Properties and Controversies of Hypoxic Pulmonary Vasoconstriction

Reductionist models are useful in defining subcellular mechanisms, however it is crucial that the defining characteristics of HPV are preserved in the experimental models. HPV is a response to the decrease in Po2 of the terminal airways and alveoli. Thus, a nominal decrease in alveolar Po2 giving rise to arterial Po2 of over 55 mmHg can trigger HPV (117). Earlier studies have shown that mixed venous 02 saturation failed to trigger pulmonary vasoconstriction (43), and HPV only occurs when a concomitant decrease in alveolar Po2 is less than 50 mmHg (85). However a component of the hypoxic response may relate to pre-capillary PA Po2 (67). HPV is strongest in resistance PA (43, 51). The hypoxic response is rapid and reversible within seconds (Fig. 3A) (46).

Pulmonary Hypertension Vasoconstriction

Figure 3. HPV is intrinsic to the resistance PA and depends on extracellular Ca2+. A: When rat lungs and kidneys are perfused in series, hypoxia (induced by ventilating the lungs with hypoxic gas) causes pulmonary vasoconstriction and renal vasodilation in the presence of NO synthase and prostaglandin synthesis blockers. B: SMCs from small- (<200 >tm) and medium- (200-600 |im) sized PAs constrict to hypoxia, whereas SMC from large (>800 nm) PAs and systemic (cerebral) arteries do not. C: The L-type Ca2+ channel blocker verapamil reverses HPV. D: [Ca2+Ij in PASMC increases in response to superfusion with a hypoxic solution or angiotensin II (A-II) (Reproduced from Refs. 17,70).

Figure 3. HPV is intrinsic to the resistance PA and depends on extracellular Ca2+. A: When rat lungs and kidneys are perfused in series, hypoxia (induced by ventilating the lungs with hypoxic gas) causes pulmonary vasoconstriction and renal vasodilation in the presence of NO synthase and prostaglandin synthesis blockers. B: SMCs from small- (<200 >tm) and medium- (200-600 |im) sized PAs constrict to hypoxia, whereas SMC from large (>800 nm) PAs and systemic (cerebral) arteries do not. C: The L-type Ca2+ channel blocker verapamil reverses HPV. D: [Ca2+Ij in PASMC increases in response to superfusion with a hypoxic solution or angiotensin II (A-II) (Reproduced from Refs. 17,70).

Most studies of HPV in isolated lungs examine the initiation of HPV. Thus they focus on a short duration of hypoxic exposure and often differ in rationale and design from studies of sub-acute hypoxia in humans or in isolated PA rings. In vivo, it appears that HPV occurs in two continuous, constrictor phases. In humans, HPV increases in a progressive biphasic manner with a smaller initial rapid constrictor phase followed by a gradual increase in pulmonary vascular resistance over 2-3 hrs which then plateaus for at least 8 hours hypoxia (32). In PA rings, a biphasic response has also been noted, although there is more disagreement about the basis/importance of these two components of the response. Bennie et al. described a phase 1 constriction which was endothelium independent, and a later phase 2 constriction that was endothelium dependent (20). However, in another study of isolated arterial rings, Leach et al. found that hypoxia causes a phase 1 constriction reaching a peak within 2-3 min, followed by a slowly developing (>45 min) contraction (phase 2). They noted that the phase 1 transient contraction was similar in large and small PAs and mesenteric arteries whilst the sustained phase 2 response was seen only in the PAs (54). Removing the endothelium abolished phase 2 and had no significant effect on phase 1 in large PAs, but reduced phase 1 in small arteries by 40% (54). Although HPV in vivo is biphasic, the response is one of progressive constriction (i.e., there is not transient constriction which first abates before a more sustained phase begins). However, consistent with the proposed mechanism of HPV (126), it has been noted that verapamil substantially reduces phase 1 and abolished phase 2 constriction.

When resistance PAs were cannulated and pressurized to 10-20 mmHg (similar to in vivo conditions), a monophasic contraction was achieved (59, 65). In the absence of an intact endothelium, HPV could be restored by pretreatment with endothelin (ET-1), suggesting that some priming effect by the endothelium may be necessary (59). However, we have found that a monophasic response can be elicited from non-pressurized resistance mouse PAs without pharmacological priming (12). Leach et al. also used priming to cause preconstriction (54). It is probable that intergroup differences in describing the endothelium-dependence of the response relate in part to issues such as the vascular segment studied and the use of priming (preconstriction). Moreover, removing endothelium from small PAs is challenging and may inadvertently damage the vessel. Nonetheless, numerous endothelium-derived vasoconstrictor substances enhance HPV (leukotrienes, endothelin) and numerous endothelium-derived vasodilators reduce HPV (nitric oxide, adrenomedullin, prostaglandin I2) (6, 59). Consistent with this, hypoxic contraction has been elicited in isolated resistance PASMCs, and is notably absent in proximal PASMCs or SMCs from systemic arteries (122). Thus, while the endothelium unquestionably plays an important role in determining the amplitude and kinetics of HPV, there appears to be a core HPV response that can be elicited from the artery in the absence of endothelium. Likewise, the core of the carotid body's hypoxic response (63) and the 02-response of the human DA (74) can be seen ex vivo in cellular preparations that lack endothelium. In the case of the ductus arteriosus, the 02 sensor works normally in the presence of effective endothelin inhibition (73).

HPV and most other 02 sensor systems are dependent on influx of extracellular Ca2+, and the primary portal of entry is the L-type voltage-sensitive Ca2+ channel. L-type Ca2+ channel antagonists inhibit most (>80%) of the hypoxic constrictor response (Fig. 3C) whilst the Ca2+ channel agonist BAYK8644 enhances HPV (8, 36, 38, 69, 70). This dependence on extracellular Ca2+ for activation of the 02 sensor pathway is also true in the ductus arteriosus (73, 120), the carotid body (78, 111) and the adrenomedullary cell (62). Although hypoxia also causes release of Ca2+ from intracellular pools (Fig. 3D), the relative role of intracellular release of Ca2+ remains controversial (123).

While the voltage-sensitive Ca2+ channels have some intrinsic 02 sensitivity (33), they are largely responding to changes in membrane potential, as determined by K+ channels (4). Lloyd demonstrated a Po2-dependent contraction of PAs treated with the K+ channel blocker procaine (60). Subsequently, it was shown that hypoxia depolarizes PASMCs. The implied ability of hypoxia to inhibit K+channels was directly demonstrated in 1992 (93) and was subsequently confirmed by other groups (113, 134). K+ channel inhibition depolarizes the plasma membrane and activates the voltage-gated Ca2+ channel to increase intracellular [Ca2+] (126). Hypoxia and metabolic inhibitors cause constriction only in the pulmonary circulation, whereas they cause vasodilation in most systemic vascular beds (10, 61, 103). Indeed, the response of even the proximal PAs to hypoxia is predominantly vasodilation (11, 20). The localization of the hypoxic response appears to result from diversity in the local expression of (Insensitive K+ channels, with these voltage-gate K+ channels (Kv) being predominantly functional in resistance (vs conduit) PAs (11), a finding recently confirmed by another group (112). Within the vasculature, hypoxia-sensitive whole cell K+ current is specific to PASMC, and is not found in renal (93) or splanchnic (134) arterial SM. However, 02 sensitive K+ channels are found in all other 02-sensitive tissues (26, 64, 86, 93,120,130,134). Progress has been made recently in determining the molecular identity and regulatory pathways by which these channels respond to changes in Po2.

In an interesting parallel to the carotid body, chronic hypoxia causes hypertrophy ofPASMCs and diminishes the magnitude ofthe response to acute hypoxic ventilation. This is also true in PAs isolated from humans with chronic obstructive pulmonary disease (COPD). HPV was diminished in PAs from hypoxic patients (71), but was preserved in PAs from normoxic COPD patients (87). The magnitude of HPV in vitro was inversely related to the systemic P02 in these chronically patients (87). Thus both PAs and carotid bodies down-regulate their 02 sensing functions in response to chronic hypoxia.

This chapter will specifically deal with the pathway of how 02-sensitive K+ channels and the network of mitochondria that permeate the vascular SMC interact to generate HPV. We will explore an increasingly accepted redox mechanism for HPV (3, 7, 10, 17, 72, 74), which may have relevance most 02-sensitive tissues. This pathway involves PASMC mitochondria acting as redox sensors, producing activated oxygen species (AOS) in proportion to P02, which serve as diffusible mediators that modulate the activity of several 02-sensitive K+ channel (e.g., Kv1.5 and Kv2.1) (Fig. 4). These redox sensitive K+ channels control tone through their effects on membrane potential and the L-type Ca2+ channel. Before delving into the interaction of all three factors as a "functional hypoxic-sensing unit", the characteristics of each component will be examined.

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