WHR 1049, a potent metabolite of lidamidine, has antidiarrheal and antimotility effects on the small intestine in rats.

Lidamidine HCl has been suggested to be effective in treating certain motor disorders of the gastrointestinal tract. Lidamidine has alpha-2 agonist as well as local anesthetic properties. We studied the antimotility and antidiarrheal activity of WHR 1049, a hepatic metabolite of lidamidine known to have some activity and to persist longer in the serum than does lidamidine. We recorded the intestinal myoelectric activity of fasted unanesthetized rats with bipolar electrodes implanted on their proximal jejunum. We found that lidamidine HCl, given by gavage, inhibited fasting myoelectric activity in a dose-dependent manner (using 0.5-4.0 mg/kg). Neither saline nor tetracaine inhibited myoelectric activity. WHR 1049 given by gavage also inhibited myoelectric activity and was 30 times as potent as lidamidine (milligram per milligram, using 0.0625- to 0.25-mg/kg doses). Pretreatment with yohimbine (5 mg/kg s.c.), before administration of WHR 1049, decreased the myoelectric activity inhibition by two-thirds (but did not completely block it). Castor oil (1 ml/200 g b.wt.) was given to induce diarrhea and did so when given alone or with saline (vehicle) pretreatment. When these animals were pretreated with 0.25 mg/kg of WHR 1049, the same dose of castrol oil did not induce diarrhea for a 6-hr observation period. We conclude that WHR 1049 is a potent metabolite of lidamidine that inhibits myoelectric activity, has significant alpha-2 agonist activity and blocks induced diarrhea. Because tetracaine does not inhibit myoelectric activity we suggest that the local anesthetic properties of lidamidine do not account for any of the myoelectric activity inhibition. WHR 1049 may account for much of the antimotility and antidiarrheal activity of lidamidine.

Dopamine and norepinephrine in the gastrointestinal tract of mice and the effects of neurotoxins.

Evidence is lacking for neurons containing dopamine and acting as a neurotransmitter in the gastrointestinal tract. The relative percentage of dopamine to norepinephrine in noradrenergically innervated tissues (e.g., spleen) is known to be relatively constant within a species, and an increased percentage in any given tissue supports the premise that dopaminergic cells are present. We measured levels of norepinephrine, dopamine and the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) from segments of the gastrointestinal tract of mice after injection of: 1) saline (control); 2) 6-hydroxydopamine (6-OHDA); or 3) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. In control tissues the ratio of dopamine/norepinephrine was higher (P less than .001) than in the spleen; DOPAC was present and the DOPAC/dopamine ratios were similar to those in the central nervous system (where dopaminergic neurons are present). Dopamine and norepinephrine were decreased by 6-OHDA in most myenteric plexus/smooth muscle tissues compared with controls and DOPAC was unmeasurable in most samples after 6-OHDA. In contrast, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine decreased norepinephrine but not dopamine in the smooth muscle/myenteric plexus. High dopamine/norepinephrine percentages, 6-OHDA depletion of dopamine and presence of DOPAC together suggest the presence of dopamine-containing neurons in the myenteric plexus of the gastrointestinal tract of mice.

Chronic alterations in jejunal myoelectric activity in rats due to MPTP.

Parkinsonian patients may have symptoms consistent with intestinal pseudo-obstruction, but a primary intestinal abnormality has not been shown. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), after conversion to a toxic metabolite via the monoamine oxidase system, can induce Parkinson's disease by destroying dopaminergic neurons in the substantia nigra in humans and primates. Rodents have some catecholamine depletion but much less so than primates. Using chronic bipolar electrodes on the proximal jejunum of Wistar rats, we show significant, chronic migrating myoelectric complex disruption (P less than 0.001) and prolongation of irregular spike activity (P less than 0.001). Pargyline (a monoamine oxidase inhibitor) pretreatment significantly blocked these myoelectric changes. Sinemet (L-dopa and carbidopa), given after MPTP to replete dopamine, decreased the MPTP-induced migrating myoelectric complex disruption. Jejunal myenteric plexus dopamine levels were significantly decreased (to 61% of control) after MPTP but after much higher doses than were required to disrupt migrating myoelectric complex activity (180 mg/kg total vs. 30 mg/kg). Dopamine in the central nervous system was not depleted. We conclude that MPTP causes intestinal myoelectric disruption (which can be blocked by pargyline and decreased by Sinemet) possibly through enteric, but not central, nervous system effects.