Remote Limb Ischemic Preconditioning Attenuates Cerebrovascular Depression During Sinusoidal Galvanic Vestibular Stimulation via α ₁ ‐Adrenoceptor–Protein Kinase Cε–Endothelial NO Synthase Pathway in Rats

Abstract

BackgroundVasovagal syncope (VVS) is characterized by hypotension and bradycardia followed by lowering of cerebral blood flow. Remote limb ischemic preconditioning (RIPC) is well documented to provide cardio‐ and neuroprotection as well as to improve cerebral blood flow. We hypothesized that RIPC will provide protection against VVS‐induced hypotension, bradycardia, and cerebral hypoperfusion. Second, because endothelial nitric oxide synthase has been reported as a mediator of cerebral blood flow control, we hypothesized that the mechanism by which RIPC primes the vasculature against VVS is via the α1‐adrenoceptor–protein kinase Cε–endothelial nitric oxide synthase pathway.Methods and ResultsWe utilized sinusoidal galvanic vestibular stimulation in rats as a model of VVS. RIPC attenuated the lowerings of mean arterial pressure, heart rate, and cerebral blood flow caused by sinusoidal galvanic vestibular stimulation, as well as improving behavior during, and recovery after, stimulation. RIPC induced elevated serum norepinephrine, increased expression of brain α1‐adrenoceptors, and reduced brain expression of norepinephrine transporter 1. Antagonizing adrenoceptors and norepinephrine transporter 1 prevented RIPC protection of cerebral perfusion during sinusoidal galvanic vestibular stimulation.ConclusionsTaken together, this study indicates that RIPC may be a potential therapy that can prevent VVS pathophysiology, decrease syncopal episodes, and reduce the injuries associated with syncopal falls. Furthermore, the α1‐adrenoceptor–protein kinase Cε–endothelial nitric oxide synthase pathway may be a therapeutic target for regulating changes in cerebral blood flow.

COVID-19: Oxidative Preconditioning as a Potential Therapeutic Approach

“…The antioxidative stress actions of preconditioning cooperate with its anti-inflammatory effects by activation of Akt and ERK1/2 as well as downregulation of NF-kB signaling . In addition, preconditioning increases the activity of antioxidant enzymes that function as scavengers such as catalase and decreases generation of free radicals by pro-oxidant enzymes such as nitric oxide synthase. − ROS are generated constantly by viral infections and their replication . In addition, central mediators implicated in preconditioning have been observed in cellular adaptation to both viral stress and hypoxia.…”

A Review of Humoral Factors in Remote Preconditioning of the Heart

“…Norepinephrine as a humoral factor in RIP was first proposed by Dickson et al 18 Indeed, norepinephrine titers in the blood increase after RIP. 88 It should be noted that the stimulation of b-adrenergic receptors in the period preceding ischemia can promote an increase in cardiac tolerance to I/R, 89,90 so norepinephrine cannot be discounted as both a neurogenic and a humoral factor in RIP.…”

“…A humoral pathway for the implementation of cardioprotection with RIP was demonstrated in various preconditioning models. Further studies of the mechanism for the development of heart RIP suggest that it may involve hydrophobic peptides, 25 endogenous opioids (opioid peptides), 26,27,30,31,33,34 prostanoids, 42 endocannabinoids 44 and endovanilloids, 54 calcitonin, a gene-related peptide 55,82 as well as adenosine, 14,36 -39 leukotrienes, 86 norepinephrine, 88 adrenomedullin, 91 glycine, 93 and microRNAs. 116 -120…”