Biomedical subjects

A C Sullivan

Publications and source records attributed to A C Sullivan.

At least 37 records · Page 2Linked to original sources

PubMed1987

A pharmacotherapeutic approach to the regulation of hyperinsulinemia and obesity.

A selective inhibitor of thromboxane synthase, Ro 22-3581 has been shown to be a useful tool for investigating the relationship between hyperinsulinemia and obesity. These studies have established that the pharmacologic normalization of the hyperinsulinemia associated with elevated weights in genetically obese and diet-induced obese rats resulted in decreased weight gain or weight loss. This effect was shown to be reversible, partially independent of the suppression of food intake, dependent on a functional endocrine pancreas, and not diabetogenic. However, these studies have not established a cause and effect relationship between the inhibition of thromboxane synthase activity by Ro 22-3581 and its suppression of insulin secretion and circulating insulin levels.

Animals↗

PubMed1987

Studies on the antiobesity activity of tetrahydrolipstatin, a potent and selective inhibitor of pancreatic lipase.

In summary, THL is a potent inhibitor of pancreatic lipase, which is both selective and irreversible in its action in vitro. It is also likely that THL inhibits pancreatic lipase in vivo, since its acute administration to mice and squirrel monkeys suppresses absorption of dietary triglycerides, without an apparent alteration in the absorption of fatty acids. The marked loss in body weight and carcass fat of DIO rats with subchronic administration of THL strongly suggests that inhibition of pancreatic lipase is a feasible strategy for the treatment of obesity. Whether obese humans will overeat in response to a reduction in body energy stores is not known. However, it is probable that compliance to a therapy which maintains the present level of food intake while inducing excretion of dietary fat, will be greater than a reducing diet alone or conjunction with the currently available antiobesity drugs.

Animals↗

PubMed1986

The effect of diet and chronic obesity on brain catecholamine turnover in the rat.

Male Sprague-Dawley rats were fed a high calorie, high fat diet for 3 months to produce chronic diet-induced obesity (DIO) in which they gained 70% more weight than chow-fed controls. Thirty-six percent of the rats fed the DIO diet resisted the development of obesity (DR), gaining no more weight than chow-fed controls but serving as a comparison for the effects of the diet alone on the metabolism of brain catecholamines. The major influence of dietary composition was upon norepinephrine (NE) metabolism. Both DIO and DR rats had increased turnover of NE (107-217%) and/or shorter NE half-lives (42-67%) than controls in the hypothalamic paraventricular (PVN) and dorsomedial (DMN) nuclei and the median eminence (ME); dopamine (DA) turnover was similarly accelerated in the PVN. The DR rats alone exhibited decreased NE levels with increased disappearance of NE in frontal cortex and increased disappearance of DA in the ventromedial hypothalamic nucleus (VMH). The major effect of chronic obesity alone was a 31-33% decrease in DMN DA turnover and an 80% decrement in ME DA turnover associated with a 61% decrease in DA levels as compared to chow-fed controls. Therefore, the major effect of a high calorie, high fat diet was a diffuse acceleration of brain NE and DA turnover while chronic obesity led to decreased DA turnover in the DMN and ME.

Animals↗

PubMed1986

Metabolic features of diet-induced obesity without hyperphagia in young rats.

Diet-induced obesity (DIO) developed in 1-mo-old male Sprague-Dawley rats over an 8-wk period on a relatively high-fat (16%) high-calorie (4.6 kcal/g) diet (DIO diet). Percent carcass lipid (56%) and body weight gain (15%) were greater, whereas food intake was decreased over the first 3-5 wk in DIO diet-compared with chow-fed controls. Overall, 8-wk body weight gain (15%), percent carcass lipid (26%), and feed efficiency (15%) were greater, but food intake was not increased. Norepinephrine (NE) turnover rate, indicative of organ sympathetic activity, increased in interscapular brown adipose tissue (IBAT; 57-218%), heart (21-44%), and pancreas (25%) during the first 3 wk and remained elevated for the entire 8 wk. IBAT weight (51%) and in vitro lipolytic capacity (68%) increased by 1 wk and brown adipocyte size (43%) by 3 wk; IBAT thermogenic capacity (maximal NE-stimulated in vitro O2 consumption) increased by 5 wk (39%). Plasma insulin levels were similar in both diet groups over the entire 8-wk period. Why DIO diet-fed rats had increased metabolic efficiency is unknown, but activation of IBAT metabolism and thermogenesis failed to prevent the development of DIO.

Adipose Tissue, Brown↗

PubMed1986

Beta-1 receptor is the predominant beta-adrenoreceptor on rat brown adipose tissue.

A new in vitro radioligand binding assay is described for brown adipose tissue using the beta adrenergic antagonist [3H]CGP 12177 (4-(3-t-butylamino-2-hydroxypropoxy)-[5,7-3H]benzimidazol-2-one). Binding was saturable and stereoselectively inhibited by propranolol. There was 60 to 80% specific binding using either 30 microM l-isoproterenol or 10 microM l-propranolol to define nonsaturable binding. [3H]CGP 12177 was bound to partially purified membranes from collagenase-separated brown adipocytes with a Kd of 0.84 nM, as determined from kinetic studies, and 1.24 +/- 0.13 nM as found by equilibrium binding studies; maximum binding was 14.2 +/- 0.9 fmol/mg of protein. Membranes from whole-pad homogenates had a similar Kd of 1.17 +/- 0.14 nM but twice the maximum number of binding sites (28.5 +/- 4.4 fmol/mg of protein). Intact brown adipocytes had a Kd of 0.55 nM and a maximum binding of 29.4 +/- 1.5 fmol X 10(-6)/cell or 17,700 sites per cell. Competitive binding studies showed about 80% of the binding sites to be of the beta-1 and 20% of the beta-2 subtype. The pA2 values derived from inhibition of isoproterenol-stimulated in vitro oxygen consumption in intact brown adipocytes by the beta-1 selective antagonist metoprolol and beta-2 selective lCl 118551 were in close agreement with their respective K1 values at the beta-1 receptor as derived from competitive binding studies. These data strongly suggest that the beta-1 adrenoreceptor on brown adipose tissue is primarily responsible for the initiation of thermogenesis in this tissue.

Adipose Tissue, Brown↗

PubMed1985

Inhibition of canine gastric secretion by the prostanoid Ro 22-6923.

The synthetic prostanoid, Ro 22-6923, was studied for its effects on canine gastric secretion. Histamine-stimulated acid secretion was inhibited for up to 8 hr after an orally administered dose of 0.25 mg/kg Ro 22-6923. In the Amdrup (modified Pavlov) pouch model, Ro 22-6923 significantly inhibited food-stimulated acid secretion at an oral dose of 0.5 mg/kg. The effect lasted for 4 hr and was of greater intensity than that observed with 5 mg/kg cimetidine. The ED50 for Ro 22-6923 in this model was 0.25 mg/kg and 0.09 mg/kg for oral and intrapouch administration, respectively. Natural prostaglandin E2 was inactive up to 1 mg/kg orally, but had an ED50 of 0.08 mg/kg when administered directly into the pouch. The results indicate that Ro 22-6923 is a potent, long-acting antisecretory drug that may be useful in the therapy of peptic ulcer disease in man.

Animals↗

PubMed1985

Changes in lipid metabolism in diet-induced obesity.

Mature male Sprague-Dawley rats fed a powdered Purina Chow diet containing corn oil and condensed milk (CM) were compared to rats fed a Purina Chow diet (control). CM rats gained more weight and consumed more calories over a 73-day period than the control rats. The increased weight gain and body fat in CM rats was accompanied by increased cell number in retroperitoneal and inguinal but not epididymal fat pads while cell size was unchanged in all three pads. After obesity had developed there was an increase in insulin levels, lipolysis, hepatic fatty acid synthesis, and fatty acid oxidation. While CM rats demonstrated hyperinsulinemia and hyperglycerolemia, they maintained normal glucagon and glucose levels. They demonstrated higher rates of fatty acid synthesis in isolated hepatocytes but not in vivo, suggesting that a greater potential for fatty acid synthesis in CM rats was masked in vivo by the inhibitory action of dietary lipids. Beta-oxidation of (1-14C) palmitate in vivo and in vitro, and in vivo ketogenesis were greater in CM than in chow fed rats. These studies demonstrate that, after the development of obesity, CM rats, like genetically obese Zucker rats, are hyperinsulinemic and have elevated levels of fatty acid synthesis. However, unlike obese Zucker rats, CM rats displayed an increase in beta-oxidation. These studies suggest that increased insulin levels and hepatic fatty acid synthesis may contribute to dietary obesity (as they do to genetic obesity), whereas increased fatty acid oxidation in dietary obesity may be a compensatory response to maintain a lower body weight.

Adipose Tissue↗

PubMed1985

Effects of inhibitors of carbohydrate absorption or lipid metabolism on meal patterns of Zucker rats.

Peripherally active anorectic agents represent a new approach to the pharmacological management of obesity. Two inhibitors of carbohydrate absorption: an alpha-glucosidase inhibitor, acarbose (Bay g 5421) and a alpha-amylase inhibitor, Ro 12-2272, were compared with two novel inhibitors of lipid metabolism: an inhibitor of human pancreatic lipase (Ro 20-0083) and of hepatic fatty acid synthesis (Ro 22-0654). All drugs were presented as diet admixtures over 3 or 4 consecutive days. Total food and water intakes, the temporal pattern of feeding, and the average meal frequency and meal size were measured using computerized data collection procedures. Inhibitors of carbohydrate absorption failed to suppress food intake in either obese or lean Zucker rats and had no effect on the parameters of feeding. In contrast, inhibitors of lipid metabolism reduced food intake by 56-77% by reducing both meal frequency and meal size. Direct inhibition of lipid metabolism may be a viable mechanism for anti-obesity agents.

Acarbose↗

PubMed1985

Brown adipose and metabolic features of chronic diet-induced obesity.

Half of the 3-mo male Sprague-Dawley rats fed a high-fat (DIO) diet for 5 mo became obese and had increased carcass lipid (106%) and plasma insulin levels (61%), despite 8% less total energy intake than chow-fed controls. Their interscapular brown adipose tissue (IBAT) was 52% heavier with 45% more lipid and larger uni- and multilocular cells. Norepinephrine turnover was normal in their hearts, pancreases, and aortas but undetectable in IBAT where in vitro lipolysis, but not O2 consumption (VO2), was enhanced. Half the rats fed the DIO diet ate 17% fewer calories, gained weight equally to controls, but still had 34% more carcass lipid. Their IBAT was heavier, contained 103% more protein, with no detectable norepinephrine turnover, whereas maximal lipolysis was 73% lower and maximal VO2 was the same or even lower than controls. IBAT VO2 was stimulated by switching 8-mo chow-fed controls to the DIO diet for 7 days (which caused a 480% greater weight gain) but not by switching 8-mo obese rats to chow for 3 days. Therefore metabolic efficiency was increased while BAT VO2 and norepinephrine turnover were unchanged or reduced compared with controls by either chronic obesity or a high-fat diet.

Adipose Tissue, Brown↗

PubMed1985

Inhibition of acid secretion and gastric lesions in rats by the prostanoid Ro 22-6923.

The synthetic prostanoid Ro 22-6923 was studied for its ability to inhibit gastric secretion and to protect the gastric mucosa against the injurious effects of stress, indomethacin and ethanol. Ro 22-6923 inhibited basal acid secretion when administered intragastrically or intraduodenally to animals with a gastric fistula. The pH of the gastric juice promptly increased and remained above 5 for 3 h after an intragastric dose of 10 micrograms/kg and the pH remained above 4 for more than 3 h after this dose given intraduodenally. The increase in pH was associated with reduction of acid concentration and H+ output. Ro 22-6923 inhibited histamine-stimulated gastric secretion in a perfused stomach preparation with an ED50 of 15 micrograms/kg compared to values of 43, 126 and 289 micrograms/kg for prostaglandin (PG)E2, ranitidine and cimetidine, respectively. The synthetic prostanoid protected the gastric mucosa from the injurious effects of stress (oral ED50 values of 0.2 and greater than 1.0 mg/kg for Ro 22-6923 and PGE2, respectively) and indomethacin (oral ED50 0.07 and 0.06 mg/kg for Ro 22-6923 and PGE2, respectively). Cimetidine and ranitidine, at high doses, were effective against the mucosal damage produced by stress (ED50 values greater than 100 mg/kg) and indomethacin (ED50 values greater than 10 mg/kg). Ro 22-6923, but not PGE2 or 16, 16-dimethyl PGE2, inhibited dibutyryl cyclic AMP-induced [14C]aminopyrine accumulation by isolated parietal cells, indicating that the prostanoid has a direct inhibitory effect on H+ secretion. The results on the antisecretory and cytoprotective properties of Ro 22-6923 suggest this drug could be potentially useful in the pharmacotherapy of peptic ulcer disease.

Aminopyrine↗

PubMed1985

Mechanisms of appetite modulation by drugs.

The regulation of appetite is a complex process that we are just beginning to understand. It consists of both central and peripheral elements and involves the integration by the brain of a variety of signals from peripheral organs transmitted by neurotransmitters, peptides, hormones, and metabolites. All available anorectic drugs act by central mechanisms and have several disadvantages including limited effectiveness, side effects on the central nervous system, the development of tolerance, abuse potential, and rebound hyperphagia on discontinuance. Several appetite-modulating agents have been tested in animals that act by peripheral mechanisms and do not produce tolerance or rebound hyperphagia, which suggests that peripherally acting anorectic drugs may provide novel therapeutic approaches to disorders of appetite regulation in humans.

Animals↗

PubMed1985

Effect of the synthetic prostanoid Ro 22-6923 on gastric secretion and blood flow in Heidenhain pouch dogs.

The synthetic trimethyl prostanoid Ro 22-6923 was studied for its effects on histamine-stimulated gastric acid secretion in Heidenhain pouch dogs. The prostanoid (at a p.o. dose as low as 0.05 mg/kg) produced significant inhibition of gastric acid secretion induced by 12 micrograms/kg/h of histamine for 5 h. A dose of 0.5 mg/kg p.o. produced a significant antisecretory effect within 45 min that lasted for 8.5 h. Cimetidine (5 mg/kg p.o.) produced an inhibitory effect on acid output equivalent to the 0.5-mg/kg dose of Ro 22-6923, but the duration of the cimetidine effect was less than 6 h. Administration of Ro 22-6923 i.v. (0.25 mg/kg) inhibited acid output for longer than 8 h. Against a 25-micrograms/kg/h histamine challenge, Ro 22-6923 (0.5 and 1.0 mg/kg) inhibited acid output to an equal degree but for a longer duration than cimetidine (5 mg/kg). Pepsin output was totally inhibited by 0.5 mg/kg of Ro 22-6923, whereas 5 mg/kg of cimetidine inhibited pepsin output by approximately 60%. Pepsin activity in the gastric juice was reduced by Ro 22-6923 and was increased by cimetidine. Blood flow, as estimated by the aminopyrine clearance technique, was reduced slightly by Ro 22-6923 and cimetidine. However, the ratio of clearance to acid secretory rate increased with both compounds, suggesting a direct effect of Ro 22-6923 and cimetidine on acid secretion at the parietal cell level. The results suggest that Ro 22-6923 may be a useful therapeutic agent for peptic ulcer disease in humans.

Animals↗

PubMed1985

Decreased hepatic production of very low density lipoproteins following activation of fatty acid oxidation by Ro 22-0654.

In fed rat livers perfused with [1-14C]oleic acid, Ro 22-0654 (4-amino-5-ethyl-3-thiophenecarboxylic acid methyl ester hydrochloride), an inhibitor of fatty acid synthesis, activated ketogenesis and decreased the secretion of triglyceride in very low density lipoproteins (VLDL). Ro 22-0654 was without effect on total oleic acid uptake and utilization by the liver. The liver triglyceride content, urea synthesis, and bile production were also unaffected. Ro 22-0654 increased the conversion of both exogenous and endogenous fatty acid substrates to ketone bodies, while decreasing the secretion of triglyceride synthesized from both of these sources. Depressed fatty acid synthesis accounted for a relatively small portion of the decrease in secretory triglyceride derived from endogenous sources. 14CO2 from [1-14C]oleic acid was unchanged by Ro 22-0654. This drug decreased the malonyl-CoA content of rat liver freeze-clamped in vivo, providing an explicable mechanism for its activation of fatty acid oxidation. Hepatic citrate was also diminished. The present studies indicate the following sequence of events in the liver of fed rats following the administration of Ro 22-0654: decreased formation of citrate and malonyl-CoA, decreased fatty acid synthesis via decreased carbon supply and increased fatty acid oxidation via stimulation of acylcarnitine formation, decreased synthesis of triglyceride from both endogenous and exogenous fatty acids, resulting in the decreased formation and secretion of VLDL.

Animals↗

PubMed1984

Antiobesity effects of a novel lipid synthesis inhibitor (Ro 22-0654).

The present studies were conducted to determine the antiobesity effects of a novel inhibitor of hepatic fatty acid synthesis, 4-amino-5-ethyl-3-thiophene-carboxylic acid methyl ester hydrochloride (Ro 22-0654/001). Weight gain was decreased by treatment with Ro 22-0654 in Sprague Dawley and in lean or obese Zucker rats. Food intake was only transiently suppressed during the first few days of each study. The decreased weight gain in treated rats could be accounted for almost entirely by a decrease in total body lipid levels. Hepatic fatty acid synthesis was inhibited following two months of treatment, in rats fed either a 1% or 10% corn oil diet. It is suggested that the inhibition of hepatic fatty acid synthesis may account, in part, for the reduced weight gain.

Animals↗

PubMed1984

Central activation and peripheral function of sympatho-adrenal and cardiovascular systems in the Zucker rat.

Electrical stimulation of the hypothalamus in anesthetized lean and obese Zucker rats produced equivalent activation of the sympatho-adrenal system (assessed by plasma norepinephrine [NE] and epinephrine [E] levels) and cardiovascular systems (assessed by monitoring intra-arterial blood pressure and heart rate). Basal plasma E levels were 11% higher and basal heart rates were 20% higher in obese than lean rats. Binding of beta-adrenergic antagonist, [3H] dihydroalprenolol to cardiac membranes was equal but there was a slightly lower affinity for various adrenergic agonists in the hearts of obese compared to lean rats. These results suggest that there are no striking abnormalities in the central pathways for activation of the sympatho-adrenal and cardiovascular systems of obese Zucker rats comparable to those previously described in the peripheral sympatho-adrenal system and other specific organs of these animals [8, 9, 12-15].

Adrenal Glands↗

PubMed1984

Effects of diet and obesity on brown adipose metabolism.

The effect of diet-induced obesity on interscapular brown adipose tissue (IBAT) was assessed after feeding male Sprague-Dawley rats a high-fat diet for 3-5 mo beginning at 3 mo of age. IBAT pads in 6-mo-old obese rats were heavier (22%), had more lipid (71%), and larger unilocular cells (38%) than chow-fed controls. Mitochondrial morphology, beta-adrenergic receptor binding ([ 125I]iodocyanopindolol), and norepinephrine-stimulated lipolysis were similar in IBAT from obese and control rats. When 8-mo-old chow-fed rats were switched to the high-fat diet for 7-14 days, IBAT pads became hypercellular without cell hypertrophy and with a 70% increase in norepinephrine-induced lipolysis. However, when 8-mo-old obese rats that had been on the high-fat diet for 5 mo were switched to chow for 3 days, IBAT cellularity was unchanged, but norepinephrine-induced lipolysis was increased 70%. Therefore, in lean and obese 6- to 8-mo-old rats, short-term dietary manipulation led to metabolic activation, whereas chronic diet-induced obesity on a stable diet was associated with a return of IBAT metabolism to control levels.

Adipose Tissue↗

PubMed1984

Defective brown adipose oxygen consumption in obese Zucker rats.

The thermogenic capacity and morphologic characteristics of interscapular brown adipose tissue (IBAT) were assessed in 3- to 4-mo-old male, lean and obese Zucker rats. Pads from obese rats were threefold heavier and contained similar numbers of cells but an average of 50% fewer multilocular cells than pads from lean rats and 40% less mitochondrial protein per pad. The maximal number of beta-adrenoreceptor binding sites, as assessed by [125I]iodocyanopindolol binding to isolated brown adipocytes from obese rats was 50% of that in lean rats on a per cell and per pad basis. Basal and norepinephrine (NE)-stimulated in vitro oxygen consumption in isolated brown adipocytes from lean rats correlated directly with the proportion of mutilocular cells present. This correlation was not seen in cells from obese rats that had a 50% decrease in their basal respiratory rates and could not be further stimulated by excess NE or fatty acid. Electron micrographs of IBAT from obese rats revealed distorted mitochondrial shapes and cristae patterns and the presence of numerous inclusion bodies. Because NE-stimulated lipolysis had previously been shown to be normal in the obese Zucker rat, these data suggest that defective BAT thermogenesis in the obese rat is due to an inability of mitochondria to utilize free fatty acids for the production of enhanced oxygen consumption.

Adipose Tissue, Brown↗

PubMed1984

Diet-dependent hyperplastic growth of adipose tissue in hypothalamic obese rats.

Accelerated production of fat cells is often seen in dietary obesity in rats but not in obesity occurring in response to damage to the medial area of the hypothalamus (MH). The basis for this difference was examined. MH damage (MHD) was produced in rats by either electric current or small knife cuts. Rats were then fed either chow or a high-fat high-sugar diet (HFS) for up to 6 mo. Fat cell production did not accelerate during the 1st 16 wk after MHD in rats fed only chow, but acceleration clearly occurred in rats fed HFS during only 4 wk. At 18 wk after MHD rats fed only chow showed evidence of accelerated fat cell production. However, there was greater acceleration after MHD in HFS-fed rats held to the same weight gain as chow-fed rats. Rats allowed to freely eat HFS for 6 mo after MHD showed extremely large increases in body weight and fat cell number. The plateau in body weight often seen in rats fed only chow after MHD did not occur. Because HFS-feeding promoted unimpeded production of fat cells, accelerated weight gain induced by MHD could continue indefinitely. These findings suggest that enlargement of fat cells and components of the diet act synergistically in the promotion of adipocyte hyperplasia in adult rats and also suggest that accelerated weight gain after MHD is not due to elevation of a set point for body weight or body fat.

Adipose Tissue↗