Blunted Hypoxic Pulmonary Vasoconstriction in Experimental Neonatal Chronic Lung Disease

Abstract

Rationale: Neonatal chronic lung disease (CLD), caused by prolonged mechanical ventilation (MV) with O 2 -rich gas, is the most common cause of long-term hospitalization and recurrent respiratory illness in extremely premature infants. Recurrent episodes of hypoxemia and associated ventilator adjustments often lead to worsening CLD. The mechanism that causes these hypoxemic episodes is unknown. Hypoxic pulmonary vasoconstriction (HPV), which is partially controlled by O 2 -sensitive voltage-gated potassium (K v ) channels, is an important adaptive response to local hypoxia that helps to match perfusion and ventilation in the lung. Objectives: To test the hypothesis that chronic lung injury (CLI) impairs HPV. Methods: We studied preterm lambs that had MV with O 2 -rich gas for 3 weeks and newborn rats that breathed 95%-O 2 for 2 weeks, both of which resulted in airspace enlargement and pulmonary vascular changes consistent with CLD. Measurements and Main Results: HPV was attenuated in preterm lambs with CLI after 2 weeks of MV and in newborn rats with CLI after 2 weeks of hyperoxia. HPV and constriction to the K v 1.x-specific inhibitor, correolide, were preferentially blunted in excised distal pulmonary arteries (dPAs) from hyperoxic rats, whose dPAs exhibited decreased K v 1.5 and K v 2.1 mRNA and K 1 current. Intrapulmonary gene transfer of K v 1.5, encoding the ion channel that is thought to trigger HPV, increased O 2 -sensitive K 1 current in cultured smooth muscle cells from rat dPAs, and restored HPV in hyperoxic rats. Conclusions: Reduced expression/activity of O 2 -sensitive K v channels in dPAs contributes to blunted HPV observed in neonatal CLD.

Validation of high-resolution echocardiography and magnetic resonance imaging vs. high-fidelity catheterization in experimental pulmonary hypertension

“…They found a normal PAAT of 134 Ϯ 20 ms in humans and a PAAT of 88 Ϯ 25 ms in those with mPAP Ͼ20 mmHg (5); in rats, PAAT duration is ϳ4 times shorter (33.4 Ϯ 1.1 vs. 22.1 Ϯ 1.4, in control vs. PAH; Table 1). We have been able to use PAAT to detect hypoxic pulmonary vasoconstriction in vivo (30) and to assess regression of experimental PAH (26). Echo correlates with Cath hemodynamics and has the advantage of being noninvasive.…”

“…Recent miniaturization and refinement of imaging technology for rodents such as high-frequency Echo probes (Ͼ30 MHz) and high-field-strength MRI machines (9.4 T) have facilitated noninvasive characterization of the pulmonary circulation in rodents (1,14,30). These newer noninvasive methods have not been simultaneously analyzed and validated against the micromanometer-tipped cardiac catheters, another advance in rodent physiological assessment.…”

Regulation of the Pulmonary Circulation in the Fetus and Newborn

“…Constriction of distal pulmonary arteries to the K v 1.x-specific inhibitor was attenuated along with decreased K v 1.5 and K v 2.1 mRNA and K ϩ current. Intrapulmonary gene transfer of K v 1.5 increased O 2 -sensitive K ϩ current in PASMCs and restored hypoxic pulmonary vasoconstriction (489). Perinatal hypoxia in mice can have long-term effects into adulthood as evidenced by increased BK and K v channel activity and higher BK ␣-subunit and K v 1.5 ␣-subunit protein expression in pulmonary arteries of adult mice exposed to perinatal hypoxia (384).…”

Antenatal Sildenafil Treatment Attenuates Pulmonary Hypertension in Experimental Congenital Diaphragmatic Hernia

“…Intrapulmonary arteries (diameter Ͻ100 m, lengthϭ2 mm) were mounted in a wire myograph (Myodaq; Danish Myo Technology, Denmark) and bathed in a Krebs-Henseleit buffer bubbled with 21% O 2 /5% CO 2 /balance N 2 27 . Pulmonary arteries were preconstricted with the thromboxane A2 analog U-46619 (10 -7 M), and isometric changes in response to NO donor 2-(N,N-diethylamino)-diazenolate-2-oxide (DEANO) (10 -7 Ϫ10 -5 M) were compared between PAs from the 4 age-matched groups.…”