Acetylcholinesterase blockade does not account for the adverse cardiovascular effects of the antitumor drug irinotecan: a preclinical study.
This study investigates the mechanisms that account for the adverse cardiovascular effects of the antitumor drug irinotecan. The activities of irinotecan, its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), and camptothecin were assayed in urethane-anesthetized rats to determine their effects on heart rate and blood pressure. In vitro experiments were performed to assess the effects of test drugs on acetylcholinesterase activity. Intravenous irinotecan (10 micromol/kg) decreased heart rate and blood pressure, but SN-38, camptothecin, or intracerebroventricular irinotecan had no effect. The bradycardic and hypotensive responses induced by irinotecan were abolished by bilateral vagotomy or atropine. Physostigmine caused a transient bradycardia, followed by a tachycardic response, and promoted a marked increment of blood pressure. Vagotomy or atropine prevented the bradycardic action of physostigmine, whereas the tachycardic and hypertensive responses were sensitive to atropine, but not to vagotomy. Five minutes after irinotecan administration (10 micromol/kg i.v.), its concentration in plasma and atrial tissue accounted for 2.29 +/- 0.19 micromol/L and 1.08 +/- 0.16 micromol/kg, respectively. The in vitro activity of human erythrocyte acetylcholinesterase was significantly inhibited by irinotecan (-21.5% at 100 microM) or physostigmine (-84.8% at 1 microM), whereas SN-38 or camptothecin had no effect. Rat atrial acetylcholinesterase was also significantly inhibited in vitro by irinotecan (-16.9% at 100 microM). The present results indicate that irinotecan exerts depressant effects on both heart rate and arterial blood pressure. A direct activation of cholinergic receptors or an interaction with central nervous sites does not appear to account for these inhibitory actions, whereas a blockade of acetylcholinesterase seems to occur at concentrations of irinotecan that may not be relevant in clinical settings.
Blandizzi
C
C
Division of Pharmacology and Chemotherapy, University of Pisa, Pisa, Italy.
De Paolis
B
B
Colucci
R
R
Di Paolo
A
A
Danesi
R
R
Del Tacca
M
M
D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000633:toxicity*; D001285:Atropine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology / Q000633:toxicity*; D002319:Cardiovascular System / Q000187:drug effects* / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000097:blood / Q000633:toxicity*; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D006325:Heart Atria / Q000187:drug effects / Q000201:enzymology; D006339:Heart Rate / Q000187:drug effects; D000077146:Irinotecan; D008297:Male; D010830:Physostigmine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018709:Statistics, Nonparametric; D014630:Vagus Nerve / Q000502:physiology
D000972:Antineoplastic Agents, Phytogenic; D002800:Cholinesterase Inhibitors; D000077146:Irinotecan; D001285:Atropine; D010830:Physostigmine; D000110:Acetylcholinesterase; D002166:Camptothecin