*3.3.1 Ca2+ exchange through plasma membrane*

Voltage-gated Ca2+ channels regulate [Ca2+]i through sensing electrical signals to allow Ca2+ entering the cell. High voltage-activated L-type channels are broadly found in the cardiovascular system. L-type Ca2+ channel inhibitors, such as dihydropyridines, phenylalkylamines, and benzothiazepines, are a major class of drugs for treating CVDs [42]. The opening probability of L-type Ca2+ channel can be

**9**

*Nitric Oxide and Oxidative Stress-Mediated Cardiovascular Functionality: From Molecular…*

its opening probability to hyperpolarize the cell membrane [44, 45]. The hyperpolarized cell membrane can no longer send electrical signals to activate the Ca2+ channel, and therefore, Ca2+ influx is inhibited. Besides PKG, high NO level also

Ca2+ pumping ATPase located on the cell membrane also extrudes Ca2+ from the cytosol. It binds Ca2+ with a high affinity and forces Ca2+ out of the cell even when [Ca2+]i is very low to maintain the low [Ca2+]i level at rest [47]. PKG can stimulate

cytosolic Ca2+, but its Ca2+ binding affinity is low [47]. This mechanism is crucial for preventing cells from the cytotoxicity of an acute high Ca2+ concentration. The

Ca2+ pump ATPase also resides on the ER responsible for the uptake of cytosolic Ca2+ into the ER. NO pathway regulates ER Ca2+ pumping through phosphorylation of phospholamban by PKG [51]. Mainly identified in cardiac tissues, phospholamban is an inhibitor of SR Ca2+ pump. Phospholamban is normally phosphorylated by PKA, which diminishes its inhibitory effect to Ca2+ pump [52]. Interestingly, in neonatal cardiomyocytes and vascular SMCs, NO pathway also demonstrated relaxation effect through differentially phosphorylating phospholamban [53, 54]. Inosital 1,4,5-trisphosphate (IP3) is a critical messenger molecule that can induce Ca2+ release from the ER reservoir. IP3 receptor resides on the ER and works as a chemical-activated Ca2+ channel. NO-cGMP pathway can reduce IP3 generation [55], and PKG can phosphorylate and inactivate IP3 receptor in vascular SMCs to

Independent from NO-Ca2+ pathway, in SMCs NO also increases MLCP activity and limits MLCK activity, resulting in a dephosphorylation shift of myosin light chain phosphorylation balance [15]. Thus, myosin cross-bridge cycling is inhibited,

Anatomic alterations in the cardiovascular structure directly deteriorate cardiovascular functions. NO is a multifunctional regulator for homeostasis in the cardiovascular system. An intact endothelial layer is the hub for NO generation. Pathological changes in NO generation can trigger various local flaws that may

Deviant NO level causes change of endothelial permeability, a key characteristic for mass transfer and extravasation. Interestingly, increase, decrease, and no change of vascular permeability due to the presence of NO have been reported. Using

channels. PKG can activate the Na+

channels to achieve aorta relaxation in a cGMP-independent

/Ca2+ exchanger is more effective in quickly removing

/Ca2+ exchanger is the stored sodium electrochemical gradient

/K+

channel and increases

channel to cause more Na<sup>+</sup>

*DOI: http://dx.doi.org/10.5772/intechopen.82556*

directly activates K<sup>+</sup>

driving force for Na<sup>+</sup>

created by Na<sup>+</sup>

Unlike Ca2+ pump, Na+

/K+

*3.3.2 Ca2+ exchange through ER*

inhibit ER Ca2+ release [35, 56].

causing smooth muscle relaxation.

fashion [46].

lowered by PKG indirectly [43]. PKG phosphorylates the K+

the Ca2+ pump, initiating the expulsion of cytosolic Ca2+ [48].

accumulated to indirectly facilitate Ca2+ removal [49, 50].

*3.3.3 Ca2+-independent muscle relaxation regulated by NO*

**4. Vascular structural integrity mediated by NO**

progress to be systematic cardiovascular issues with time.

**4.1 NO-induced alterations in endothelial permeability**

*Nitric Oxide and Oxidative Stress-Mediated Cardiovascular Functionality: From Molecular… DOI: http://dx.doi.org/10.5772/intechopen.82556*

lowered by PKG indirectly [43]. PKG phosphorylates the K<sup>+</sup> channel and increases its opening probability to hyperpolarize the cell membrane [44, 45]. The hyperpolarized cell membrane can no longer send electrical signals to activate the Ca2+ channel, and therefore, Ca2+ influx is inhibited. Besides PKG, high NO level also directly activates K<sup>+</sup> channels to achieve aorta relaxation in a cGMP-independent fashion [46].

Ca2+ pumping ATPase located on the cell membrane also extrudes Ca2+ from the cytosol. It binds Ca2+ with a high affinity and forces Ca2+ out of the cell even when [Ca2+]i is very low to maintain the low [Ca2+]i level at rest [47]. PKG can stimulate the Ca2+ pump, initiating the expulsion of cytosolic Ca2+ [48].

Unlike Ca2+ pump, Na+ /Ca2+ exchanger is more effective in quickly removing cytosolic Ca2+, but its Ca2+ binding affinity is low [47]. This mechanism is crucial for preventing cells from the cytotoxicity of an acute high Ca2+ concentration. The driving force for Na<sup>+</sup> /Ca2+ exchanger is the stored sodium electrochemical gradient created by Na<sup>+</sup> /K+ channels. PKG can activate the Na<sup>+</sup> /K+ channel to cause more Na<sup>+</sup> accumulated to indirectly facilitate Ca2+ removal [49, 50].
