Perinatal hypoxia triggers alterations in K⁺channels of adult pulmonary artery smooth muscle cells

Abstract

August 24, 2007; doi:10.1152/ajplung.00126.2007.-Adverse events during the perinatal period, like hypoxia, have been associated with adult diseases. In pulmonary vessels, K ϩ channels play an important role in the regulation of vascular tone. In the fetus, Ca 2ϩ -activated K ϩ channels (K Ca) are predominant, whereas from birth voltage-gated K ϩ channels (K V) prevail in the adult. We postulated that perinatal hypoxia could alter this maturational shift and influence regulation of pulmonary vascular tone in relation to K ϩ channels in adulthood. We evaluated the effects of perinatal hypoxia on KV and KCa channels in the adult main pulmonary artery (PA) using a murine model. Electrophysiological measurements showed a greater outward current in PA smooth muscle cells of mice born in hypoxia than in controls. In controls, only KV channels contributed to this current, whereas in mice born in hypoxia both KV and KCa channels were implicated. KV channel activity was even higher in mice born in hypoxia than in controls. Therefore, perinatal hypoxia results in increased KCa and KV channel activity in adult PA. Moreover, PA of adults born in hypoxia displayed higher large-conductance KCa ␣-subunit and KV1.5 ␣-subunit protein expression than controls. Interestingly, relaxation induced by nitric oxide (NO) donors [S-nitroso-N-acetyl-D,L-penicillamine, 2-(N,N-diethylamino)-diazenolate-2-oxide] in isolated PA of control mice was not mediated by KCa channels and only slightly by KV channels, whereas following perinatal hypoxia both KCa and KV channels contributed to this relaxation. Thus perinatal hypoxia results in altered expression and activity of different K ϩ channels in the adult main PA, which could contribute to modifications of pulmonary vasoreactivity.mouse; potassium ion channel activity; potassium ion channel blockers; nitric oxide donors ADVERSE EVENTS IN THE PERINATAL period may predispose to pathological responses later in life. In utero growth restriction and perinatal hypoxia have been involved in the development of adult diseases such as coronary artery disease, systemic hypertension, stroke, and non-insulin-dependent diabetes mellitus (4,5,12).Several lines of evidence indicate that chronic pulmonary vascular diseases and altered pulmonary vascular reactivity in adulthood may be associated with a perinatal hypoxic insult (13,15,20,31,42,44). Human and animal studies showed that individuals having suffered from a transient hypoxic insult in utero and/or soon after birth displayed exaggerated pulmonary vasoconstrictive responses when reexposed to hypoxia later in life (9, 14 -18, 42, 45). The mechanisms underlying the exaggerated pulmonary vasoconstrictor responsiveness and the resulting altered lung circulation in adulthood following a perinatal hypoxic event have not been elucidated so far.

Chronic Prenatal Hypoxia Down-Regulated BK Channel Β1 Subunits in Mesenteric Artery Smooth Muscle Cells of the Offspring

“…In the present study, whole-cell recording demonstrated a significantly decrease in BK channel current density in MA myocytes from Hy offspring, similar to the previous report on the renal interlobar artery myocytes following prenatal hypoxia [49]. However, an early study demonstrated that prenatal hypoxia increased whole-cell BK channel current density and BK channel α-subunit expression in pulmonary artery smooth muscle cells from male mice offspring [50]. The nature of those discrepancies may be caused by differences in animal strain, various organ used, and hypoxia conditions.…”

Role of Large-conductance Calcium-activated Potassium Channels of Coronary Arteries in Heart Preservation

“…24,25 Most studies on the effect of hypoxia on BK Ca were conducted in pulmonary arteries. 26,27 Because our previous studies suggested that H-R impairs EDHF-mediated relaxation in both coronary microarteries and cardiac veins, 18,19,28,29 in the present study we investigated the effect of ischemia on the EDHF-targeting channels in VSMC BK Ca , by using the patch-clamp technique and isometric force measurement.…”

Ca2+-independent PLA2 controls endothelial store-operated Ca2+ entry and vascular tone in intact aorta

“…However, to control that the inhibitory effect of BEL on endotheliumdependent relaxations is not due to a direct effect on smooth muscle, the effect of iPLA 2 inhibition with BEL was investigated on the endothelium-independent relaxation triggered by the NO donor DEA/NO (26). As shown in Fig.…”