Upregulation of vascular calcium channels in neonatal piglets with hypoxia-induced pulmonary hypertension.
Inhibition of voltage-gated, L-type Ca(2+) (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 (DeltaPtp) in the corresponding isolated perfused lungs were 20.5 +/- 2.1 mmHg (CH) and 11.6 +/- 0.8 mmHg (N). Nifedipine reduced the elevated DeltaPtp in isolated lungs of CH piglets by 6.4 +/- 1.3 mmHg but only reduced DeltaPtp in lungs of N piglets by 1.9 +/- 0.2 mmHg. Small pulmonary arteries from CH piglets also demonstrated accentuated Ca(2+)-dependent contraction, and Ca(2+) 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 Ca(L) 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 Ca(L) channels in small pulmonary arteries in vivo and the resulting abnormal Ca(2+)-dependent resistance may contribute to the pathogenesis of PAH.
Hirenallur-S
Dinesh K
DK
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham St., Little Rock, AR 72205, USA.
Haworth
Steven T
ST
Leming
Jeaninne T
JT
Chang
James
J
Hernandez
Guillermo
G
Gordon
John B
JB
Rusch
Nancy J
NJ
D000818:Animals; D000831:Animals, Newborn; D001808:Blood Vessels / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002908:Chronic Disease; D005786:Gene Expression Regulation; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications* / Q000503:physiopathology; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D008168:Lung / Q000378:metabolism / Q000503:physiopathology; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism; D011652:Pulmonary Circulation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013552:Swine; D015854:Up-Regulation
D015220:Calcium Channels; D021122:Protein Subunits; D012333:RNA, Messenger; D002118:Calcium
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