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.