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.
Zhao
Qing
Q
Guangdong Province Key Laboratory of Shock and Microcirculation Research, Department of Pathophysiology, Southern Medical University, Guangzhou, China.
Zhao
Ke-seng
KS
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D018613:Microscopy, Confocal; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D012771:Shock, Hemorrhagic / Q000378:metabolism* / Q000503:physiopathology
D020746:Calcium Channels, L-Type; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D002118:Calcium; D009638:Norepinephrine