Abstract
Numerous studies support the concept that centrally acting antihypertensive drugs, such as imidazolines, mediate sympathoinhibition not only via activation of central nervous α2-adrenoceptors (α2-AR) but also via imidazoline-1 receptors (I1-R). An additional presynaptic involvement in sympathetic neurotransmission of imidazolines, via I1-R independent of α2-AR, is still controversial and remains to be clarified in the heart. Concentration response curves on endogenous norepinephrine (NE) overflow evoked by stimulation of epicardial postganglionic sympathetic nerves in isolated buffer-perfused rat hearts were performed for brimonidine, moxonidine, rauwolscine, 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane (AGN192403), and efaroxan. To unmask an I1-R-mediated effect of moxonidine, hearts were pre-exposed in additional experiments with brimonidine or rauwolscine with or without AGN192403 or efaroxan, respectively. Moxonidine reduced stimulated NE overflow (log EC50: −6.15 ± 0.14). AGN192403, a selective ligand at I1-R, had no influence on the dose-response curve of moxonidine (log EC50: −6.01 ± 0.25). After pre-exposure to brimonidine [ stimulation 1 (S1) + stimulation 2 (S2); 10−5M], the inhibitory action of moxonidine was potentiated compared with control (32.0 ± 2.8 versus 73.13 ± 3.0%) and completely abolished with AGN192403 or efaroxan. This effect was also totally inhibited by pre-exposure with indomethacin (10−7M) and tricyclodecan-9-yl-xanthogenate (D-609), an inhibitor of phosphatidylcholine-selective phospholipase C (PC-PLC; 10−7M). Conversely, moxonidine was without modulating efficacy under α2-AR-blockade by rauwolscine. In summary, we demonstrate that moxonidine reduces NE release independently of I1-R, demonstrating the prominent effect of α2-AR in cardiac tissue under basal conditions. We also demonstrate that I1-R are involved in NE release under conditions of α2-AR-stimulation involving both a pathway of prostaglandins and PC-PLC.
- The American Society for Pharmacology and Experimental Therapeutics
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