Role of store-operated calcium channels and calcium sensitization in normoxic contraction of the ductus arteriosus.
BACKGROUND
At birth, the increase in oxygen causes contraction of the ductus arteriosus, thus diverting blood flow to the lungs. Although this contraction is modulated by substances such as endothelin and dilator prostaglandins, normoxic contraction is an intrinsic property of ductus smooth muscle. Normoxic inhibition of potassium channels causes membrane depolarization and calcium entry through L-type calcium channels. However, the studies reported here show that after inhibition of this pathway there is still substantial normoxic contraction, indicating the involvement of additional mechanisms.


RESULTS
Using ductus ring experiments, calcium imaging, reverse-transcription polymerase chain reaction, Western blot, and cellular electrophysiology, we find that this depolarization-independent contraction is caused by release of calcium from the IP3-sensitive store in the sarcoplasmic reticulum, by subsequent calcium entry through store-operated channels, and by increased calcium sensitization of actin-myosin filaments, involving Rho-kinase.


CONCLUSIONS
Much of the normoxic contraction of the ductus arteriosus at birth is related to calcium entry through store-operated channels, encoded by the transient receptor potential superfamily of genes, and to increased calcium sensitization. A clearer understanding of the mechanisms involved in normoxic contraction of the ductus will permit the development of better therapy to close the patent ductus arteriosus, which constitutes approximately 10% of all congenital heart disease and is especially common in premature infants.
Hong
Zhigang
Z
Department of Medicine, VA Medical Center and University of Minnesota, Minneapolis, MN 55417, USA.
Hong
Fangxiao
F
Olschewski
Andrea
A
Cabrera
Jesus A
JA
Varghese
Anthony
A
Nelson
Daniel P
DP
Weir
E Kenneth
EK
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D004373:Ductus Arteriosus / Q000196:embryology / Q000502:physiology*; D063388:Endocannabinoids; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D007546:Isoquinolines / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008610:Menthol / Q000494:pharmacology; D020748:Mibefradil / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology; D009544:Niflumic Acid / Q000494:pharmacology; D010084:Oxidation-Reduction; D010100:Oxygen / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D053284:Polyunsaturated Alkamides; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011817:Rabbits / Q000196:embryology; D012430:Ruthenium Red / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D019789:Tetraethylammonium / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D054460:rho-Associated Kinases
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D001095:Arachidonic Acids; D001896:Boron Compounds; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D063388:Endocannabinoids; D007093:Imidazoles; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D008301:Maleimides; D053284:Polyunsaturated Alkamides; D015221:Potassium Channels; D013449:Sulfonamides; D012430:Ruthenium Red; D008610:Menthol; D020748:Mibefradil; D009544:Niflumic Acid; D019789:Tetraethylammonium; D019284:Thapsigargin; C109986:2-aminoethoxydiphenyl borate; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D013890:Thiourea; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D009543:Nifedipine; C070515:bisindolylmaleimide I; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D010100:Oxygen; D002118:Calcium; C078814:anandamide; C000543:cyclopiazonic acid