Positive inotropic effects of dexmedetomidine in the human atrium

Abstract ID 96052 Poster Board 468 Dexmedetomidine is an approved drug. It is used as a sedative agent and as an analgesic agent. These neurological effects are explained by a stimulatory effect of dexmedetomidine on brain α₂-adrenoceptors. Dexmedetomidine has about tenfold higher selectivity at α₂-adrenoceptors over α₁-adrenoceptors compared to its parent compound clonidine. Dexmedetomidine was recently noted to increase mortality in subgroups of patients for unknown reasons. Clonidine activates α₁-adrenoceptors and H₂-histamine receptors in the human atrium. We hypothesized the same would apply to dexmedetomidine. Therefore, we performed contraction experiments in isolated paced (1 Hz) left atrial preparations from mice that overexpress the human H2 histamine receptor (H₂-TG) or from littermate wild type mice (WT) and paced human right atrial preparations (HAP) from patients undergoing cardiac surgery. We measured force of contraction under isometric conditions. In left atrial preparations from H₂-TG, only in the presence of 0.1 μM rolipram (an inhibitor of phosphodiesterase IV), dexmedetomidine concentration and time dependently exerted a positive inotropic effect (PIE). This PIE positive inotropic effect of dexmedetomidine (10 μM) was completely abolished by additionally applied cimetidine (10 μM). In human atrial preparations, dexmedetomidine exerted likewise a time and concentration PIE that started a 1 μM and was maximum at 10 μM, the highest concentration studied (n= 5, p<0.05). The PIE of dexmedetomidine (10 μM) was not antagonized by subsequently applied 10 μM cimetidine or 50 μM cimetidine. In contrast, the PIE of dexmedetomidine was antagonized by 10 μM propranolol, additionally applied. We conclude that dexmedetomidine like clonidine has a PIE in isolated human atrial preparations. We hypothesize that dexmedetomidine unlike clonidine might release cardiac noradrenaline. This released noradrenaline then stimulates cardiac β-adrenoceptors. Thus, dexmedetomidine might be an indirect sympathomimetic agent in the human atrium but a H₂-histamine receptor agonist in H₂-TG. The actions of dexmedetomidine are species dependent. In the human heart, dexmedetomidine could lead to arrhythmias and this might explain why dexmedetomidine can increase the mortality in some groups of patients.