Involvement of TRPV1-containing peripheral sensory efferents in hemodynamic responses in a rat hemorrhagic shock model

Background: Mechanisms underlying hemodynamic disturbance in hemorrhagic shock are not completely understood. Transient receptor potential vanilloid 1-expressing afferents are involved in hemorrhagic shock pathology, and transient receptor potential vanilloid 1 antagonist, capsazepine, acts on the central nervous system to improve mortality in a rat hemorrhagic shock model. In contrast, transient receptor potential vanilloid 1-positive efferents promote vasoactive reactions through the release of neuropeptides, including calcitonin gene-related peptides. This study aimed to investigate whether transient receptor potential vanilloid 1-positive peripheral sensory efferents are involved in hemodynamic responses after hemorrhagic shock. Methods: Male rats underwent hemorrhagic shock (mean arterial pressure 30 mm Hg for 90 min, followed by resuscitation for 30 min) and received capsazepine (5 mu M/kg) 30 min after shock induction. A separate cohort of rats subjected to hemorrhagic shock received hCGRP(8-37) (300 mu g/kg), a calcitonin gene-related peptide receptor antagonist, at 30, 60, or 90 minutes after shock induction. The 24-hour survival rate, mean arterial pressure, heart rate, arterial blood gas, and plasma calcitonin gene-related peptide levels were measured. Tissue blood flow and oxygenation both in the mesentery and skeletal muscle were also assessed. Results: Capsazepine treatment prevented the hemorrhagic shock-induced increase in plasma calcitonin gene-related peptide levels, and hCGRP(8-37) treatment improved the 24-h survival rates after hemorrhagic shock at a time-dependent manner. The hCGRP(8-37)- or capsazepine-treated rats exhibited tissue oxygenation and metabolic conditions comparable to those in control rats at the end of the experiment. Conclusion: Transient receptor potential vanilloid 1 plays a crucial role in hemodynamic responses to hemorrhagic shock, partly via calcitonin gene-related peptide release, involved in its peripheral sensory efferent functions. The hCGRP(8-37) appears to improve peripheral circulatory failure, which may be useful as adjunct treatment after hemorrhagic shock. (C) 2020 Elsevier Inc. All rights reserved.