Abstract
Background The calcium-sensing receptor (CaSR) plays a fundamental role in extracellular calcium homeostasis in humans. Surprisingly, CaSR is also expressed in non-homeostatic tissues and is involved in regulating diverse cellular functions. The objective of this study was to determine if Calhex-231 (Cal), a negative modulator of CaSR, may be beneficial in the treatment of traumatic hemorrhagic shock (THS) by improving cardiovascular function, and investigated its relationship to oxidative stress and the mitochondrial fusion-fission pathway. Methods Rats that had been subjected to traumatic hemorrhagic shock were used as models in this study. Hypoxia-treated vascular smooth muscle cells (VSMCs) were also used. The effects of Cal on cardiovascular function, animal survival, hemodynamic parameters, and vital organ function in THS rats were observed, and the relationship to oxidative stress and mitochondrial fusion-fission was investigated. Results Cal significantly improved hemodynamics, elevated blood pressure, increased vital organ blood perfusion and local oxygen supply, and markedly improved the survival outcomes of THS rats. Furthermore, Cal significantly improved vascular reactivity after THS, including the pressor response of THS rats to norepinephrine (NE), and also the contractile response of superior mesenteric arteries, mesenteric arterioles, and isolated VSMCs to NE. Cal also restored the THS-induced decrease in myosin light chain (MLC) phosphorylation, which is the principal mechanism responsible for VSMC contraction and vascular reactivity. Inhibition of MLC phosphorylation antagonized the Cal-induced restoration of vascular reactivity following THS. Cal decreased oxidative stress indexes and increased antioxidant enzyme levels in THS rats, and also reduced reactive oxygen species levels in hypoxic VSMCs. In addition, THS induced expression of mitochondrial fission proteins Drp1 and Fis1, and decreased expression of mitochondrial fusion protein Mfn1 in vascular tissues. Cal reduced expression of Drp1 and Fis1, but did not affect Mfn1 expression. In hypoxic VSMCs, Cal inhibited hypoxia-induced mitochondrial fragmentation and preserved mitochondrial morphology. Conclusions Calhex-231 exhibits outstanding potential for effective therapy of traumatic hemorrhagic shock, due to its ability to improve hemodynamics, increase vital organ blood perfusion, and markedly prolong animal survival. These beneficial effects result from its protection of vascular function via inhibition of oxidative stress and mitochondrial fission.
Hemostatic Resuscitation in Traumatic Hemorrhagic Shock: Case Report
