Modification of the duration of action and pharmacodynamics of arecoline by tetraisopropylpyrophosphoramide.

Tetraisopropylpyrophosphoramide (ISO-OMPA) pretreatment in the mouse was examined for its ability to prolong the time course of arecoline (ARE) concentration using brain ARE concentration as an index. Brain ARE levels were also correlated with acetylcholine (ACh) and choline concentrations. Pretreatment with 40 mg kg-1 ISO-OMPA increased ARE brain concentrations from 3 nmoles g-1 to 76 nmoles g-1 15 min after i.p. administration of 25 mg kg-1 ARE. ARE (25 mg kg-1) alone significantly increased brain ACh and choline levels. In time course studies, administration of ARE (15 mg kg-1) produced a peak brain level of 7.9 nmoles g-1 at 3 min. ISO-OMPA pretreatment increased the peak level of ARE to 46.5 nmoles g-1 and the peak time to 7-15 min. The time of maximum brain elevation of ACh and choline produced by ARE alone lagged slightly behind the peak level time observed for ARE. ARE alone produced a maximal increase in ACh and choline levels to 34.1 and 57.1 nmoles g-1, respectively. In the presence of ISO-OMPA, ARE further increased ACh and choline levels to 48.2 and 103 nmoles g-1, respectively. After i.p. administration the highest concentration of ARE was found in the cortex, followed by the subcortex, and cerebellum. A significant elevation of ACh was observed in the cortex.

Decreased plasma cholinesterase activity enhances cocaine toxicity in mice.

The illicit use of cocaine continues in epidemic proportions. Despite the incidence of life-threatening complications from cocaine use, little is known of the individual determinants of cocaine toxicity. In vitro analysis demonstrating that cocaine is poorly metabolized by the serum of patients with low plasma cholinesterase (PCh) activity (succinylcholine sensitivity) led to the hypothesis that altered PCh activity might modulate cocaine toxicity. An in vivo mouse model was created to test this theory. Mice were pretreated s.c. with either parathion [a mixed plasma and red blood cell cholinesterase (RBCCh) inhibitor], tetraisopropyl pyrophosphoramide (a selective PCh inhibitor) or placebo, and cholinesterase activity was determined at 24 hr. Incremental doses of i.p. cocaine were administered in a controlled and blinded fashion, and lethality was observed. Ten mg/kg s.c. parathion produced a mean suppression of 68 +/- 9 and 61 +/- 8% of PCh and RBCCh activity, respectively. One mg/kg s.c. tetraisopropyl pyrophosphoramide produced a mean suppression of 78 +/- 3 and 9 +/- 8% of PCh and RBCCh activity, respectively. Each pretreatment produced a statistically significant increase in cocaine lethality throughout the dose-response curve. Our results suggest that PCh activity is an important determinant of cocaine toxicity. This effect appears to be independent of either RBCCh activity or manifestations of organophosphate intoxication.

Increased canine pancreatic acinar cell damage after organophosphate and acetylcholine or cholecystokinin.

Sublethal doses of organophosphate anticholinesterases cause acute pancreatitis in dogs within 2 h. In vitro studies using canine pancreatic fragments have also demonstrated that the peak of amylase release in response to acetylcholine is shifted far to the left after incubation with the organophosphates echothiophate (10(-4) M) or tetraisopropyl pyrophosphoramide (iso-OMPA) (10(-3) M), indicating an increased sensitivity of response. The present in vitro study examined whether there was also an increased susceptibility to acinar cell damage at the electron microscopic level after acetylcholine or cholecystokinin. Minced pieces of whole fresh canine pancreas 2-3 mm in size were placed in buffered Eagle's solution and gassed with 100% O2. After pretreatment 1 h with echothiophate or iso-OMPA, they were then incubated with acetylcholine (10(-5) M). Other tissues preincubated with echothiophate were stimulated with cholecystokinin (10(-9) M). These are submaximal doses for untreated canine pancreatic fragments. After acetylcholine and echothiophate or acetylcholine and iso-OMPA, there was extensive acinar damage with the appearance of large vacuoles and lakes, and interstitial edema. There was evidence of intense supramaximal stimulation and lateral exocytosis. Similar destructive changes were seen after echothiophate and cholecystokinin. In control sections from tissues stimulated with acetylcholine (10(-5) M) or cholecystokinin (10(-9) M, there were lumenal exocytotic patterns typical of submaximal stimulation. Other controls, organophosphate alone and unstimulated basal conditions, showed only minor changes. It is concluded that the increased sensitivity to acetylcholine after organophosphate incubation correlates with an increased susceptibility to acinar ultrastructural damage from acetylcholine and cholecystokinin.