Nitric Oxide in the Pulmonary Vasculature

Abstract

Abstract-Homeostasis in the pulmonary vasculature is maintained by the actions of vasoactive compounds, including nitric oxide (NO). NO is critical for normal development of the pulmonary vasculature and continues to mediate normal vasoregulation in adulthood. Loss of NO bioavailability is one component of the endothelial dysfunction and vascular pathology found in pulmonary hypertension (PH). A broad research effort continues to expand our understanding of the control of NO production and NO signaling and has generated novel theories on the importance of pulmonary NO production in the control of the systemic vasculature. This understanding has led to exciting developments in our ability to treat PH, including inhaled NO and phosphodiesterase inhibitors, and to several promising directions for future therapies using nitric oxide-donor compounds, stimulators of soluble guanylate cyclase, progenitor cells expressing NO synthase ( Key Words: nitric oxide Ⅲ pulmonary vasculature Ⅲ pulmonary hypertension treatment T he low resting tone of the pulmonary circulation is established at birth 1 and is modulated by the balance of vasoconstrictors (endothelin-1, thromboxane A 2 , and serotonin) and vasodilators (prostacyclin and NO) produced by the pulmonary endothelium (reviewed in 2 ). Vasoconstriction of the pulmonary vasculature in response to acute hypoxia is the clearest divergence from the systemic vasculature, which is characterized by hypoxic vasodilation in the periphery. The acute hypoxic response in the pulmonary bed is thought to be critical for matching ventilation with perfusion. Disruption of the balance of pulmonary vasodilators and vasoconstrictors, for example by environmental stress (eg, prolonged hypoxia) or endothelial dysfunction, can lead to the pulmonary vasoconstriction, vascular smooth muscle cell (VSMC) proliferation, and in situ thrombosis that characterize pulmonary hypertension (PH).NO is a free radical gas that diffuses from its site of production in the endothelial cell to its target, soluble guanylate cyclase (sGC), in the VSMC. In this classical NO signaling pathway, activation of sGC enhances cyclic guanosine monophosphate (cGMP) production, which in turn mediates vasodilatation. Alternative NO signaling pathways involve the oxidation of NO to nitrite 3 or reactions of NO with protein thiols to form S-nitrosothiols (SNOs), 4 NO derivatives that can function as vasodilators or as posttranslational modifiers of protein function. Intriguing new theories are founded on the interaction of nitrite and SNOs with hemoglobin (Hb): by exploiting the allosteric nature of Hb within red blood cells (RBCs), the NO signal is transported to the periphery, where its vasodilator potential enables selective delivery of oxygenated blood to hypoxic tissue.

Overview of Clinical Lung Transplantation

“…Nitric oxide has been shown to improve oxygenation, reduce pulmonary artery pressure without affecting systemic pressure, and shorten the duration of mechanical ventilation in case series (Date et al 1996;Ardehali et al 2001). Its primary effect is likely due to improvement in V/Q matching because NO is delivered to alveoli that are ventilated, although NO also has important anti-inflammatory properties related to neutrophil, macrophage, and platelet function (Coggins and Bloch 2007). PGE 1 infusion can also be helpful in treating severe PGD because it down-regulates inflammation in the acutely reperfused lung.…”

Quaternary Structure Controls Ligand Dynamics in Soluble Guanylate Cyclase

“…It plays a critical role in regulation of vascular blood pressure (4), lung airway relaxation (5), and immune response (6). In heterodimeric sGC, the GTP catalytic site is located presumably at the interface between both subunits, whereas the sensing domain in ␤-subunit contains the heme group necessary for NO binding.…”

The potential of Angeli's salt to decrease nitric oxide scavenging by plasma hemoglobin

“…NO also modulates vascular permeability [6][7][8], angiogenesis [9,10], platelet adhesion and aggregation [11][12][13], and leukocyte adhesion [14][15][16]. Thus, NO bioavailabilty is important in maintaining several aspects of homeostasis and its dysfunction contributes to a large variety of diseased states [17][18][19][20][21][22][23][24].…”