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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:913.)
© 2008 American Heart Association, Inc.

Cell Biology and Signaling

CNGA2 Channels Mediate Adenosine-Induced Ca²⁺ Influx in Vascular Endothelial Cells

Kwong-Tai Cheng; Yuk-Ki Leung; Bing Shen; Yuk-Chi Kwok; Ching-On Wong; Hiu-Yee Kwan; Yu-Bun Man; Xin Ma; Yu Huang; Xiaoqiang Yao

From the Li Ka Shing Institute of Health Sciences and Department of Physiology, Faculty of Medicine, the Chinese University of Hong Kong, China.

Correspondence to Xiaoqiang Yao, PhD, Department of Physiology, The Chinese University of Hong Kong, Hong Kong, China. E-mail yao2068{at}cuhk.edu.hk

Abstract

Objectives— Adenosine is a cAMP-elevating vasodilator that induces both endothelium-dependent and -independent vasorelaxation. An increase in cytosolic Ca²⁺ ([Ca²⁺]_i) is a crucial early signal in the endothelium-dependent relaxation elicited by adenosine. This study explored the molecular identity of channels that mediate adenosine-induced Ca²⁺ influx in vascular endothelial cells.

Methods and Results— Adenosine-induced Ca²⁺ influx was markedly reduced by L-cis-diltiazem and LY-83583, two selective inhibitors for cyclic nucleotide-gated (CNG) channels, in H5V endothelial cells and primary cultured bovine aortic endothelial cells (BAECs). The Ca²⁺ influx was also inhibited by 2 adenylyl cyclase inhibitors MDL-12330A and SQ-22536, and by 2 A_2B receptor inhibitors MRS-1754 and 8-SPT, but not by an A_2A receptor inhibitor SCH-58261 or a guanylyl cyclase inhibitor ODQ. Patch clamp experiments recorded an adenosine-induced current that could be inhibited by L-cis-diltiazem and LY-83583. A CNGA2-specific siRNA markedly decreased the Ca²⁺ influx and the cation current in H5V cells. Furthermore, L-cis-diltiazem inhibited the endothelial Ca²⁺ influx in mouse aortic strips, and it also reduced 5-N-ethylcarboxamidoadenosine (NECA, an A₂ adenosine receptor agonist)-induced vasorelaxation.

Conclusion— CNGA2 channels play a key role in adenosine-induced endothelial Ca²⁺ influx and vasorelaxation. It is likely that adenosine acts through A_2B receptors and adenylyl cyclases to stimulate CNGA2.

Key Words: CNGA2 channels • adenosine • cAMP • endothelial cells • Ca²⁺