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Insights From Atrial Fibrillation Genomics: From Bedside to Bench and Back Again.

ABSTRACT: From the bedside of patients contributing samples to large genome-wide association studies for atrial fibrillation (AF), over 100 AF risk loci have been identified. The top locus is near a gene implicated in pulmonary vein formation; the ostia of the pulmonary veins harbor initiating triggers of AF, and isolation of these areas is the cornerstone of ablation therapies for AF. Transcriptomic studies suggest that AF is associated with impaired or overwhelmed responses to cell stress. A dual risk model proposes that in genetically-susceptible individuals, inadequate transcriptional responses to stress predispose to AF in later life. Drugs targeting metabolic, oxidative, or protein handling stress may be novel upstream agents to bring back to the bedside for study in the prevention of AF.

SUBMITTER: Chung MK

PROVIDER: S-EPMC8421131 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Dexmedetomidine Diminishes Halothane Anesthetic Requirements in Rats Through a Postsynaptic Alpha 2 Adrenergic Receptor. By Segal IS, Vickery RG, Walton JK, Doze VA, and Maze M. ANESTHESIOLOGY 1988; 125:590-4. Abstract reprinted with permission.The effect of 4(5)-[1-(2,3-dimethylphenyl)ethyl]imidazole (medetomidine), the ?2 adrenergic agonist, on anesthetic requirements was investigated in rats anesthetized with halothane. Halothane MAC was determined before and after either dexmedetomidine (D-enantiomer) or levomedetomidine (L-enantiomer) 10, 30, and 100 ?g/kg, or vehicle intraperitoneally. There was a dose-dependent increase in MAC with the D-, but not the L-, stereoisomer. At the highest dose of dexmedetomidine (100 ?g/kg), halothane could be discontinued for up to 30?min with no response to tail clamping. To determine whether ?2 adrenoreceptors mediated this effect of dexmedetomidine on MAC, cohorts of rats were pretreated with idazoxan, 10?mg/kg intraperitoneally, a highly selective ?2 antagonist. This completely prevented the reduction of MAC caused by dexmedetomidine. To determine whether the reduction of MAC caused by dexmedetomidine was mediated in part through either opiate or adenosine receptors, groups of rats were pretreated with either naltrexone, 5?mg/kg intraperitoneally, an opiate antagonist, or 8-phenyltheophylline, 2.5?mg/kg intraperitoneally, an A1 adenosine antagonist. These two pretreatments did not alter the reduction of MAC by dexmedetomidine. To determine whether postsynaptic mechanisms mediate the anesthetic effect of dexmedetomidine, rats were depleted of central catecholamine stores with either n-(2-chloroethyl)-n-ethyl-2-bromobenzylamine or reserpine and ?-methyl-para-tyrosine, and MAC was determined before and after each dose of dexmedetomidine. While the catecholamine-depleted rats had a lower basal MAC than the vehicle controls, there was still a profound reduction in halothane MAC after administration of dexmedetomidine. The reduction of MAC by dexmedetomidine was blocked with idazoxan in the catecholamine-depleted rats. These data indicate that the reduction of MAC caused by dexmedetomidine is mediated through ?2 adrenoreceptors with no apparent involvement of either opiate or A1 adenosine receptors. Data from catecholamine-depleted rats suggest that the mediating mechanism must involve site(s) other than or in addition to the presynaptic ?2 adrenergic receptors on noradrenergic neurons. The authors conclude that central postsynaptic ?2 adrenergic receptors mediate a significant part of the reduction of anesthetic requirements caused by dexmedetomidine.

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Insights From Atrial Fibrillation Genomics: From Bedside to Bench and Back Again.

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