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(Circulation. 2006;114:1372-1379.)
© 2006 American Heart Association, Inc.

Congenital Heart Disease

Role of Store-Operated Calcium Channels and Calcium Sensitization in Normoxic Contraction of the Ductus Arteriosus

Zhigang Hong, MD, PhD; Fangxiao Hong, MD; Andrea Olschewski, MD; Jesus A. Cabrera, MD, PhD; Anthony Varghese, PhD; Daniel P. Nelson, BS; E. Kenneth Weir, MD

From the Department of Medicine, VA Medical Center and University of Minnesota, Minneapolis (Z.H., J.A.C., A.V., D.P.N., E.K.W.); Department of Anesthesiology, Beijing Friendship Hospital, affiliated with Capital University of Medical Science, Beijing, China (F.H.); and Experimental Anesthesiology, Department of Anesthesiology, University of Graz Medical School, Graz, Austria (A.O.).

Correspondence to E. Kenneth Weir, MD, VA Medical Center 111C, One Veteran’s Dr, Minneapolis, MN 55417. E-mail weirx002{at}umn.edu

Received November 2, 2005; de novo received May 19, 2006; revision received July 24, 2006; accepted July 27, 2006.

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.

Methods and 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 10% of all congenital heart disease and is especially common in premature infants.

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