Vol. 303, Issue 3, 1163-1170, December 2002

Presynaptic Effects of Moxonidine in Isolated Buffer Perfused Rat Hearts: Role of Imidazoline-1 Receptors and ₂-Adrenoceptors

Ulrich Schäfer, Christof Burgdorf, Astrid Engelhardt, Thomas Kurz and Gert Richardt

Medizinische Klinik II, Medizinische Universität zu Lübeck, Lübeck, Germany

Numerous studies support the concept that centrally acting antihypertensive drugs, such as imidazolines, mediate sympathoinhibition not only via activation of central nervous ₂-adrenoceptors (₂-AR) but also via imidazoline-1 receptors (I₁-R). An additional presynaptic involvement in sympathetic neurotransmission of imidazolines, via I₁-R independent of ₂-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); 10⁵M], 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 (10⁷M) and tricyclodecan-9-yl-xanthogenate (D-609), an inhibitor of phosphatidylcholine-selective phospholipase C (PC-PLC; 10⁷M). Conversely, moxonidine was without modulating efficacy under ₂-AR-blockade by rauwolscine. In summary, we demonstrate that moxonidine reduces NE release independently of I₁-R, demonstrating the prominent effect of ₂-AR in cardiac tissue under basal conditions. We also demonstrate that I₁-R are involved in NE release under conditions of ₂-AR-stimulation involving both a pathway of prostaglandins and PC-PLC.