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This Article Full Text Full Text (PDF) All Versions of this Article: 295/5/L915    most recent 90286.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Hirenallur-S., D. K. Articles by Rusch, N. J. PubMed PubMed Citation Articles by Hirenallur-S., D. K. Articles by Rusch, N. J.

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

¹Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas; ²Children's Hospital Research Institute; ³Department of Pediatrics, Medical College of Wisconsin; and ⁴Zablocki Veterans Administration Medical Center, Milwaukee, Wisconsin

Submitted 23 April 2008 ; accepted in final form 2 September 2008

Inhibition of voltage-gated, L-type Ca²⁺ (Ca_L) 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 Ca_L 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 (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 Ptp in isolated lungs of CH piglets by 6.4 ± 1.3 mmHg but only reduced 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 _1C-subunit of the Ca_L channel was similar between small pulmonary arteries from N and CH piglets, a profound and persistent upregulation of the vascular _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 Ca_L channels in small pulmonary arteries in vivo and the resulting abnormal Ca²⁺-dependent resistance may contribute to the pathogenesis of PAH.

neonate; pulmonary circulation; vascular smooth muscle cells