Chronic alcohol consumption increases sensitivity to the anorexic effect of cholecystokinin.

In this study we examined the ability of intraperitoneal cholecystokinin COOH-terminal octapeptide (CCK-8; 0.2, 0.6, and 2.0 micrograms/kg) to suppress food intake in rats that had consumed a control diet, 6-8 g.kg-1.day-1 of ethanol (EtOH) in sucrose, or sucrose alone for 6 mo. Both the EtOH- and sucrose-fed rats developed significant dietary obesity. After 3 mo, the EtOH group was significantly more sensitive to CCK-8 than the sucrose and control groups, while the responses of the sucrose and control groups were comparable. In contrast, after 6 mo the EtOH and sucrose groups' response to CCK-8 was no longer significantly different. After 6 mo there were no significant differences in basal or postprandial plasma CCK-8 levels. The sucrose group had significantly higher basal insulin levels than the control and EtOH groups, and postprandial insulin levels, relative to basal, were significantly elevated in the EtOH group. Basal glucose levels did not differ among groups. Postprandial glucose levels (relative to baseline) were significantly lower in the EtOH group compared with the other groups and in fact never rose above baseline levels. These results are consistent with the hypothesis that EtOH, when taken on a chronic basis, increases the sensitivity to CCK-8.

Cholecystokinin octapeptide decreases food intake in white-crowned sparrows.

White-crowned sparrows maintained on short days (9:15-h light-dark cycle) were peripherally injected with 1.0, 4.0, and 16 micrograms/kg ip of cholecystokinin octapeptide (CCK-8). Meal size over the subsequent 30 min was significantly depressed in a dose-dependent fashion. Water intake was not affected. The anorexic effect caused by 4.0 micrograms/kg was attenuated by 100 micrograms/kg of the type-A CCK receptor antagonist MK-329 but not by 300 micrograms/kg of the type-B CCK receptor antagonist L 365,260, suggesting that CCK-induced suppression of food intake in this species is mediated by a CCK-A receptor. Administration of both CCK-A and CCK-B receptor antagonists alone resulted in no change in meal size. These experiments suggest that white-crowned sparrows, when weight stable, respond to CCK-8 in a manner comparable with several mammalian species.

CCK satiety is differentially mediated by high- and low-affinity CCK receptors in mice and rats.

Cholecystokinin-JMV-180 (JMV-180) is an analogue of cholecystokinin C-terminal octapeptide (CCK-8), which has been shown to be an agonist at the proposed CCK pancreatic high-affinity site and a functional antagonist at the pancreatic low-affinity site in rats and to have agonist activity at both high- and low-affinity sites in the mouse. In this study we used JMV-180 to evaluate the potential participation of these two CCK-A sites in the satiety effect of CCK-8 in rats and mice. When tested at doses that ranged from 0.01 to 9.2 mumol/kg, JMV-180 did not reliably affect food intake of solid or liquid test diets in rats. When combined with CCK-8 (3.2 or 8.5 nmol/kg) JMV-180 dose dependently reversed the satiety effect of CCK-8. In contrast to these results in the rat, both JMV-180 (3.7-14.8 mumol/kg) and CCK-8 (1.7-6.8 nmol/kg) dose dependently reduced the intake of 20% sucrose in mice. Both CCK-8- and JMV-180-induced suppression of food intake were attenuated by the CCK-A antagonist MK-329 (24.8 nmol/kg). The results of these studies suggest that agonist activity at sites pharmacologically similar to the CCK pancreatic high-affinity site is not sufficient for expression of CCK satiety, whereas agonist activity at low-affinity-like sites is necessary to reduce food intake. Thus the anorexic activity of CCK appears to be mediated through an interaction with a receptor site pharmacologically similar to the pancreatic low-affinity CCK receptor site.

Satiety induced by endogenous and exogenous cholecystokinin is mediated by CCK-A receptors in mice.

To investigate the relative participation of peripheral (CCK-A) and central (CCK-B) cholecystokinin (CCK) receptors in satiety induced by endogenous CCK, we examined the effect of the CCK-A antagonist MK-329 (10-315 micrograms/kg) and the CCK-B antagonist L 365260 (0.1-315 micrograms/kg) on intake of a 20% sucrose solution in mildly food-deprived mice. Intraperitoneal injection of MK-329 elicited a dose-related increase in sucrose consumption with a minimal effective dose of 31.5 micrograms/kg. This dose increased sucrose intake 23% and the highest dose tested, 315 micrograms/kg, increased sucrose intake 63% above baseline. In contrast to MK-329, intraperitoneal administration of L 365260 had no effect on sucrose intake at doses up to 315 micrograms/kg. To examine the contribution of these two CCK receptor subtypes in satiety induced by exogenous CCK, CCK-8 (8 micrograms/kg) was administered alone and in combination with MK-329 and L 365260. MK-329 (10 micrograms/kg) significantly attenuated the satiety effect of CCK-8, and L 365260 (100 micrograms/kg) was without effect. These results suggest that the peripheral CCK receptor subtype mediates satiety induced by endogenous and exogenous CCK in the mouse.

(-)threo-chlorocitric acid decreases sham feeding of sucrose in rats.

The contribution of changes in rate of gastric emptying to the anorectic effect of (-)-threo-chlorocitric acid (chlorocitrate) was assessed by examining the effect of this drug in sham feeding rats, a preparation where gastric distention does not occur. Gavage administration of chlorocitrate (100-400 mg.kg-1) decreased sham and real feeding of 20% sucrose in a dose-related manner. In sham-feeding rats, the minimal effective dose was 200 mg.kg-1. The anorectic effect was evident at 60 min after 200 mg.kg-1 and 30 min after 400 mg.kg-1. In real-feeding rats, the minimal effective dose was 100 mg.kg-1 and for all doses tested the effect was apparent at the 15-min time point. In a second experiment, the effect of chlorocitrate (100-400 mg.kg-1) on gastric emptying of 20% sucrose was examined. Chlorocitrate (200 and 400 mg.kg-1) had a modest but significant inhibitory effect on gastric emptying; however, the effect was not dose-related. Inasmuch as chlorocitrate decreased sham feeding, its anorectic effect cannot be solely attributed to inhibition of gastric emptying. However, because chlorocitrate was more potent in the real-feeding condition relative to sham feeding, and the time course of the response in the two feeding conditions was different, part of chlorocitrate's anorectic effect may depend on postingestive cues such as gastric distention.

Failure to detect increases in brain dopamine metabolism in rats sham feeding sucrose and corn oil.

In a recent study we found that when rats sham fed 6% sucrose, 10% sucrose, and 100% corn oil, the rank order of inhibitory potency for D-1 and D-2 receptor antagonists was 6% sucrose greater than 10% sucrose greater than 100% corn oil. In a complementary study, sham-feeding rats preferred 100% corn oil greater than 10% sucrose greater than 6% sucrose as measured by two-bottle preference tests. The preferences are evidence for the rank order of reward value of these solutions. In the present study we tested the hypothesis that the relative antagonist potencies were due to differential release of DA, dependent on the reward value of the sham-fed solution. Dopamine metabolism, estimated by the ratio of dihydroxphenylacetic acid (DOPAC) to DA, was measured in forebrain-DA terminal fields during sham feeding of 100% corn oil, 6% sucrose, and 10% sucrose. The results did not support our hypothesis: no increase in DA metabolism was observed after the sham feeding of any solution.

Obese and lean Zucker rats differ in preferences for sham-fed corn oil or sucrose.

Obese Zucker rats show greater preference for fatty foods in dietary selection studies than do lean rats. We wished to evaluate the preference for dietary fats in Zucker rats in the absence of postingestive cues. Zucker rats (6 lean and 6 obese) were fitted with gastric cannulas for sham feeding. All sham-feeding tests lasted for 30 min. On training days, rats were sham fed 100% corn oil or, on alternate days, rats were sham fed various concentrations of sucrose in volumes yoked to intakes of corn oil. On preference test days, rats were offered 100% corn oil and one sucrose concentration simultaneously for sham feeding. During preference tests, obese rats preferred 100% corn oil to 10% sucrose, whereas lean rats preferred 10% sucrose to 100% corn oil. Obese rats equally preferred 17.5% sucrose and 100% corn oil, whereas lean Zucker rats equally preferred 2.5% sucrose and 100% corn oil. When sucrose concentration was increased to 20% both obese and lean Zucker rats preferred sucrose to 100% corn oil. These results combined with our previously reported results showing that intraduodenally administered fats do not differ in satiating potency for obese and lean Zucker rats (6) strongly suggest that the preference of obese rats for fatty foods is largely mediated by orosensory mechanisms.

The potency of D-1 and D-2 receptor antagonists is inversely related to the reward value of sham-fed corn oil and sucrose in rats.

Intraperitoneal injection of 50 micrograms.kg-1 of the selective dopamine D-1 receptor antagonist, SCH 23390, significantly decreased sham feeding of 6% and 10% sucrose solutions, but not sham feeding of 100% corn oil. Intraperitoneal injection of raclopride, a D-2 antagonist, elicited a significant dose-dependent (200-400 micrograms.kg-1) decrease in sham intake of both sucrose concentrations and corn oil at doses that did not increase the latency to sham feed or produce overt motor impairment. The rank order of inhibitory potency for both SCH 23390 and raclopride was 6% sucrose greater than 10% sucrose greater than 100% corn oil. In a second experiment, we found that in 2-bottle preference tests, the rank order of preference for these three liquids was 100% corn oil greater than 10% sucrose greater than 6% sucrose. Assuming that preference measured the relative reward value of the liquids, the potencies of the two antagonists were inversely related to the reward value of the liquid that was sham fed. This result supports but does not prove the dopamine hypothesis of the positive reinforcing effect of orosensory stimulation by nutrients. In addition, the differential selectivity of the two antagonists for different classes of nutrients suggests that normal sensory and/or hedonic processing of sham-fed sucrose depends on stimulation of both D-1 and D-2 receptors, but the normal sensory and/or hedonic processing of sham-fed corn oil depends primarily, perhaps exclusively, on stimulation of D-2 receptors.

Lesion of vagal afferent terminals impairs glucagon-induced suppression of food intake.

Selective hepatic branch vagotomy impairs glucagon-induced inhibition of food intake. However, the relative importance of afferent and efferent neurons in glucagon satiety has not been directly investigated. In this experiment, lesions were placed in the area postrema (AP) and immediately subjacent nucleus of the solitary tract (NTS) where hepatic vagal afferents have been reported to terminate. We found that these lesions impaired glucagon-induced satiety under testing conditions similar to those that reveal a glucagon satiety deficit in rats with selective hepatic branch vagotomies. Since these lesions did not damage the underlying dorsal motor nucleus of the vagus, our results suggest that our AP/NTS lesions impaired glucagon satiety by damaging terminal fields of vagal afferent neurons. Finally, our lesions did not impair satiety induced by cholecystokinin (CCK), a response mediated by gastric vagal afferent neurons. This latter result suggests that the vagal afferent terminal fields required for glucagon- and CCK-induced satiety are not coextensive.

D-1 and D-2 receptor antagonists decrease corn oil sham feeding in rats.

Intraperitoneal injection of the highly selective D-1 and D-2 receptor antagonists, SCH 23390 and (-)-raclopride, respectively, produced a dose-related decrease in the intake of corn oil in a 30-min, sham-feeding test. The threshold dose for a significant decrease in intake was 100 micrograms.kg-1 for SCH 23390 and 200 micrograms.kg-1 for raclopride. These doses did not impair rats' latencies to initiate sham feeding, and they did not produce any overt motor deficits. These data, therefore, are consistent with the hypothesis that central dopaminergic activity at both D-1 and D-2 receptors is necessary for the normal processing of the sensory and/or hedonic effects of the oral stimuli produced by corn oil during sham feeding.

Glucagon satiety: diurnal variation after hepatic branch vagotomy or intraportal alloxan.

Hepatic vagotomized and hepatic portal alloxan-injected rats and their controls were tested for glucagon satiety at three time points during the circadian photoperiod: 6 hr into the light cycle with no food deprivation using a palatable liquid food; at the onset of the dark cycle after 6 hr food deprivation using pelleted rat chow; and 3 hr into the dark cycle after 9 hr food deprivation using pelleted chow. Glucagon failed to suppress intake in hepatic vagotomized and alloxan-treated rats when tests were conducted during the light cycle or at the onset of the dark cycle. In contrast, in tests conducted 3 hr into the dark cycle, glucagon suppressed food intake significantly in both hepatic vagotomized and alloxan-treated rats. Glucagon suppressed food intake significantly in controls in all tests. These results indicate that the hepatic vagus is not the sole mediator or glucagon satiety. Moreover, the fact that alloxan-treated rats and hepatic vagotomized rats responded in a similar manner to glucagon at all testing times suggests that hepatic portal alloxan treatment damages hepatic vagal fibers.

Trendelenburg pulmonary embolectomy for cardiac arrest secondary to massive pulmonary embolism.

Cardiac arrest secondary to massive pulmonary embolism is rarely reversible by nonsurgical measures. A patient sustained refractory cardiac arrest and was resuscitated by Trendelenburg pulmonary embolectomy without cardiopulmonary bypass. This report describes the diagnosis and treatment of this 37-year-old man and provides a review of the literature on pulmonary embolectomy for patients in whom cardiac arrest has occurred. Awareness of the feasibility of salvaging patients with cardiac arrest secondary to massive pulmonary embolism may lead to wider application of pulmonary embolectomy when conventional resuscitation is unsuccessful.

Glucagon-induced inhibition of feeding is impaired by hepatic portal alloxan injection.

Subdiabetogenic doses of alloxan injected into the hepatic portal vein of rats abolished glucagon-induced inhibition of feeding (glucagon satiety) both in daytime tests using a palatable food and in nighttime tests using their standard pelleted diet. In contrast, inhibition of food intake by cholecystokinin and epinephrine and stimulation of feeding by 2-deoxy-D-glucose were not impaired by alloxan. Alloxan-induced deficits in glucagon satiety did not appear to result from generalized hepatocellular necrosis, because satiety deficits outlasted histological signs of toxicity and because furosemide, which produced a similar degree of hepatotoxicity, did not impair glucagon satiety. In addition, alloxan's effects were not associated with impaired glycogen storage or mobilization. Recovery of glucagon satiety occurred in some animals but not until 3-6 mo after alloxan. The degree of recovery was inversely related to alloxan dose. Our results indicate that, when administered into the hepatic portal vein, alloxan may be a relatively specific toxin for cells involved in the mediation of glucagon satiety. The specificity of the deficit and the time course of recovery suggest that the alloxan-sensitive cells may be hepatic vagal neurons.

Suture material as a factor in the occurrence of anastomotic false aneurysms. An analysis of 26 cases.

False aneurysm formation is a well-recognized late complication of prosthetic graft insertion. Despite the fact that other etiologic factors may be involved, the behavior of the suture material remains of central importance. In a retrospective review of 1,330 peripheral vascular cases, we found 26 cases involving a total of 39 false aneurysms, or an incidence of 2% (26/1,330). Twenty-four of these were directly attributable to failure of the monofilament plastic suture or silk suture material. Braided Dacron suture was used in the original anastomosis in another seven cases, and in these instances the false aneurysms were not related to suture failure but were association with such factors as previous endarterectomy, failure of arterial wall, and chronic hypertension. None of the 39 aneurysms was secondary to infection or trauma. These results emphasize the importance of using a braided, nonabsorbable suture material to ensure the continued integrity of an anastomosis involving prosthetic grafts.

Improved results of carotid endarterectomy in patients with symptomatic coronary disease: an analysis of 1,546 consecutive carotid operations.

The significant risk of fatal myocardial infarction after carotid endarterectomy in patients with coronary disease long has been recognized. In 1,546 consecutive carotid endarterectomies performed in 1,238 patients over the last 10 years, angina pectoris was present in 17% (212/1,238) of patients; a further 32% (396/1,238) of patients were asymptomatic, but had a history of myocardial infarction. The perioperative mortality (30 day) in the 1,306 consecutive endarterectomies in 1,026 patients without symptomatic coronary artery disease was 1.5% (15/1,026 patients). Of the 212 patients with symptoms, 85 carotid endarterectomies were performed in 77 patients without prior coronary bypass operation with an operative mortality of 18.2% (14/77 patients). The remaining 135 patients had 155 carotid endarterectomies but were treated by either prior coronary artery bypass (84 patients) or simultaneous carotid endarterectomy and coronary artery bypass (51 patients) with an operative mortality of 3% (4/135 patients). The greatly improved survival in those patients with symptomatic coronary disease who had a coronary artery bypass prior to or at the same time as carotid endarterectomy, and the absence of permanent neurological deficit in the 51 of these 135 patients who had simultaneous carotid endarterectomy and coronary artery bypass suggests that significantly improved survival can be achieved after carotid endarterectomy in these high risk patients by the use of simultaneous coronary artery bypass surgery.

Ribonuclease II activity in a "presumptive" ribonuclease II-deficient mutant.

A mutant strain of Escherichia coli previously thought to possess low levels of ribonuclease II activity has normal levels of ribonuclease II after partial purification of this enzyme from crude extracts.