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(Circulation Research. 2004;94:e97.)
© 2004 American Heart Association, Inc.

UltraRapid Communications

High Blood Pressure Upregulates Arterial L-Type Ca²⁺ Channels

Is Membrane Depolarization the Signal?

Aleksandra Pesic, Jane A. Madden, Miodrag Pesic, Nancy J. Rusch

From the Department of Pharmacology and Toxicology (A.P., M.P., N.J.R.), The Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wis; and the Department of Neurology (J.A.M.), Medical College of Wisconsin and Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wis.

Correspondence to Nancy J. Rusch, PhD, Prof, Department of Pharmacology and Toxicology Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail nrusch{at}mcw.edu

Long-lasting Ca²⁺ (Ca_L) channels of the Ca_v1.2 gene family contribute to the pathogenesis of abnormal arterial tone in hypertension. The physiological stimulus that enhances Ca_L channel current in the vascular smooth muscle cells (VSMCs) remains unknown. The present study investigated if high blood pressure triggers an upregulation of vascular Ca_L channel protein. Rat aortae were banded between the origins of the left renal (LR) and right renal (RR) arteries to selectively elevate blood pressure in the proximal RR arteries. After 2 days, the immunoreactivity on Western blots corresponding to the pore-forming _1C subunit of the Ca_L channel was increased 3.25-fold in RR compared with LR arteries. This finding persisted at 28 days and was associated with abnormal Ca²⁺-dependent tone and higher Ca_L currents in the VSMCs exposed to high pressure. Based on microelectrode studies indicating that RR arteries were depolarized compared with LR arteries, further studies examined if membrane depolarization, an inherent response of VSMCs to high blood pressure, increased _1C expression. Isolated rat renal arteries were cultured for 2 days in low K⁺ (4 mmol/L) or depolarizing high K⁺ (30 mmol/L) media. Arteries preconditioned in high K⁺ showed a 5.47-fold increase in _1C expression, enhanced Ca_L channel current, and elevated Ca²⁺-dependent tone. These findings provide the first direct evidence that high blood pressure upregulates the Ca_L channel _1C subunit in VSMCs in vivo and suggest that membrane depolarization is a potential signal involved in this interaction that may contribute to the development of abnormal vascular tone.

Key Words: calcium channels • _1C subunit • membrane potential • vascular smooth muscle • hypertension

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