Neumann, Joachim and Pockes, Steffen and Humphrys, Laura J. and Moennich, Denise and Forster, Lisa and Kirchhefer, Uwe and Hofmann, Britt and Gergs, Ulrich (2024) Clonidine stimulates force of contraction via histamine H₂ receptors in the human atrium. NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 397. pp. 617-626. ISSN 0028-1298, 1432-1912
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Clonidine has various clinical effects mediated by agonism of & alpha;(1)- or & alpha;(2)-adrenoceptors and the blocking of hyperpolarization-activated-nucleotide-gated pacemaker channels (HCN). It is unknown whether clonidine can also stimulate human cardiac histamine H-2 receptors (hH(2)Rs). We used isolated electrically stimulated left and spontaneously beating right atrial preparations from mice overexpressing the hH(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. Clonidine (1, 3, and 10 & mu;M) 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 & mu;M) increased the force of contraction in isolated human right atrial preparations. The positive inotropic effect in the human atrium was attenuated by cimetidine (10 & mu;M). Clonidine increased the beating rate of the isolated spontaneously beating guinea pig right atrium and acted as a H2R partial agonist. Furthermore, clonidine showed binding to the guinea pig H2R (100 & mu;M) using HEK cells in a recombinant expression system (pK(i) < 4.5) but hardly to the human H2R. These data suggest that clonidine can functionally activate cardiac human H2R.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ALPHA-ADRENOCEPTORS; ADENYLATE-CYCLASE; RECEPTORS; INHIBITION; AGONISTS; GENE; Clonidine; Human atrium; Mouse atrium; Histamine H2 receptor |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 05 Apr 2024 04:42 |
| Last Modified: | 05 Apr 2024 04:42 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60628 |
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