Nitric Oxide as a Central Molecule in Hypertension: Focus on the Vasorelaxant Activity of New Nitric Oxide Donors

Figures

• 

  Figure 1. Nitric oxide (NO) induces relaxation in vascular smooth muscle cells (VSMC). The activation of G-protein coupled receptor (GPCR) stimulates phospholipase C (PLC), which is responsible for cleavage of membrane phospholipids to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). The latter binds to the IP3 receptor in sarcoplasmic reticulum (SR) to promote Ca2+ extrusion, which, together with DAG, evokes Ca2+ influx through voltage-operated Ca2+ channels (Cav) at the cellular membrane. The linkage of Ca2+ to calmodulin promotes endothelial nitric oxide synthase (eNOS) activation, which, in turn, triggers the formation of NO and citrulline from arginine and O2. This enzyme requires cofactors such as nicotinamide adenine dinucleotide phosphate (NADPH), flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and tetrahydrobiopterin (BH4). In case of an increase in reactive oxygen species (ROS), they react with NO and induce peroxynitrite (ONOO−) production. NO spreads to VSMC where it binds to soluble guanylyl cyclase (sGC) and causes the formation of 3,5-cyclic guanosine monophosphate (cGMP), which stimulates the cGMP-protein kinase G (PKG). This kinase negatively…

• 

  Figure 2. Mechanisms involved in NO-related hypertension. The effects of angiotensin II (Ang-II) are mediated by its binding to angiotensin type 1 (AT1R) and type 2 (AT2R) receptors. AT1R is responsible for the classic pro-hypertensive activity of Ang-II, including NADPH oxidase activation and reactive oxygen species (ROS) production. Ang-II undergoes the action of angiotensin converting enzyme type 2 (ACE2) into angiotensin 1–7 (Ang-(1–7)), which classically interacts with Mas receptor (MasR) and induces the PI3K/Akt pathway activation and consequent phosphorylation of eNOS. The activation of MasR also downregulates NADPH activity, reducing ROS levels. Furthermore, Ang-(1–7) can also bind to AT2R, which stimulates the bradykinin (BK)–NO cascade. It is important to highlight that, when activated, the BK targets such as the B2 receptors induce NO production. NO, in turn, is responsible for stimulating the β-arrestin pathway that promotes AT1R desensitization and internalization of the receptor. In summary, the increase in NO (from endothelial and neuronal nitric oxide synthase—eNOS and nNOS, respectively) promotes a decrease in oxidative stress, inducing downregulation of sympathoexcitation…