Interactions of the cardiac chronotropic effects of rilmenidine with the autonomic nervous system in conscious dogs: comparison with clonidine.
1. The cardiac chronotropic effects of rilmenidine (10-100 micrograms kg-1) and clonidine (1-10 micrograms kg-1) were studied in conscious dogs with chronic atrioventricular block. 2. Rilmenidine and clonidine initially (< 3 min) decreased atrial rate, although the effect was not related to dose. More lastingly, ventricular rate was decreased in a dose-related manner (ratio, 1:21). Rilmenidine lowered mean blood pressure only at 100 micrograms kg-1, while clonidine had the same effect at doses of 5 micrograms kg-1 upward (ratio, 1:15). 3. When administered after atropine and pindolol, rilmenidine (50 micrograms kg-1) produced a decrease in atrial rate, with an identical intensity but longer duration than under basal conditions. When clonidine (2.5 micrograms kg-1) was given after atropine, no chronotropic atrial effect was observed. However, when clonidine (2.5 micrograms kg-1) was given after pindolol, it produced a decrease in atrial rate that was more marked, both in intensity and duration, than under basal conditions. After phenoxybenzamine, rilmenidine decreased atrial rate with a more marked and lasting effect than observed under basal conditions. Clonidine produced a bradycardic atrial effect identical to the basal effect. After yohimbine, rilmenidine and clonidine decreased atrial rate with an intensity similar to that under basal conditions, although the time course was totally different. 4. When given after atropine, rilmenidine (50 micrograms kg-1) and clonidine (2.5 micrograms kg-1) decreased ventricular rate as under basal conditions, whereas after pindolol and phenoxybenzamine, both drugs decreased ventricular rate less markedly than under basal conditions, both in intensity and duration. After yohimbine, rilmenidine and clonidine produced no chronotropic ventricular effect. 5. These results show that (a) the initial atrial bradycardia caused by rilmenidine results from both a decrease in sympathetic tone and an increase in cholinergic activity; while the effect of clonidine is caused mainly by the enhancement of cholinergic activity. For both drugs, alpha 2-adrenoceptors are involved at least in the initiation of the effect; (b) the very short duration of atrial bradycardia may result from reflex buffering in response to ventricular bradycardia. This buffering is less effective when heart rate was high; and (c) the ventricular bradycardia caused by both drugs is mainly the result of a decrease in sympathetic tone in response to the stimulation of alpha 2-adrenoceptors. The results also suggest that negative chronotropic postsynaptic alpha 2-adrenoceptors could be involved in the ventricular bradycardia.
Boucher
M
M
INSERM U. 195, Faculty of Medicine, Clermont-Ferrand, France.
Dubar
M
M
Chapuy
E
E
Chassaing
C
C
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000097:blood / Q000494:pharmacology*; D001285:Atropine / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002908:Chronic Disease; D003000:Clonidine / Q000494:pharmacology*; D003864:Depression, Chemical; D004285:Dogs; D005260:Female; D006327:Heart Block; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D010080:Oxazoles / Q000097:blood / Q000494:pharmacology*; D010643:Phenoxybenzamine / Q000494:pharmacology; D010869:Pindolol / Q000494:pharmacology; D000077769:Rilmenidine; D015016:Yohimbine / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D018727:Muscarinic Antagonists; D010080:Oxazoles; D010643:Phenoxybenzamine; D015016:Yohimbine; D001285:Atropine; D010869:Pindolol; D003000:Clonidine; D000077769:Rilmenidine