Nitric Oxide and Related Aspects Underlying Angina

Figures

• 

  Fig. (1). Physiological Nitric Oxide (NO) formation pathways. NO production using xanthine oxidoreductase (XOR) can be synchronized with nitric oxide synthase (NOS). NO turnover pathway is dependent on co-substracts as molecular oxygen (O2) and NADPH and cofactors such flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), tetrahydrobiopterin (BH4), heme and binding calmodulin (CAL) for NO synthesis.

• 

  Fig. (2). NOS isoforms and reactive oxygen species (ROS) production through electron flowing. A) NOS enzyme schematic structure with main cofactors. B) Normal electron flowing in NOS enzyme: electron from flavin derived cofactors goes to Heme domain together with, but faster than, the electron transfer from BH4; however, before the next catalytic cycle can proceed, the BH4 has to be reduced. These oxidations lead to limitation of ROS production. C: electron flowing through NOS enzyme in hypertension: there is a disruption in BH4 oxidation, leading to NOS uncoupling, reduced no production and, consequently, increased ROS.

• 

  Fig. (3). Nociceptive sensitization related to NO/ROS cascade. Neurotransmitter glutamate is secreted from the nociceptor terminal to the synaptic cleft and sensitizes AMPA receptors (AMPAr) on dorsal horn cells membrane. In long-term, the changes in membrane polarization affect the NMDA receptors (NMDAr). NMDAr sensitization allows the Ca+2 influx, which is essential to the neuronal Nitric Oxide Synthase (nNOS) activation. The nNOS activation is possible only if the inactive nNOS has all the cofactors (FAD, FMN, L-arginine and BH4) dimerized. For this, a lesion also increases the GTP cyclohydrolase (GCH1) levels, enhancing BH4. Ultimately, NO produced in the dorsal horn cells are released back into the synaptic cleft for closing guanyl synthase-induced K+ channels and for releasing Substance P. Respectively, the results are the opiate resistance in chronic pain and neural remodeling and hypersensitization.