Physiologic effects of nitric oxide on the vascular system

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NO is released continuously by vascular endothelial cells through the action of eNOS, and this basal release regulates vascular tone. NO is important in the maintenance of resting vascular tone (22), in particular the regulation of coronary resistance vessels as well as pulmonary, renal, and cerebral vascular resistance (23,24). NO production is highest in the resistance vessels and may be important in the regulation of vascular tone of various vascular beds (25), as well as blood pressure (BP) control. NO also modulates vascular tone by regulating the expression of various endothelial vasoconstrictors and growth factors, including platelet-derived growth factor-B and endothelin-1 (ET-1) (26).

NO appears to be involved in the regulation of myocardial contractility by a cGMP-dependent mechanism. This regulation is possibly via the microvascular endothelium, which is in close proximity to cardiac myocytes. Increased iNOS in cardiac myocytes produces a level of NO that reduces myocardial contractility significantly (27). NO can also modulate myocardial contractility by decreasing the intracellular levels of cyclic adenosine monophosphate in response to ^-adrenergic stimulation (28).

Fig. 1. Hyperglycemia and endothelium-derived vasocative substances. Hyperglycemia decreased the bioavailability of nitric oxide (NO) and prostacyclin (PGI2) and increased the synthesis of vasoconstrictor prostanoids and endothelin (ET-1) via multiple mechanisms (see text). PLC, phospholipase C; DAG, diacylglycerol; PKC, protein kinase C; eNOS, endothelial nitric oxide synthase: Thr, thrombin; NAD(P)H Ox, nicotinamide adenine dinucleotide phosphate oxidase; O2-, superoxide anion; OONO-, peroxynitrite; MCP, monocyte chemoattractant protein-1; NFkb, nuclear factor K b; TNF, tumor necrosis factor; Ils, interleukins; COX-2, cyclooxygense-2. (Reproduced with permission from ref. 127.)

Fig. 1. Hyperglycemia and endothelium-derived vasocative substances. Hyperglycemia decreased the bioavailability of nitric oxide (NO) and prostacyclin (PGI2) and increased the synthesis of vasoconstrictor prostanoids and endothelin (ET-1) via multiple mechanisms (see text). PLC, phospholipase C; DAG, diacylglycerol; PKC, protein kinase C; eNOS, endothelial nitric oxide synthase: Thr, thrombin; NAD(P)H Ox, nicotinamide adenine dinucleotide phosphate oxidase; O2-, superoxide anion; OONO-, peroxynitrite; MCP, monocyte chemoattractant protein-1; NFkb, nuclear factor K b; TNF, tumor necrosis factor; Ils, interleukins; COX-2, cyclooxygense-2. (Reproduced with permission from ref. 127.)

NO also serves to maintain the integrity of the vascular endothelium through its interaction of both platelets and leukocytes with the vessel wall. Substances released during platelet activation (ADP), or the coagulation cascade (thrombin) stimulate NO production (29). NO is then released from the endothelium into the vessel lumen, in which it interacts with platelets and disaggregates them via a cGMP-dependent mechanism (30). NO also serves to attenuate leukocyte-vascular wall interactions. Inhibition of NO promotes leukocyte adhesion to the endothelium and causes a rapid increase in microvascular permeability and vascular leakage that is characteristic of an acute inflammatory response (31).

In vitro (32) and in vivo (33) studies have demonstrated that NO can also attenuate vascular smooth muscle proliferation. Animal studies have shown that L-arginine, the substrate for NOS, impairs neointimal proliferation after vascular injury (34).

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