Comparative Physiology of 02 Sensors

HPV is not the only homeostatic mechanism that optimizes systemic 02 delivery. Mammals also have 02 sensors in the systemic vasculature (carotid body) and airway (neuroepithelial body). In addition, there are powerful 02 sensor systems that are primarily active in the fetus or during the transitional period at birth (e.g., the ductus arteriosus SMC and the adrenomedullary cell).

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t Endothelin I t Prostaglandins f NOS

tHIF

t Endothelin f Erythropoetin f NOS

Modulators

Hypoxia 1

Decreased pETC Activity Altered A¥m

Kv Channel Inhibition \

PASMC Depola rization Activation of L-type Ca:* Channel

Increased Ca* Influx/lCa"]^ Vasoconstriction

Sensor

Mediator

Effector

Figure 1. Proposed mechanism for HPV: An updated version of the redox hypothesis.

In adult mammals, PASMCs and the type 1 cells ofthe carotid body (CB) are the predominant 02 sensing cells. Both these sensors respond rapidly (within seconds) to moderate hypoxia, in the airway (e.g., PASMC) or systemic (e.g., CB) circulation. The response of both cell types to hypoxia optimizes tissue 02 delivery and ATP production. In the lung, hypoxia causes contraction ofPASMC in small arteries, thereby redistributing blood to optimally-ventilated lobes; whilst in the carotid body, hypoxia activates type I cells leading to increased nerve discharge and hyperventilation. Although the response to hypoxia is tissue specific, most specialized systems share components of the mechanism underlying HPV. Specifically these rapidly responding cardiovascular and pulmonary sensors appear to involve a redox 02 sensor (possibly the mitochondria or NADPH oxidase) and a membrane effector pathway (probably one or more 02- and redox-sensitive K+ channels (Fig. 2) (4). These acute compensatory pathways are distinct from but relevant to the slower onset mechanisms that are triggered when hypoxia persists, such as right ventricular hypertrophy, PA remodeling, and polycythemia, which result from activation of hypoxia inducible factor, HIF (131).

Additional 02 sensors are also active in the fetus. The role of various 02 sensors in fetus is somewhat different than in the adult, in large part because the normal fetal Po2 is, by adult standards, very low (P02 -20-30 mmHg). The ductus arteriosus (DA) connecting the pulmonary artery and aorta is one of the vessels that act as an 02 sensor. In the normal fetus the placenta provides oxygenation. The DA is tonically open and shunts blood away from the non-

expanded fetal lungs. After the first breath, the increase in P02 triggers DA smooth muscle cell (DASMC) contraction, thereby directing blood to the pulmonary vasculature. In addition to the DA response, adrenomedullary cells also release catecholamines in response to hypoxia, which prepares the fetus for stress during labor (36,48). It now appears that each of these 02 sensing systems consists of a sensor that alters the production of a mediator in response to changes in P02. The mediator, in turn, alters the function of one or more effectors, which ultimately mediate the physiologic response of the system (73, 74). Teleologically it is optimal that the sensor responds to levels of hypoxia that are mild or brief enough so that ATP levels are preserved, averting tissue damage. An array of 02 sensing systems has evolved to maintain the Po2 within a tight physiological range, thus stabilizing ATP production and promoting survival during the periodic exposures to hypoxia that occurs in most aerobic lives. Often the sensor, mediator, and effector are linked in a functional unit. It appears that in many of these specialized tissues the sensor is the proximal portion of the mitochondrial electron transport chain (ETC), the mediators are ETC-derived activated oxygen species (AOS), and the effectors are redox-sensitive plasmalemmal K+ channels. Although there may not be a single 02 sensor, and despite the fact that response to hypoxia are modified by genetics and by neurohormonal factors, there is evidence suggesting that the proximal mitochondrial ETC isinvolved 02 sensing in several tissues and species (7, 72).

Normoxia Rotcnone

Figure 2. Hypoxia inhibits K+ channels in rat resistance PASMCs. A: Whole cell K+ current inhibition in response to hypoxia and rotenone (a complex I ETC blocker), B: PASMCs depolarize in response to hypoxia (Reproduced from Ref. 26).

Normoxia Rotcnone

Figure 2. Hypoxia inhibits K+ channels in rat resistance PASMCs. A: Whole cell K+ current inhibition in response to hypoxia and rotenone (a complex I ETC blocker), B: PASMCs depolarize in response to hypoxia (Reproduced from Ref. 26).

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