Voltage-gated K⁺ channels at an early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets

Abstract

Our purpose was to determine whether smooth muscle cell membrane properties are altered in small pulmonary arteries (SPA) of piglets at an early stage of pulmonary hypertension. Piglets were raised in either room air (control) or hypoxia for 3 days. A microelectrode technique was used to measure smooth muscle cell membrane potential (E(m)) in cannulated, pressurized SPA (100- to 300-microm diameter). SPA responses to the voltage-gated K(+) (K(V)) channel antagonist 4-aminopyridine (4-AP) and the K(V)1 family channel antagonist correolide were measured. Other SPA were used to assess amounts of K(V)1.2, K(V)1.5, and K(V)2.1 (immunoblot technique). E(m) was more positive in SPA of chronically hypoxic piglets than in SPA of comparable-age control piglets. The magnitude of constriction elicited by either 4-AP or correolide was diminished in SPA from hypoxic piglets. Abundances of K(V)1.2 were reduced, whereas abundances of both K(V)1.5 and K(V)2.1 were unaltered, in SPA from hypoxic piglets. At least partly because of reduced amounts of K(V)1.2, smooth muscle cell membrane properties are altered such that E(m) is depolarized and K(V) channel family function is impaired in SPA of piglets at an early stage of chronic hypoxia-induced pulmonary hypertension.

Reactive Oxygen Species Scavengers Improve Voltage‐Gated K+ Channel Function in Pulmonary Arteries of Newborn Pigs with Progressive Hypoxia‐Induced Pulmonary Hypertension

“…We previously reported similar abnormalities in PASMC membrane properties in PRAs from piglets exposed to in vivo hypoxia for 3 days. 19 Thus, our new findings support and extend Figure 3. Effect of treatment with the ROS generator menadione on responses to 4-aminopyridine (4-AP) in arteries from normoxic piglets of the 10-day exposure group (n ¼ 12 untreated arteries and n ¼ 11 menadione-treated arteries).…”

“…These differences in PASMC Em between PRAs isolated after 10 days of normoxic versus hypoxic exposure (Table 1) mirrored the differences in PASMC Em measured in PRAs from piglets exposed to 3 days of normoxia (À51 AE 0:4 mV) versus 3 days of hypoxia (À46 AE 0:5 mV) in our previous study. 19 ] arteries, respectively). Thus, neither the presence of the endothelium nor differing transmural pressures explain differences in PASMC Em between control and hypoxic arteries.…”

“…[10][11][12]19,20 Our work has potential clinical relevance. Rather than a preventive, prophylactic approach, treatments for progressive, neonatal pulmonary hypertension are often initiated late in the disease process, typically after a diagnosis of right heart dysfunction and cor pulmonale is made.…”

“…19,20 In particular, we previously showed that Kv channel function was impaired concomitant with depolarization of PASMC Em when newborn pigs were exposed to chronic hypoxia for 3 days. 19 However, the mechanisms underlying Kv channel impairments in either newborn-or adult-animal models of pulmonary hypertension remain unclear. Reactive oxygen species (ROSs) have been shown to inhibit Kv channel function.…”

“…19,30 Normobaric hypoxia was produced by delivering compressed air and N 2 to a chamber so that oxygen content was maintained at 10%-11% O 2 (PO 2 : 60-72 Torr). CO 2 was maintained at 3-6 Torr by absorption with soda lime.…”