It has been described that the AT2R receptor can dimerize with the bradykinin receptor (B2R) in the cell membrane and with the mtNOS in the mitochondrial matrix, which, on activation, increase the production of NO in the two microenvironments [60, 61].
Other production sources of mitochondrial ROS (mtROS) include electrons derived from substrates of complex II that can be transported to oxygen and complex I , matrix enzymes , the external membrane , and the uncoupled mitochondrial NOS (mtNOS) .
The NOS has four isoforms: neuronal (nNOS), inducible (iNOS), endothelial (eNOS), and mitochondrial (mtNOS
NO is produced from L-arginine by NOS , an enzyme with different isoenzymes (neuronal NOS or nNOS, inducible NOS or iNOS, endothelial NOS or eNOS, and mitochondrial NOS or mtNOS
The brain form (bNOS), also known as cytosol, shows the expression in about 2% of brain neurons as well as in the liver and lungs, the endothelial form (eNOS) appears constitutively in endothelial cells, the hepatocyte form (hepNOS) appears in hepatocytes, and mitochondrial form (mtNOS
) is present in all cells.
Mitochondria have their own isozyme of NOS (mtNOS
) that is responsible for regulating oxygen consumption in the electron transport chain (ETC) by reversibly binding to and inhibiting cytochrome-c oxidase (complex IV).
In aging mice, the activities of brain mitochondrial enzymes (complexes I and IV and mtNOS
) are linearly correlated with neurological performance (tightrope and T-maze tests) and with median life span and negatively correlated with the mitochondrial content of lipid and protein oxidation products.
Tatoyan and Ginlivi (1998) also reported mitochondrial NOS (mtNOS
The high concentration of [Ca.sup.+2] activates mitochondrial calcium-sensitive [K.sup.+] channels (mtKca) and mitochondrial nitric oxide synthase (mtNOS
), which increases the levels of nitric oxide (N[O.sup.*]) (Figure 3) [21, 23, 33, 64, 100, 101, 107-115].
Endotoxemic shock is accompanied by a marked increase in mtNOS
activity in the heart, leading to increased production of NO, [O.sup.-.sub.2], [H.sub.2][O.sub.2], and [ONOO.sub.-], causing mitochondrial dysfunction and contractile failure .
NO is the smallest gasotransmitter, recognized as an ubiquitous intercellular messenger; it is produced by three isoforms of NO synthases (NOS): endothelial NOS (eNOS) , neuronal NOS (nNOS) , and inducible NOS (iNOS)  and mitochondrial NOS (mtNOS) .
Several studies show the presence of a new isoform of eNOS enzyme in mitochondria (mtNOS) [36,37].