title: Upregulation of vascular calcium channels in neonatal piglets with hypoxia-induced pulmonary hypertension.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham St., Little Rock, AR 72205, USA.
authors.forename: Dinesh K
authors.initials: DK
authors.lastname: Hirenallur-S
authors.forename: Steven T
authors.initials: ST
authors.lastname: Haworth
authors.forename: Jeaninne T
authors.initials: JT
authors.lastname: Leming
authors.forename: James
authors.initials: J
authors.lastname: Chang
authors.forename: Guillermo
authors.initials: G
authors.lastname: Hernandez
authors.forename: John B
authors.initials: JB
authors.lastname: Gordon
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Rusch
mesh_terms: 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
chemical_list: D015220:Calcium Channels; D021122:Protein Subunits; D012333:RNA, Messenger; D002118:Calcium
references.citation: J Lab Clin Med. 2001 Dec;138(6):367-77
references.pmid: 11753283
references.citation: News Physiol Sci. 2004 Apr;19:44-50
references.pmid: 15016901
references.citation: Urology. 1995 May;45(5):893-901
references.pmid: 7747383
references.citation: Annu Rev Cell Dev Biol. 2000;16:521-55
references.pmid: 11031246
references.citation: Am J Physiol Lung Cell Mol Physiol. 2004 Jun;286(6):L1244-54
references.pmid: 14766668
references.citation: J Bioenerg Biomembr. 2003 Dec;35(6):599-620
references.pmid: 15000522
references.citation: Am J Physiol. 1993 Dec;265(6 Pt 2):H2175-83
references.pmid: 8285257
references.citation: J Neurophysiol. 2004 Nov;92(5):2633-41
references.pmid: 15486420
references.citation: J Biol Chem. 2003 Jun 20;278(25):22316-24
references.pmid: 12679337
references.citation: Cardiovasc Res. 1981 Feb;15(2):108-19
references.pmid: 7260976
references.citation: Am J Physiol. 1994 Jan;266(1 Pt 2):H365-70
references.pmid: 8304521
references.citation: Am J Physiol. 1997 May;272(5 Pt 2):H2436-45
references.pmid: 9176315
references.citation: Am J Physiol Lung Cell Mol Physiol. 2001 Apr;280(4):L801-12
references.pmid: 11238022
references.citation: Am J Physiol Lung Cell Mol Physiol. 2003 May;284(5):L799-807
references.pmid: 12547732
references.citation: J Appl Physiol (1985). 1994 Dec;77(6):2853-62
references.pmid: 7896632
references.citation: Prog Cardiovasc Dis. 2002 Sep-Oct;45(2):115-28
references.pmid: 12411973
references.citation: Chest. 1998 Sep;114(3 Suppl):205S-207S
references.pmid: 9741570
references.citation: Circ Res. 2004 May 28;94(10):e97-104
references.pmid: 15131006
references.citation: Circulation. 2005 Sep 27;112(13):1936-44
references.pmid: 16172271
references.citation: Can J Physiol Pharmacol. 1994 Apr;72(4):327-34
references.pmid: 7922863
references.citation: Am Rev Respir Dis. 1993 Aug;148(2):519-22
references.pmid: 8342919
references.citation: Pediatr Res. 1988 Aug;24(2):186-90
references.pmid: 3186330
references.citation: Br Heart J. 1993 Nov;70(5):461-8
references.pmid: 8260279
references.citation: Respir Res. 2000;1(1):40-8
references.pmid: 11667964
references.citation: Am J Physiol Lung Cell Mol Physiol. 2003 Mar;284(3):L489-500
references.pmid: 12426238
references.citation: Am J Physiol. 1999 Jan;276(1):L155-63
references.pmid: 9887068
references.citation: Pediatr Res. 1984 Dec;18(12):1262-5
references.pmid: 6522139
references.citation: Am J Physiol Lung Cell Mol Physiol. 2003 Feb;284(2):L316-23
references.pmid: 12388340
references.citation: Microcirculation. 2006 Dec;13(8):657-70
references.pmid: 17085426
references.citation: Circ Res. 2002 Oct 18;91(8):719-26
references.pmid: 12386149
references.citation: News Physiol Sci. 2002 Aug;17:131-7
references.pmid: 12136039
references.citation: Ann Intern Med. 1991 Sep 1;115(5):343-9
references.pmid: 1863023
references.citation: Cardiovasc Res. 1982 Jun;16(6):293-303
references.pmid: 7105097
references.citation: J Bioenerg Biomembr. 1998 Aug;30(4):357-75
references.pmid: 9758332
references.citation: J Clin Invest. 1997 Nov 1;100(9):2347-53
references.pmid: 9410914
references.citation: J Physiol. 2007 Oct 1;584(Pt 1):149-65
references.pmid: 17690152
references.citation: Am J Physiol Lung Cell Mol Physiol. 2000 Feb;278(2):L276-83
references.pmid: 10666111
references.citation: Proc Natl Acad Sci U S A. 2004 Sep 21;101(38):13861-6
references.pmid: 15358862
references.citation: Pediatr Res. 1991 May;29(5):500-3
references.pmid: 1896255
references.citation: Eur Respir J. 2003 Jan;21(1):155-76
references.pmid: 12570125
references.citation: J Appl Physiol (1985). 2005 Jan;98(1):415-20
references.pmid: 15591311
references.citation: Am J Physiol. 1999 Sep;277(3):L449-56
references.pmid: 10484451
references.citation: Cell. 2000 Jul 7;102(1):89-97
references.pmid: 10929716
references.citation: J Appl Physiol (1985). 2002 Jan;92(1):67-74
references.pmid: 11744644
references.citation: Pediatr Pulmonol. 2003 Aug;36(2):94-101
references.pmid: 12833487
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: N Engl J Med. 1992 Jul 9;327(2):76-81
references.pmid: 1603139
references.citation: J Appl Physiol (1985). 1993 Oct;75(4):1854-60
references.pmid: 8282642
references.citation: Gastroenterology. 2001 Feb;120(2):480-9
references.pmid: 11159888
references.citation: J Cell Biol. 1993 Nov;123(4):949-62
references.pmid: 8227151
references.citation: Am J Physiol. 1978 Jul;235(1):H104-9
references.pmid: 677322
references.citation: Am J Physiol. 1998 Apr;274(4):L517-26
references.pmid: 9575869
references.citation: Circ Res. 2005 Apr 29;96(8):864-72
references.pmid: 15774856
references.citation: J Appl Physiol (1985). 1991 Mar;70(3):1255-64
references.pmid: 2032991
references.citation: Hypertension. 2002 Aug;40(2):214-9
references.pmid: 12154116
references.citation: Circulation. 1999 Mar 9;99(9):1197-208
references.pmid: 10069788
references.citation: Exp Physiol. 1995 Sep;80(5):843-53
references.pmid: 8546873
references.citation: J Pharmacol Exp Ther. 1992 Oct;263(1):194-200
references.pmid: 1328605