Upregulation of vascular calcium channels in neonatal piglets with hypoxia-induced pulmonary hypertension

Hirenallur-S DK, Haworth ST, Leming JT, Chang J, Hernandez G, Gordon JB, Rusch NJ. Upregulation of vascular calcium channels in neonatal piglets with hypoxia- induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 295: L915-L924, 2008. First published September 5, 2008; doi:10.1152/ajplung.90286.2008.- Inhibition of voltage-gated, L- type Ca2+ (CaL) channels by clinical calcium channel blockers provides symptomatic improvement to some pediatric patients with pulmonary arterial hypertension (PAH). The present study investigated whether abnormalities of vascular CaL channels contribute to the pathogenesis of neonatal PAH using a newborn piglet model of hypoxia-induced PAH. Neonatal piglets exposed to chronic hypoxia (CH) developed PAH by 21 days, which was evident as a 2.1-fold increase in pulmonary vascular resistance in vivo compared with piglets raised in normoxia (N). Transpulmonary pressures (Delta Ptp) in the corresponding isolated perfused lungs were 20.5 +/- 2.1 mmHg (CH) and 11.6 +/- 0.8 mmHg (N). Nifedipine reduced the elevated Delta Ptp in isolated lungs of CH piglets by 6.4 +/- 1.3 mmHg but only reduced Delta Ptp in lungs of N piglets by 1.9 +/- 0.2 mmHg. Small pulmonary arteries from CH piglets also demonstrated accentuated Ca2+ dependent contraction, and Ca2+ channel current was 3.94-fold higher in the resident vascular muscle cells. Finally, although the level of mRNA encoding the pore-forming alpha 1C-subunit of the CaL channel was similar between small pulmonary arteries from N and CH piglets, a profound and persistent upregulation of the vascular alpha 1C protein was detected by 10 days in CH piglets at a time when pulmonary vascular resistance was only mildly elevated. Thus chronic hypoxia in the neonate is associated with the anomalous upregulation of CaL channels in small pulmonary arteries in vivo and the resulting abnormal Ca-2 (+)- dependent resistance may contribute to the pathogenesis of PAH.