Pulmonary vasoconstriction greatly contributes to the elevated pulmonary vascular resistance in patients with pulmonary hypertension. A rise in cytosolic Ca²⁺ concentration ([Ca²⁺]_cyt) in pulmonary arterial smooth muscle cells (PASMCs) is a major trigger for pulmonary vasoconstriction. Presently, little is known about the nature of the store-operated channels (SOCs) in PASMCs, even though store depletion-mediated capacitative Ca²⁺ entry (CCE) is a critical mechanism for refilling the empty sarcoplasmic reticulum (SR) with Ca²⁺, and for maintaining a sustained increase in [Ca²⁺]cyt. The goal of this in vitro study was to investigate the effects of nickel and manganese on store-operated channels in canine PASMCs.

Isolated PASMCs were obtained from an enzymatically treated canine pulmonary artery. Currents were recorded at room temperature using the dialyzed whole cell recording technique. The protocol used to deplete the intracellular Ca²⁺ stores and to monitor the development of the store-operated Ca²⁺ currents, involved voltage-clamping cells at 0 mV to inactivate any voltage-dependent calcium currents. Crrents were recorded in response to a 200 ms voltage step from 120 to 40 mV in 20 mV increments every 15 seconds.

Simultaneous depletion of intracellular Ca²⁺ leads to a voltage-independent and linear store-operated Ca²⁺ current (I_SOC) reversal near 0 mV. Nickel and manganese inhibit I_SOC.

In canine PASMCs, the depletion of intracellular Ca²⁺ stores leads to the activation of ISOC, which is inhibited by nickel and manganese. These metals are non-specific inhibitors of non-selective cation channels. Our results indicate that Ni²⁺- and Mn²⁺-sensitive pathways may mediate Ca²⁺ entry, or that a class of non-selective cation channels may contribute to CCE in canine PASMCs.