, discovered in 1898, is important in NO prodrug development. NO can also combine directly with sodium methoxide, producing sodium formate and nitrous oxide through an N-methyl diazeniumdiolate reaction.

• Effect on angiogenesis

NO is a part of reactive oxygen species (ROS), and it helps in stabilising hypoxia-inducible factor (HIF)-1α and stimulating the growth factor and secretion of vascular endothelial cells. Endothelium-derived NO works as a mediator in the effects of angiogenesis. The release of NO is stimulated by vascular endothelial growth factor (VEGF) from the cultured human umbilical vein endothelial cells.

Conclusion

Multiple physiological and pathological functions in the cardiovascular system are mediated by nitric oxide (NO). Pharmacological agents that release NO are effective instruments for assessing NO’s critical function in cardiovascular physiology and therapy. Furthermore, numerous routinely used cardiovascular medications benefit the patients by regulating the NO pathway. 

Novel pharmacologically-active compounds that release NO have been created. NO is vital for various physiological and pathophysiological pathways. Hence, NO donors play a crucial role in muscle flexibility, adhesion, inflammation, angiogenesis, etc.