Developing New Organic Nitrates for Treating Hypertension: A Review

Abstract

Nitric oxide (NO) is one of the most important vasodilator molecules produced by endothelium and presents several cardiovascular effects. Although NO donors have been used since 19th century, the vascular actions of NO were only understood in the 1980s. NO acts in the vascular smooth muscle cells (VSMCs) through the activation of soluble guanylate cyclase to promote the increase in intracellular cyclic guanosine monophosphate (cGMP), which stimulates protein kinase G (PKG). The activation of NO/cGMP/PKG pathway in VSMCs leads to vasodilation. It has been established that the deficiency in NO/cGMP signaling pathway is involved in pathophysiological mechanisms of many cardiovascular diseases such as atherosclerosis, arterial hypertension (AH), angina pectoris, and pulmonary hypertension. In this context, the use of NO releasing drugs appears to be an effective alternative to replace the deficient endogenous NO and mimic the role of this molecule in the body. Organic nitrates represent the oldest class of NO donors that have been clinically applied. Unfortunately, the phenomenon of tolerance often occurs when these drugs are chronically used. It implies that higher doses are needed to reach the desired effects. Therefore, the search for and development of new compounds presenting lower tolerance effects is increasing. In this chapter, we briefly review the mechanisms by which NO leads to vasodilation. We also give some perspective on the historical background of organic nitrates discovery and their use as NO releasing drugs. In addition, we discussed the action mechanisms of the most well-known organic nitrates used in the clinical practice and its effects in AH, both in experimental and clinical studies. Furthermore, we discussed the mechanisms underlying the tolerance caused by the commonly used organic nitrates. Lastly, we highlight some achievements from our group in the development of new organic nitrates and their translational application in cardiovascular disorders.