title: Antiarrhythmic effect of the selective I1-imidazoline receptor modulator moxonidine on ouabain-induced cardiac arrhythmia in guinea pigs.
abstract: Moxonidine is a centrally acting antihypertensive agent with potent action on I1-imidazoline receptors. Moxonidine as an SIR modulator elicits a persistent reduction in circulating levels of epinephrine, demonstrating a reduction in sympathetic tone. In the first experiment the threshold dose of ouabain needed to induce ventricular arrhythmia and asystole was determined in guinea pigs, and the influence of moxonidine was tested. In a dose range of 0.1-0.4 mg/kg body weight i.v., moxonidine increased the threshold dose needed to induce ventricular tachycardia, premature ventricular beats, ventricular flutter, ventricular fibrillation, and asystole. The effect was dose-dependent and statistically significant. Clonidine, in a dose range of 0.2-0.8 mg/kg body weight i.v., also increased the threshold dose of ouabain necessary to induce different cardiac rhythm disturbances. Moxonidine was more effective than clonidine. Pretreatment with the alpha 2-receptor and I1-receptor-influencing substances efaroxan, idazoxan, and SKF 86466 attenuated the effect of moxonidine and clonidine. Efaroxan, idazoxan, or SKF 86466 alone reduced the threshold dose of ouabain necessary to induce cardiac arrhythmia as a sign for arrhythmogenic effects. The alpha 1-receptor antagonist prazosin had no influence on ouabain-induced arrhythmia. Pretreatment with prazosin reduced the moxonidine but not the clonidine effect. In the second experiment the influence of moxonidine on aconitine-induced extrasystoles (ES) in the spontaneously beating guinea pig auricle was investigated. Moxonidine in a dose of 10(-7)-10(-8) M reduced the number of ES. A 10-fold higher dose had no influence on ES number. The beta-blocking agent propranolol showed antiarrhythmic effects in both methods. The ouabain-induced cardiac arrhythmia is associated with increased sympathetic tone on central stimulation. The reduced sympathetic tone by centrally acting moxonidine via imidazoline receptors seems responsible for the antiarrhythmic effect of this drug. Clonidine also reduced the sympathetic tone via imidazoline receptor. The selectivity of clonidine to imidazoline receptors is less pronounced than is that of moxonidine. The interaction of moxonidine with imidazoline receptors is not clear. The possible interaction between imidazoline and alpha-adrenoceptors in relation to the antiarrhythmic effect of moxonidine or clonidine is also unknown. Modulation of imidazoline receptors by moxonidine could be an agonistic effect or an antagonism to an endogenous agonistic or antagonistic substance and vice versa.
authors.affiliation: Department of Pharmacology, Beiersdorf-Lilly GmbH, Hamburg, Germany.
authors.forename: H J
authors.initials: HJ
authors.lastname: Mest
authors.forename: P
authors.initials: P
authors.lastname: Thomsen
authors.forename: A
authors.initials: A
authors.lastname: Raap
mesh_terms: D000157:Aconitine / Q000494:pharmacology; D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy*; D006168:Guinea Pigs; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D054755:Imidazoline Receptors; D066298:In Vitro Techniques; D010042:Ouabain; D011955:Receptors, Drug / Q000187:drug effects*
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000889:Anti-Arrhythmia Agents; D007093:Imidazoles; D054755:Imidazoline Receptors; D011955:Receptors, Drug; D010042:Ouabain; C043482:moxonidine; D000157:Aconitine