Abstract-Renal arteries (RAs) dilate in response to hypoxia, whereas the pulmonary arteries (PAs) constrict. In the PA, O 2 tension is detected by an unidentified redox sensor, which controls K ϩ channel function and thus smooth muscle cell (SMC) membrane potential and cytosolic calcium. Mitochondria are important regulators of cellular redox status and are candidate vascular O 2 sensors. Mitochondria-derived activated oxygen species (AOS), like H 2 O 2 , can diffuse to the cytoplasm and cause vasodilatation by activating sarcolemmal K ϩ channels. We hypothesize that mitochondrial diversity between vascular beds explains the opposing responses to hypoxia in PAs versus RAs. The effects of hypoxia and proximal electron transport chain (pETC) inhibitors (rotenone and antimycin A) were compared in rat isolated arteries, vascular SMCs, and perfused organs. Hypoxia and pETC inhibitors decrease production of AOS and outward K ϩ current and constrict PAs while increasing AOS production and outward K ϩ current and dilating RAs. At baseline, lung mitochondria have lower respiratory rates and higher rates of AOS and H 2 O 2 production. Similarly, production of AOS and H 2 O 2 is greater in PA versus RA rings. SMC mitochondrial membrane potential is more depolarized in PAs versus RAs. These differences relate in part to the lower expression of proximal ETC components and greater expression of mitochondrial manganese superoxide dismutase in PAs versus RAs. Differential regulation of a tonically produced, mitochondria-derived, vasodilating factor, possibly H 2 O 2 , can explain the opposing effects of hypoxia on the PAs versus RAs. We conclude that the PA and RA have different mitochondria. Key Words: rotenone Ⅲ K ϩ channels Ⅲ redox Ⅲ pulmonary circulation Ⅲ oxygen sensor T he normoxic pulmonary circulation is vasodilated and accommodates the entire cardiac output at much lower pressures than the systemic circulation. During hypoxia, the pulmonary arteries (PAs) constrict (hypoxic pulmonary vasoconstriction, HPV), whereas systemic arteries, such as renal arteries (RAs), dilate. The mechanism of this opposing control of tone between the two vascular beds is unknown. Although the response of each bed to hypoxia is significantly modulated by the endothelium, the mechanism for the opposing responses to hypoxia appear to lie within the vascular smooth muscle cells (SMCs). Hypoxia increases intracellular Ca 2ϩ ([Ca 2ϩ ] i ) and contracts PASMCs; in contrast, isolated SMCs from systemic arteries display decreased [Ca 2ϩ ] i and relax in response to hypoxia. 1 Both the control of tone and the response of O 2 -sensitive tissues to hypoxia involve redox-sensitive mechanisms (for review, see Wolin 2 ). Activated oxygen species (AOS) are now recognized as important mediators in vascular cellular signaling. Several kinases and sarcolemmal potassium channels (K ϩ channels) are redox-sensitive and modulated by AOS. Cysteine-rich K ϩ channels are inhibited when reduced and activated when oxidized, and oxidants and AOS, including hydrogen...
Abstract-Hypoxic pulmonary vasoconstriction (HPV) is initiated by inhibition of O 2 -sensitive, voltage-gated (Kv) channels in pulmonary arterial smooth muscle cells (PASMCs). Kv inhibition depolarizes membrane potential (E M ), thereby activating Ca 2ϩ influx via voltage-gated Ca 2ϩ channels. HPV is weak in extrapulmonary, conduit pulmonary arteries (PA) and strong in precapillary resistance arteries. We hypothesized that regional heterogeneity in HPV reflects a longitudinal gradient in the function/expression of PASMC O 2 -sensitive Kv channels. In adult male Sprague Dawley rats, constrictions to hypoxia, the Kv blocker 4-aminopyridine (4-AP), and correolide, a Kv1.x channel inhibitor, were endothelium-independent and greater in resistance versus conduit PAs. Moreover, HPV was dependent on Kvinhibition, being completely inhibited by pretreatment with 4-AP. Kv1.2, 1.5, Kv2.1, Kv3.1b, Kv4.3, and Kv9.3. mRNA increased as arterial caliber decreased; however, only Kv1.5 protein expression was greater in resistance PAs. Resistance PASMCs had greater K ϩ current (I K ) and a more hyperpolarized E M and were uniquely O 2 Ϫ and correolide-sensitive. The O 2 -sensitive current (active at Ϫ65 mV) was resistant to iberiotoxin, with minimal tityustoxin sensitivity. In resistance PASMCs, 4-AP and hypoxia inhibited I K 57% and 49%, respectively, versus 34% for correolide. Intracellular administration of anti-Kv1.5 antibodies inhibited correolide's effects. The hypoxia-sensitive, correolide-insensitive I K (15%) was conducted by Kv2.1. Anti-Kv1.5 and anti-Kv2.1 caused additive depolarization in resistance PASMCs (Kv1.5ϾKv2.1) and inhibited hypoxic depolarization. Heterologously expressed human PASMC Kv1.5 generated an O 2 Ϫ and correolide-sensitive I K like that in resistance PASMCs. In conclusion, Kv1.5 and Kv2.1 account for virtually all the O 2 -sensitive current. HPV occurs in a Kv-enriched resistance zone because resistance PASMCs preferentially express O 2 -sensitive Kv-channels. Key Words: immunoelectropharmacology Ⅲ laser capture microdissection Ⅲ voltage-gated channels Ⅲ pulmonary circulation Ⅲ adenoviral gene transfer T he adult pulmonary circulation is a low-resistance circuit designed for gas exchange that is perfused by a thinwalled, afterload-intolerant right ventricle. The pulmonary vasculature consists of large, elastic, extraparenchymal "conduit" arteries and small, muscular intrapulmonary arteries, which control regional distribution of blood flow and largely determine pulmonary vascular resistance (PVR). Hypoxic pulmonary vasoconstriction (HPV) is a widely conserved mechanism for ventilation-perfusion matching. 1 With segmental hypoxia (eg, atelectasis), resistance pulmonary arteries (PAs) serving the hypoxic lobes constrict, diverting blood to better-oxygenated segments, thereby optimizing systemic PO 2 , without increasing PVR. 2,3 Microangiography 4 and micropuncture 5 reveal that HPV primarily occurs in resistance PAs (Ͻ200 mol/L diameter, division 4, and distal), with lesser contributions from larger i...
Hypoxic pulmonary vasoconstriction (HPV) is initiated by the inhibition of several 4‐aminopyridine (4‐AP)‐sensitive, voltage‐gated, K+ channels (Kv). Several O2‐sensitive candidate channels (Kv1.2, Kv1.5, Kv2.1, and Kv3.1b) have been proposed, based on similarities between their characteristics in expression systems and the properties of the O2‐sensitive K+ current (IK) in pulmonary artery smooth muscle cells (PASMCs). We used gene targeting to delete Kv1.5 in mice by creating a SWAP mouse that is functionally a Kv1.5 knockout. We hypothesized that SWAP mice would display impaired HPV. The Kv1.5 α‐subunits present in the endothelium and PASMCs of wild‐type mice were absent in the lungs of SWAP mice, whereas expression of other channels Kv (1.1, 1.2, 2.1, 3.1, 4.3), Kir 3.1, Kir 6.1, and BKCa was unaltered. In isolated lungs and resistance PA rings, HPV was reduced significantly in SWAP versus wild‐type mice. Consistent with this finding, PASMCs from SWAP PAs were slightly depolarized and lacked IKv1.5, a 4‐AP and hypoxia‐sensitive component of IK that activated between ‐50 mV and ‐30 mV. We conclude that a K+ channel containing Kv1.5 α‐subunits is an important effector of HPV in mice.
Intrapulmonary veins (PVs) contribute to pulmonary vascular resistance, but the mechanisms controlling PV tone are poorly understood. Although smooth muscle cell (SMC) K(+) channels regulate tone in most vascular beds, their role in PV tone is unknown. We show that voltage-gated (K(V)) and inward rectifier (K(ir)) K(+) channels control resting PV tone in the rat. PVs have a coaxial structure, with layers of cardiomyocytes (CMs) arrayed externally around a subendothelial layer of typical SMCs, thus forming spinchterlike structures. PVCMs have both an inward current, inhibited by low-dose Ba(2+), and an outward current, inhibited by 4-aminopyridine. In contrast, PVSMCs lack inward currents, and their outward current is inhibited by tetraethylammonium (5 mM) and 4-aminopyridine. Several K(V), K(ir), and large-conductance Ca(2+)-sensitive K(+) channels are present in PVs. Immunohistochemistry showed that K(ir) channels are present in PVCMs and PV endothelial cells but not in PVSMCs. We conclude that K(+) channels are present and functionally important in rat PVs. PVCMs form sphincters rich in K(ir) channels, which may modulate venous return both physiologically and in disease states including pulmonary edema.
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