Hypoxic Pulmonary Vasoconstriction: MODIFYING FACTORS
Several important factors modify hypoxic vasoconstriction (Table 1). While the effects of many of these factors have been repeatedly substantiated, the mechanisms of action remain largely unexplained.
Although the AHPR is present in the lungs of all mammalian species examined, there is considerable species variation in the magnitude of the response. Pigs and cows have a very vigorous response, while dogs and hamsters have a comparatively mild pressor response to alveolar hypoxia. This variability extends to individuals within a given species and among human subjects where significant differences in the strength of the response suggest the influence of unknown genetic factors. A genetic influence on the magnitude of the response is also apparent in animal studies of the adaptation to high altitude. Strains of cattle susceptible to the development of pulmonary hypertension at high altitude (“brisket disease”) have a larger acute hypoxic pressor response than nonsusceptible cattle. Different strains of rats exhibit differences in the magnitude of the response and in their susceptibility to the development of pulmonary hypertension at high altitude.
Traditionally, the acid-base status of the blood is thought to be an important modifying factor; the consensus was that acidosis potentiates, while alkalosis diminishes the magnitude of hypoxic vasoconstriction for unknown reasons. However, more recent work questions this conclusion by suggesting that any deviation from normal attenuates the response.
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Aging is associated with a decrease in the magnitude of the AHPR in animal studies, along with a decrease in vasoconstriction in response to other pharmacologic stimuli. It is not known whether such findings extend to human subjects.
Table 1—Factors Which Modify the Acute Hypoxic Pressor Response
|
Factor |
Effect on |
Reference |
|
Species |
variable |
29-31 |
|
Intei4ndividual |
variable |
32-33 |
|
Genetic |
variable |
34,35 |
|
|
acidosis f |
37,38 |
|
Age |
i |
39 |
|
Severe hypoxia |
i |
41 |
|
(Pa02<25 |
|
|
|
Repeated |
t |
42 |
|
Gender, pregnancy |
i or t |
43-47 |
|
Neural |
|
52, 54-59 |
The degree and temporal pattern of exposure to hypoxia may also affect hypoxic vasoconstriction. Graded reductions of blood Po2 are associated with corresponding graded increases in pulmonary artery pressure in the isolated perfused lung down to Pa02 values of 25-30 mm Hg. Below this point, vasodilator responses commence as Po2 is lowered further. Potentiation of the response after repeated intermittent hypoxic exposures has been observed by some investigators.
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Female gender and sex steroid hormones are additional factors associated with an alteration in the magnitude of hypoxic vasoconstriction, which may be the result of hormonal alteration of components of the vascular wall. Sylvester et al reported that estrogen treatment attenuated the AHPR in juvenile female sheep. Prostacyclin (PGI2) was implicated as the mediator of this altered reactivity since indometh- acin administration abolished this effect and simultaneously inhibited the outflow of the stable metabolite of PGI2, 6-keto PGF le from lungs of estrogen-treated animals. Data concerning alteration of the AHPR during pregnancy are conflicting; the response is diminished in the pregnant cat, rat,and dog, but increased in pregnant cattle susceptible to high- altitude disease. The recent demonstration of potentiation of the AHPR in the isolated perfused rat lung by treatment with a glucocorticoid lends support to speculation that hormonal modulation of the response may represent another important type of regulatory mechanism of pulmonary vascular reactivity. Neural influences also modify the APHR (see below).
