Role of store-operated calcium channels and calcium sensitization in normoxic contraction of the ductus arteriosus

• Published in: Circulation (New York, N.Y.) Vol. 114; no. 13; pp. 1372 - 1379
• Main Authors: ZHIGANG HONG, FANGXIAO HONG, OLSCHEWSKI, Andrea, CABRERA, Jesus A, VARGHESE, Anthony, NELSON, Daniel P, WEIR, E. Kenneth
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 26-09-2006
• Subjects: Animals; Arachidonic Acids - pharmacology; Associated diseases and complications; Biological and medical sciences; Blood and lymphatic vessels; Boron Compounds - pharmacology; Calcium - pharmacology; Calcium Channel Blockers - pharmacology; Calcium Channels, L-Type - drug effects; Calcium Channels, L-Type - physiology; Calcium Signaling - physiology; Cardiology. Vascular system; Cytosol - metabolism; Diabetes. Impaired glucose tolerance; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Ductus Arteriosus - embryology; Ductus Arteriosus - physiology; Endocannabinoids; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Imidazoles - pharmacology; In Vitro Techniques; Indoles - pharmacology; Intracellular Signaling Peptides and Proteins - physiology; Isoquinolines - pharmacology; Maleimides - pharmacology; Medical sciences; Menthol - pharmacology; Mibefradil - pharmacology; Muscle Contraction - drug effects; Muscle Contraction - physiology; Nifedipine - pharmacology; Niflumic Acid - pharmacology; Orthopedic surgery; Oxidation-Reduction; Oxygen - pharmacology; Patch-Clamp Techniques; Polyunsaturated Alkamides; Potassium Channels - drug effects; Potassium Channels - physiology; Protein-Serine-Threonine Kinases - physiology; Rabbits - embryology; rho-Associated Kinases; Ruthenium Red - pharmacology; Sulfonamides - pharmacology; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Tetraethylammonium - pharmacology; Thapsigargin - pharmacology; Thiourea - analogs & derivatives; Thiourea - pharmacology; Oxygen; Calcium; ductus arteriosus, patent; Vasoconstriction; Persistence of ductus arteriosus; Cardiovascular disease; Ductus arteriosus; Inorganic element; Contraction; ion channels; Vasomotricity; heart defects, congenital; Congenital cardiopathy
• DOI: 10.1161/CIRCULATIONAHA.106.641126
• EISSN: 1524-4539
• ISSN: 0009-7322

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.
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.
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.