Heterogeneity in the Modulation of HPV

HPV in response to a decrease in pulmonary arterial P02 raises one of the potential risks associated with local V/Q control based on constriction of pulmonary arteries in response to low Po2) namely, that of maintaining a low pulmonary vascular resistance during exercise. Part of the increase in oxygen consumption associated with exercise is accommodated by increased oxygen extraction by the working muscles, the result being a decrease in mixed venous P02. For example, in human subjects exercising at an intensity sufficient to increase cardiac output to 3.3 times the resting level, the mixed venous Po2

decreased from about 38 to about 25 Torr (87). Thus, the mixed venous Po2 can easily fall to levels for which data such as in Figure 2 predict significant HPV. Studies such as those represented in Figure 2, and (19) have been carried out at what might be considered resting to substantially below resting pulmonary arterial blood flow rates. Thus, given the expectation that, as the blood flow increases, the mixed venous Po2 would penetrate further into the small pulmonary arteries and capillaries, the results of such studies probably represent lower bounds on the potential influence of the decrease in mixed venous P02 during exercise. Thus, it would appear that the complex modulation of the hypoxic response might be directed, at least in part, at preventing its potentially pulmonary hypertensive effects during exercise. In fact, exercise has been found to result in pulmonary vasoconstriction after NO synthase and p-adrenergic receptor blockade in sheep (47).

Figure 3. The change in arterial diameter for vessels of a given normoxic "Control Diameter" that resulted from increasing blood flow into the left lower lobar artery of the ferret lung while maintaining constant vascular pressure. The 3 study conditions were "Normoxia" (alveolar Po2 = 120 Torr), "Hypoxia" (56 Torr), and "Hypoxia+L-NAME." The high flow was 4 times the low flow. Under normoxic conditions, increasing the flow had little effect on the vessel diameters as would be expected given the vessels low tone under normoxic conditions. During hypoxia the constricted vessels dilated when the flow was increased. The smaller vessels dilated the most as would be expected given that they were the most constricted as in the Figure 1A example. During hypoxia with L-NAME, increasing flow had no effect on the diameters even though the vessels were constricted. Thus, the L-NAME interfered with the flow-induced dilation of the hypoxia constricted vessels. (Modified from Ref. 12).

Increased pulmonary flow has resulted in release of NO (31, 71) or prostacyclin (15, 89), and both of these vasodilators are apparently involved in modulating the hypoxic response even under what might be considered resting

Figure 3. The change in arterial diameter for vessels of a given normoxic "Control Diameter" that resulted from increasing blood flow into the left lower lobar artery of the ferret lung while maintaining constant vascular pressure. The 3 study conditions were "Normoxia" (alveolar Po2 = 120 Torr), "Hypoxia" (56 Torr), and "Hypoxia+L-NAME." The high flow was 4 times the low flow. Under normoxic conditions, increasing the flow had little effect on the vessel diameters as would be expected given the vessels low tone under normoxic conditions. During hypoxia the constricted vessels dilated when the flow was increased. The smaller vessels dilated the most as would be expected given that they were the most constricted as in the Figure 1A example. During hypoxia with L-NAME, increasing flow had no effect on the diameters even though the vessels were constricted. Thus, the L-NAME interfered with the flow-induced dilation of the hypoxia constricted vessels. (Modified from Ref. 12).

Hypoxia+L-NAME

400 «00 »00 1000 1200 Control Diameter (jim)

Hypoxia+L-NAME

400 «00 »00 1000 1200 Control Diameter (jim)

conditions as demonstrated by the enhancement of HPV after inhibition of their production (8,55,68). Increased lung NO output is observed during exercise (13, 73), although it is not clear that the pulmonary arterial endothelium makes a significant contribution to exhaled NO. In addition, Figure 3 shows that the hypoxic response can be attenuated by increased flow in ferret lungs and that the effect is eliminated by treatment with an NO synthase inhibitor. Thus, the argument can be made that the attenuation of HPV by vasodilator mechanisms called into play by mechanical stresses on the vessel walls (12) and/or blood (85) allows cardiac output to increase during exercise without overloading the right ventricle.

An interesting twist on this concept is provided by a study from Henderson et al. (36), wherein they compared the pulmonary arterial pressure response to exercise and hypoxia between two strains of rats one designated as having low exercise capacity, LCR, and the other high exercise capacity, HCR. They observed that the elevation in pulmonary arterial pressure with hypoxia during exercise in the LCR, was absent in the HCR, even though the HCR had higher cardiac output, and they noted the potential advantage that the attenuated HPV might afford the HCR. There is also evidence that exercise training can enhance endothelium-dependent (and presumably shear stress mediated) pulmonary vasodilation (44), which might suggest an adaptation that would enhance the ability of the pulmonary arteries to avoid HPV during exercise.

While shear stress, x, modulation may serve to limit HPV during exercise or global hypoxia, it may serve to enhance the HPV response to localized hypoxia. This may be appreciated as follows. One common experimental approach for studying HPV is to perfuse lungs with constant flow and measure the changes in perfusion pressure in response to decreased inspired Po2. Then, the effects of hypoxia on the diameters, D, of hypoxia-sensitive vessels are deduced. This experimental design is consistent with the fact that pulmonary blood flow is normally determined by the cardiac output independently ofpulmonary vascular resistance. Thus, in this experimental design, as with low inspired Po2 in vivo, HPV results in a rise in the shear stress on the walls of the constricted vessels. Using relationships for Poiseuille flow to make the point, the resistance, R, of a vessel is proportional to D'l/4, and wall shear stress is proportional to D'1/3. Thus, the fractional increase in wall shear stress, for a given fractional increase in vascular resistance, (Rh-Rn)/Rn, would be:

(Th-xj/Tn = (i+((i?h-;y//yr-i where the subscripted h and n refer to the hypoxic and normoxic conditions, respectively. For example, a 100% increase, or doubling, of the resistance in a vessel would result in a 68% increase in wall shear stress. This experimental design does not reproduce what happens in the case of hypoventilation of a small region in the lungs, wherein the flow is dependent primarily on local resistance at any given cardiac output. In this case, the effect of the local alveolar hypoxia and HPV is to decrease the flow with virtually no change in the pressure at the regional arterial inlet. In that case, the shear stress on the walls ofthe constricted vessels decreases. For constant pressure driving the flow through the region, the fractional decrease in wall shear stress for a given fractional increase in vascular resistance would be:

e.g., a 100% increase in resistance would result in a 16% decrease in shear stress. Therefore, in the case of regional hypoxia, if the region is small enough, the stimulus for shear stress stimulated vasodilation decreases, releasing the HPV from shear stress dependent inhibitory modulation. As the hypoxic region becomes a larger fraction of the lung, the decrease in vessel wall shear stress within the region becomes smaller and then increases. Thus, in a sense the vessels within a hypoxic region of the lungs receive an integrated message regarding the number and/or extent of constriction of vessels within the hypoxic region(s), which is transmitted via the shear stress on the vessel walls (82). As the size of the hypoxic region increases, flow-diverting effectiveness of HPV decreases simply because the pulmonary arterial pressure begins to rise (63), but, in addition, shear stress activated modulation begins to attenuate the HPV.

Modulation of the hypoxic response has been revealed by the fact that inhibition of several vasodilator pathways (e.g., mediated by arachidonate metabolites, NO, and purine nucleotides) (8, 15, 51, 68, 85, 93) can potentiate hypoxic vasoconstriction under various experimental conditions. The hypoxic response has also been attenuated by inhibiting production of, or receptors for, various vasoconstrictors (5HT, histamine, endothelin, arachidonate metabolites, etc.), none of which is presently thought to be the mediator of the hypoxic response per se (15, 35, 45, 57). The role of endothelin receptor stimulation is probably the most timely in this context and is discussed elsewhere in this book. In isolated lung experiments, including or excluding various blood components has had dramatic although not always clearly explainable effects (9, 32, 64). Variations even within a species (49, 61) may be due to variability in the modulating (78) as well as in the mediating mechanisms. Thus, some of the heterogeneity and apparently contradictory responses observed in different preparations probably reflect the fact that the relative contributions of all these influences, known and unknown, are difficult to control or to control for.

Additional complexity is implied by the fact that, for the most extensively studied mechanical stress activated vasodilatory mechanisms involving NO or prostacyclin, both are potentially affected not only by the mechanical consequences of the constriction but also by hypoxia itself. In normoxia, NOS inhibition tends to produce small increases in pulmonary vascular resistance (68). However, NOS inhibition has typically produced substantial increases in HPV

(8, 68). The latter might be interpreted as suggesting that basal NO production attenuates HPV or that hypoxia increases either the production or effectiveness of NO. However, the endothelial NO synthase Km for oxygen has been reported to be close enough to physiologically relevant Po2 levels that hypoxia itself would be expected to directly depress NO production (42, 77). Suppression of NO production by hypoxia in whole lungs has been observed (54, 69), although the extent that this effect can be extrapolated to the small fraction of the tissue comprised of hypoxia responsive vessels and their endothelium is not clear. Hypoxia has also inhibited the uptake of the NO precursor L-arginine by pulmonary arterial endothelial cells (10).

There are parallels between the effects of NOS inhibition and cyclooxygenase inhibition on HPV. Cyclooxygenase inhibition also potentiates the hypoxic response, presumably by inhibiting prostacyclin production (15). In addition, the Km of cyclooxygenases for oxygen are in the same range as that of NOS (46), suggesting that the direct effect of hypoxia would be to decrease prostacyclin production. However, acute hypoxia has both decreased (60) and increased (70) pulmonary arterial endothelial cell prostacyclin production.

These modulating influences are more or less autocoidal in nature. More remote modulation is not as clear. Investigations into reflex modulation of hypoxic vasoconstriction have come to mixed conclusions suggesting that it can occur (84), but is perhaps not a normally dominant influence (56, 58). The extent to which that might change under various conditions, e.g., exercise and/or high altitude exposure, may warrant further examination (21, 47).

Was this article helpful?

0 0
Reducing Blood Pressure Naturally

Reducing Blood Pressure Naturally

Do You Suffer From High Blood Pressure? Do You Feel Like This Silent Killer Might Be Stalking You? Have you been diagnosed or pre-hypertension and hypertension? Then JOIN THE CROWD Nearly 1 in 3 adults in the United States suffer from High Blood Pressure and only 1 in 3 adults are actually aware that they have it.

Get My Free Ebook


Post a comment