A redox-based O2 sensor in rat pulmonary vasculature.

Abstract

The effector mechanism of hypoxic pulmonary vasoconstriction (HPV) nucleotides.10 Furthermore, lung ATP content is unchanged by hypoxia until the alveolar 02 tension is reduced below 1 mm Hg.11 Depletion of high-energy phosphates in rat lungs, accomplished by chronic ingestion of a diet rich in the false precursor /3-guanidinopropionic acid, does not alter HPV.12 Finally, the doses of several ETC inhibitors that alter vascular tone fail to deplete ATP.l0,13 An 02 sensor that monitors a redox parameter (eg, a redox ratio of couples such as GSH/ GSSG, NADH/NAD, or activated 02 species [AOS] production) rather than ATP levels might be advantageous. Changes caused by mild or moderate hypoxia could be rapidly sensed while preserving ATP at levels necessary to sustain HPV. More severe hypoxia (anoxia) might lower ATP levels and activate ATP-sensitive K' (KATp) channels, which would inhibit HPV.Another means by which hypoxia and ETC inhibitors might alter vascular tone is proposed. The ETC is responsible for the oxidation of NADH and is the major site of 02 consumption in the lung, accountXig iui greater than 56% of total lung O2 consumption.14 A small but significant portion of 02 consumed results in the production of radicals and peroxides.15-16 We hypothesized that inhibition of the proximal ETC would have two effects that tend to make the net cytosolic redox status more reduced (eg, increased ratios of NADH to NAD and GSH to GSSG). First, inhibition of by guest on

Oxygen-Sensitive Kv Channel Gene Transfer Confers Oxygen Responsiveness to Preterm Rabbit and Remodeled Human Ductus Arteriosus

“…Although all cells of aerobic organisms are sensitive to extreme hypoxia, 15,16 certain cardiovascular and pulmonary cells display specialized O 2 -sensing systems that are characterized by their rapid responses to physiological levels of hypoxia and the fact that they elicit homeostatic responses that optimize O 2 uptake, distribution, or delivery. [17][18][19][20] Although the O 2 sensor systems vary among tissues, they generally include a sensor (often the mitochondria or a NADPH oxidase 12,[21][22][23][24] ) that alters the production of a mediator (often a reactive O 2 species 12,23 ) in response to changes in PO 2 . 17 The mediator, in turn, alters the function of 1 or more effectors, which ultimately elicits the physiological response to altered PO 2 .…”

ADP-ribosyl Cyclase and Cyclic ADP-ribose Hydrolase Act as a Redox Sensor

“…Thus, ␤-NADH may promote an increase in cADPR accumulation from ␤-NAD ϩ , at least in part, by blocking the metabolism of cADPR by a cADPR hydrolase. The effect of ␤-NADH on cADPR synthesis may be of importance to the regulation of O 2 -sensing cells because the redox state of such cells is uniquely sensitive to changes in O 2 (3,20,21,22), and hypoxia has been shown to increase ␤-NADH levels in all O 2 -sensing cells studied to date (3,20,21,22,23). Previous investigations of pulmonary artery smooth muscle suggest that total tissue ␤-NAD ϩ levels may be in the mM range during normoxia and hypoxia and that during hypoxia a small fall in ␤-NAD ϩ levels yields a large increase in ␤-NADH levels.…”

“…An initial transient constriction (phase 1) is followed by a slowly developing, sustained phase of constriction (phase 2). It is widely thought that the first phase of constriction is initiated by a reduction in membrane K ϩ conductance in pulmonary artery smooth muscle cells (2)(3)(4), membrane depolarization, and Ca 2ϩ influx through voltage-gated Ca 2ϩ channels (5)(6)(7)(8). Phase 2 of the constriction is tonic and may depend on the release of a vasoconstrictor from the endothelium, which sensitizes the contractile apparatus to Ca 2ϩ (9,10).…”

“…We have investigated the role of the ␤-NAD ϩ :␤-NADH ratio in regulating cADPR synthesis in pulmonary artery smooth muscle because of the fact that (a) the cellular redox couple ␤-NAD ϩ is the recognized substrate for cADPR synthesis; (b) the redox state of O 2 -sensing cells is uniquely sensitive to changes in the level of O 2 (20); (c) hypoxia has been shown to reduce the NAD(P): NAD(P)H ratio in all O 2 -sensing cells studied to date, including carotid body type I cells (20,21), airway neuroepithelial cells (22), and pulmonary artery smooth muscle cells (3,23); and (d) the hypoxia-induced fall in the NAD(P): NAD(P)H ratio in carotid body type I cells occurs with a time course similar to the hypoxia-induced increase in intracellular Ca 2ϩ (21). We report that the enzyme activities for cADPR synthesis and metabolism are particularly high in pulmonary artery smooth muscle, as opposed to systemic artery smooth muscle.…”

Oxidative stress and oxidant signaling in obstructive sleep apnea and associated cardiovascular diseases

“…Further, ROS has been shown to directly promote growth of vascular smooth muscle cells [110]. While the production of ROS during chronic hypoxia has been controversial [111][112][113], evidence also suggests the roles of ROS in signaling pathways for the development of pulmonary hypertension [114][115][116].It appears that OSA symptoms are heterogeneous in nature and the resultant consequences differ accordingly. For example, an early study by Bradley et al [117] identified that 12% of OSA patients had right heart failure and these patients had a substantially lower awake arterial PO 2 , suggesting that sustained hypoxia activates signals to promote pulmonary hypertension and right ventricular heart failure.…”