Dihydropyridine calcium channel antagonists disrupt migrating myoelectric complexes and counteract intestinal disorders associated with morphine withdrawal diarrhea.
The effects of two dihydropyridine (DHP) calcium channel antagonists, nifedipine and nimodipine, on migrating myoelectric complexes (MMCs) of the small intestine were studied in naive and morphine-dependent rats. In addition, the effects of two other calcium channel antagonists, verapamil and diltiazem, on the MMCs were investigated. Nifedipine (1.0-4.0 mg kg-1 intravenously) or nimodipine (1.0-4.0 mg kg-1 intravenously) had an inhibitory effect on the spontaneously occurring MMCs, whereas verapamil (2.5-5.0 mg kg-1 intravenously) or diltiazem (2.5-5.0 mg kg-1 intravenously) had no effect. Bay K 8644 (0.25 mg kg-1 intravenously), a DHP calcium channel agonist, instantly reversed the inhibition induced by nifedipine or nimodipine. When given alone, Bay K 8644 induced irregular spiking activity. In morphine-dependent rats with regular MMCs naloxone (1.0 mg kg-1 intravenously) induced intense spiking activity and profuse diarrhea. Nifedipine (2.0 and 4.0 mg kg-1 intravenously) and nimodipine (2.0 and 4.0 mg kg-1 intravenously) given before naloxone prevented the intense, abstinence-evoked spiking and associated diarrhea. In healthy volunteers nimodipine at an infusion rate of 2 mg h-1 for 4 h did not inhibit the fasting motility pattern. Our findings indicate that DHP-binding sites are involved in the regulation of MMC in the rat and that drugs acting as antagonists at these sites can be used to suppress morphine withdrawal diarrhea and, tentatively, other functional disorders of the intestine.
Thollander
M
M
Dept of Pharmacology, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden.
Hellström
P M
PM
Svensson
T H
TH
D000328:Adult; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003967:Diarrhea / Q000139:chemically induced / Q000503:physiopathology*; D004095:Dihydropyridines / Q000494:pharmacology*; D005215:Fasting; D005769:Gastrointestinal Motility / Q000187:drug effects; D006801:Humans; D007410:Intestinal Diseases / Q000139:chemically induced / Q000503:physiopathology*; D007421:Intestine, Small / Q000187:drug effects; D008297:Male; D009020:Morphine / Q000009:adverse effects*; D016065:Myoelectric Complex, Migrating / Q000187:drug effects*; D009553:Nimodipine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D009553:Nimodipine; D009020:Morphine