Inhibition of L-type calcium channels in arteriolar smooth muscle cells is involved in the pathogenesis of vascular hyporeactivity in severe shock.

The objective was to investigate the changes in the function of L-type calcium (L-Ca2+) channels of arteriolar smooth muscle cells (ASMCs) in the genesis of vascular hyporeactivity during severe shock. A hemorrhagic shock (HS) model was reproduced in rats, and the responsiveness of arterioles in the cremaster muscle to norepinephrine (NE) was measured. The inward currents of L-Ca2+ channel and intracellular concentration of Ca2+ ([Ca2+]i) level in isolated ASMCs were measured using patch clamp and fluorescent probe techniques. The arteriolar vasoreactivity was significantly reduced with a 12.5-fold increase of NE threshold level 2 h post-HS. Meanwhile, the inward currents through L-Ca2+ channels of ASMCs were significantly decreased at different holding potentials, and the maximal inward current was only 26.7% of control value in the shock group. The increased intracellular concentration of Ca2+ level of ASMCs stimulated by NE was reduced to 32.0% of control value 2 h post-HS. Administration of the L-Ca2+ channel stimulator, Bay K8644, partially restored the NE threshold level and transiently increased the mean arterial pressure during HS, lending further support to the importance of ASMC L-Ca2+ channel inhibition in the genesis of low vasoreactivity in vivo during severe shock. Our results suggest that stimulation of L-Ca2+ channels of ASMCs might be a potential therapeutic approach for treatment of refractory hypotension in severe shock.