Clonidine stimulates force of contraction via histamine H2 receptors in the human atrium

Introduction: Clonidine has various clinical effects mediated by agonism of α 1 - or α 2 -adrenoceptors and the blocking of HCN-channels. It is unknown whether clonidine can also stimulate human cardiac histamine H 2 receptors (hH 2 R). Methods: : We used isolated electrically stimulated left and spontaneously beating right atrial preparations from mice overexpressing the h H 2 R specifically in the heart (H 2 -TG), and spontaneously beating right atrial preparations of guinea pigs for comparison. Moreover, we studied isolated electrically stimulated muscle strips from the human right atrium. Results: Clonidine (1, 3, 10 µM) increased force of contraction in isolated left atrial preparations from H 2 -TG mice. In contrast, clonidine reduced the spontaneous beating rate in right atrial preparations from H 2 -TG. Clonidine raised the beating rate in guinea pig right atrial preparations. Clonidine failed to increase the force of contraction but reduced beating rate in wild type litter mate mice (WT). In WT, histamine failed to increase the force of contraction in left atrial preparations and beating rate in right atrial preparations. Clonidine (10 µM) increased the force of contraction in isolated human right atrial preparations. These effects in the human atrium were attenuated by cimetidine (10 µM). Clonidine increased the beating rate of the isolated spontaneously beating guinea pig right atrium and acted as a H 2 R partial agonist. Furthermore, clonidine showed binding to the guinea pig H 2 R (100 µM) using HEK cells in a recombinant expression system (p K i < 4.5) but not to the human H 2 R. Conclusions: : These data suggest that clonidine can activate cardiac human histamine H 2 receptors.