Title:Nitric Oxide Donors as Potential Drugs for the Treatment of Vascular Diseases Due to Endothelium Dysfunction
Volume: 26
Issue: 30
Author(s): Michele Paulo, Daniela E. F. R. Costa, Daniella Bonaventura, Claure N. Lunardi and Lusiane M. Bendhack*
Affiliation:
- Department Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirao Preto- University of Sao Paulo Av. Do Cafe SN,Brazil
Keywords:
NO donors, endothelial dysfunction, vascular diseases, NO production, tolerance to nitrovadilators, cGMP.
Abstract: Endothelial dysfunction and consequent vasoconstriction are a common condition in patients with
hypertension and other cardiovascular diseases. Endothelial cells produce and release vasodilator substances that
play a pivotal role in normal vascular tone. The mechanisms underlying endothelial dysfunction are multifactorial.
However, enhanced reactive oxygen species (ROS) production and consequent vasoconstriction instead of
endothelium-derived relaxant generation and consequent vasodilatation contribute to this dysfunction considerably.
The main targets of the drugs that are currently used to treat vascular diseases concerning enzyme activities
and protein functions that are impaired by endothelial nitric oxide synthase (eNOS) uncoupling and ROS production.
Nitric oxide (NO) bioavailability can decrease due to deficient NO production by eNOS and/or NO release
to vascular smooth muscle cells, which impairs endothelial function. Considering the NO cellular mechanisms,
tackling the issue of eNOS uncoupling could avoid endothelial dysfunction: provision of the enzyme cofactor
tetrahydrobiopterin (BH4) should elicit NO release from NO donors, to activate soluble guanylyl cyclase. This
should increase cyclic guanosine-monophosphate (cGMP) generation and inhibit phosphodiesterases (especially
PDE5) that selectively degrade cGMP. Consequently, protein kinase-G should be activated, and K+ channels
should be phosphorylated and activated, which is crucial for cell membrane hyperpolarization and vasodilation
and/or inhibition of ROS production. The present review summarizes the current concepts about the vascular
cellular mechanisms that underlie endothelial dysfunction and which could be the target of drugs for the treatment
of patients with cardiovascular disease.
