A Three-dimensional Analysis of Blood Vessels in Bronchioloalveolar Carcinoma

The three-dimensional architecture of blood vessels within lung adenocarcinomas has not been well studied. In 19 cases with bronchioloalveolar carcinoma with central fibrosis, we three-dimensionally examined blood vessel architecture in 150 m thick sections stained with elastin staining and anti-CD34 antibody. We examined four regions: normal alveoli and three regions within the tumor including an area adjacent to the normal alveoli (external area), an area in which tumor cells were replacing epithelial cells (replacement area), and a central fibrotic area (fibrotic area). Elastin staining showed that elastic fibers formed the framework of the alveoli, and the alveolar structure shrank more strongly to the center of the tumor due to folding of alveolar walls invaded by adenocarcinoma cells. We also measured three vessel parameters in these four regions. The vessel diameters were 4.08±1.10 m, 3.95±1.02 m, 5.04±1.56 m, and 6.11±2.23 m, the circumferences of those vessels seen as complete circles were 43.11±12.78 m, 43.71±12.87 m, 95.21±39.32 m, and 126.77±54.65 m; the lengths between vessel bifurcations were 13.28±3.08 m, 13.47±4.58 m, 24.91±9.66 m, and 41.82±28.08 m in the normal alveoli, and the external, replacement, and fibrotic areas, respectively. Blood vessel architecture changed such that the vessels became larger and coarser towards the center of the tumor. Our three-dimensional analysis suggests continuous remodeling of alveolar capillaries rather than angiogenesis within bronchioloalveolar carcinoma.     

Carbachol Prolongs Ventricular Repolarisation through Nitric Oxide Release in an Intact Heart

Aims: The primary aim of the study was to investigate the effect of carbachol on ventricular repolarisation in an intact animal heart. Methods: In five sheep, carbachol was administered to the left circumflex coronary artery (LCX) at 1.0 and 2.5 mol/ml/min respectively for 3 min. Multiple unipolar ECGs were acquired from the epicardium of LCX territory. Activation-recovery interval (ARI) was analysed from these ECGs. Administration of carbachol at 2.5 mol/ml/min was also repeated after pre-treatment with nitro-L-arginine (20 mg/kg), a nitric oxide synthase inhibitor. Results: Carbachol at 1.0 or 2.5 mol/ml/min resulted in a T wave inversion and ARI prolongation in the LCX territory. The increase in ARI at 1.0 and 2.5 mol/ml/min was 38 ± 17 and 58 ± 14 ms respectively (p < 0.05). T wave inversion and ARI prolongation at 2.5 mol/ml/min was diminished by pre-treatment with nitro-L-arginine. Conclusions: Carbachol results in a dose-dependent prolongation in ventricular repolarisation in this open-chest animal model. This effect is partially mediated by endogenous nitric oxide.     

High plasma leucine concentrations without neurological symptoms in a patient with classical maple syrup urine disease

It has been found that the amino acid analyser used in this study systematically overestimated plasma leucine at high concentrations. The concentration reported as 2249 mol/L had a true value of 1430 mol/L and leucine values reported as >2000 mol/L were approximately 1500 mol/L.     

Pharmacological evidence for beta3 adrenoceptors in the control of rat gastric acid secretion

The effect of the ₃-adrenoceptor agonist BRL37344 on gastric acid secretion evoked by different secretory stimuli was investigated in anaesthetized rats with lumen-perfused stomachs in comparison with the ₂-adrenoceptor agonist clenbuterol. Intravenous injections of BRL37344 (1–10 mol/kg) and clenbuterol (0.01–1 mol/kg) dose-dependently reduced 2-deoxy-D-glucose-induced acid secretion, with BRL37344 about forty times less potent than clenbuterol. BRL37344 (0.1–3 mol/kg) inhibited pentagastrin-induced acid output, whereas clenbuterol was effective only at high doses (10–100 mol/kg). The inhibitory effect of BRL37344 on pentagastrin-induced acid secretion was not modified by the nonselective –adrenoceptor antagonist propranolol, but it was prevented by bupranolol, a ₃-adrenoceptor antagonist. Furthermore, neither BRL37344 (10 mol/kg) nor clenbuterol (100 mol/kg) modified the acid secretion induced by histamine. These data suggest that ₃ adrenoceptors have an inhibitory role in the control of rat gastric acid secretion induced by indirect stimuli.     

B cell adrenoceptors and sulphonylurea-induced insulin release in mouse islets

Summary Interactions of tolbutamide and glibenclamide with B cell adrenoceptors have been reported. This study evaluated the possible role of such interactions in the stimulation of insulin release. Mouse islets were incubated in the presence of 10 mmol/l glucose alone or with tolbutamide (10 mol/l) or glibenclamide (0.02 mol/l). At 0.01–10 mol/l, blockers of ₂-adrenoceptors (yohimbine, idazoxan) or ₁-adrenoceptors (prazosin) had practically no effect on glucose-induced insulin release and did not affect its potentiation by sulphonylureas, except for a slight increase by 10 mol/l prazosin and idazoxan. Nonspecific -blockers (phentolamine, dihydroergotamine) increased control release at 10 mol/l, but only the latter amplified the response to tolbutamide. Blockers of -adrenoceptors were tested at 0.1–100 mol/l: propranolol (₁, ₂), metoprolol (₁) and compound ICI 118-551 (₂). They increased glucose-induced insulin release at 100 mol/l but variably altered the effect of sulphonylureas. Blockers of adrenoceptors have, thus, no effect on insulin release in vitro at therapeutic concentrations. At high concentrations, they non-specifically affect the action of sulphonylureas. We conclude that an interaction with B cell adrenoceptors is not involved in the insulinotropic action of sulphonylureas.     

Cellular ionic effects of insulin in normal human erythrocytes: a nuclear magnetic resonance study

Summary Elevated erythrocyte cytosolic free calcium, and suppressed free magnesium and pH values are associated with the hyperinsulinaemia and insulin resistance of hypertension, obesity, and Type 2 (non-insulin-dependent) diabetes mellitus. To determine the role of insulin in this process, we utilized ¹⁹F- and ³¹P-nuclear magnetic resonance spectroscopy to study the cellular ionic effects of insulin in vitro on normal human erythrocytes. Insulin elevated cytosolic free calcium levels in a dose- and time-dependent manner. The effect began at 10 U/ml, peaked at 200 U/ml, and continued at both the 500 U/ml and 1000 U/ml doses. At 200 U/ml, free calcium levels rose from 24.6±2.5 nmol/l to a peak value at 120 min of 66.4±11 nmol/l (p<0.05 vs basal), levels remaining elevated throughout the incubation (45.7±5.6 nmol/l at 60 min, and 47.9±9.1 nmol/l at 180 min, p<0.05 vs basal, respectively). Similarly, insulin also increased intracellular free magnesium at all time points (basal: 177± 11 mol/l; 60 min: 209±19 mol/l; 120 min: 206±22 mol/l; and 180 min: 202±12 mol/l; p<0.05 vs basal at all times). No insulin-induced changes in pH were observed. We conclude (i) that insulin in physiological concentrations may participate in regulating divalent cations in the mature human erythrocyte, (ii) that insulin per se cannot account for the previously described cellular ionic lesions of hypertension and diabetes, and (iii) that future clinical studies of cell ion metabolism should be conducted in the fasting state, be controlled for ambient circulating insulin levels, or both.     

C-reactive protein (CRP) levels in systemic lupus erythematosus (SLE)

Summary CRP levels in 194 serum samples from 43 SLE patients were measured. Patients with inactive disease have levels below 10 g/ml; patients with active SLE have higher levels, but never over 50 g/ml. In the presence of infection or inflammatory processes, regardless of the activity of SLE, the levels are significantly higher (p<0.05), and well over 50 g/ml. Both active SLE patients and inactive SLE patients with local infections have levels between 10 g/ml and 50 g/ml. In this situation, the presence of anti-DNA antibodies strongly suggests disease activity (82% versus 9%, p<0.05). The clinical and physiopathological meaning of these findings is discussed.     

Inhibition of biliary phospholipid and cholesterol secretion by cefoperazone

The effect of cefoperazone, a third-generation cephalosporin, on biliary lipid secretion in rats was examined. Rats were anesthetized with ether and the mid-lumbar vein and common bile duct cannulated. Bile acid secretion was maintained by intravenous taurocholic acid infusion (28 mol/hr). A 1-hr control period was followed by intravenous cefoperazone infusion at either submaximal (20 mol/hr), or supramaximal (60 mol/hr) concentrations. At the cefoperazone infusion rate of 20 mol/hr (biliary secretion of 7.1±1.6 mol/hr) phospholipid secretion fell 19% and cholesterol secretion fell 31%; at a cefoperazone infusion rate of 60 mol/hr (biliary secretion rate of 27.1±5.1 mol/hr) phospholipid and cholesterol secretion were further reduced 40% and 56%, respectively, of controls. All changes were significant (P<0.01). Inhibition of both cholesterol and phospholipid secretion paralleled each other, was dose-dependent, and reversible. Cefoperazone's inhibitory action was abolished at a bile acid infusion rate of 108 mol/hr. Cefoperazone was not found to be associated with bile acid micelles or mixed micelles as determined by ultracentrifugation and gel filtration. Thus, the effect of cefoperazone on biliary lipid secretion is not due to the impairment of mixed micelle formation in the canalicular lumen but rather its inhibitory effect appears to be due to a presecretory event.     

In vitro kinetics of insulin release by microencapsulated rat islets: effect of the size of the microcapsules

Summary Microencapsulation has been proposed to protect islets of Langerhans against immune rejection in xenogenic transplantation. However, to achieve glucose homeostasis in human diabetic patients, insulin release by microencapsulated islets must increase in response to a glucose load. We microencapsulated isolated rat islets using the alginate-polylysine procedure. Capsule size was found to range from 300 to 800 m, and microencapsulated islets were separated according to their size. Groups of 10 microencapsulated islets, either small (350 m) or large (650 m) were placed in plastic microwells, in minimal Eagle's culture medium containing either 5.5 mol/l glucose (basal) or 16.5 mol/l glucose and 5.5 mol/l theophylline (stimulatory medium). The increase in insulin concentration in the surrounding medium was then serially determined over 30 min: (1) With the small capsules, insulin concentration rose from 199 ±20 to 297 ±58 U/ml in basal medium, and from 236 ±23 to 510 ±121 U/ml in stimulatory medium (n = 10 preparations), the difference between the data obtained with the basal or the stimulatory medium being significant (p<0.01) from the 5th min onwards. (2) With large capsules, insulin concentration increased from 182±9 to 266±44 U/ml, and from 216 ±19 to 297 ±34 U/ml in basal and stimulatory medium, respectively, with no apparent significant difference. The magnitude of insulin secretion in response to glucose by unencapsulated islets was, under similar conditions, seven-fold greater. We conclude therefore that the size of the microcapsules is an essential parameter which has to be considered for the optimisation of the microencapsulation procedure.     

Reduction of platelet aggregation induced by euglycaemic insulin clamp

Summary To examine the effect of serum insulin independent of the level of blood glucose in vivo on platelet aggregation in healthy individuals, a euglycaemic insulin clamp was applied up to 4 h. During the clamp, blood glucose at 5.0 mmol/l and insulin levels at 100 U/ml were maintained. Blood samples were drawn before, 2 and 4 h after the start of the insulin clamp. The platelet aggregation induced by 1 mol/l and 2 mol/l ADP, 1 g/ml collagen and 2.7 mol/l epinephrine was measured in the blood samples. Platelet aggregation induced by adenosine diphosphate, collagen and epinephrine in the 4 h sample was significantly reduced from the pre-clamp value of 8.4% to 3.9% (p<0.05), 26.2% to 7.0% (p<0.01) and 31.8% to 9.1% (p<0.01), respectively. On the other hand, when the same individuals were infused with physiological saline and blood glucose (4.4 mmol/l) and insulin level (10 mIU/l) were kept within normal values, there was no difference between the values of induced platelet aggregation in samples drawn before and during the insulin infusion. It was concluded that hyperinsulinaemia reduces platelet aggregation in vivo when euglycaemia was maintained.     

Granulocyte Elastase in Cirrhotic Patients with Spontaneous Bacterial Peritonitis

Granulocyte elastase (GE) is a powerfulproteolytic enzyme that is released by PMNs whendegranulated in infectious processes. The aim of thisstudy was to measure GE in ascites and plasma ofcirrhotic patients with spontaneous bacterial peritonitis(SBP). We studied 29 cirrhotic patients, 17 of themhaving SBP (group A). Twelve patients with noninfectedascites formed the control group (group B). At the time of diagnosis of SBP, GE levels inascites (183.17 ± 86.11 g/liter) and plasma(114.6 ± 35.99 g/liter) were higher in groupA than in group B (27.41 ± 11.54 g/liter, P< 0.00001 and 82.54 ± 20.52 g/liter, P = 0.01,respectively). Levels of GE in ascites had a high valuefor discriminating between patients with and withoutSBP. In the patients who responded to the initialantibiotic treatment, these values significantly decreasedin ascites (67.69 ± 54.22 g/liter, P = 0.003)and plasma (67 ± 22.39 g/liter, P = 0.01) 48hr after therapy was started, in parallel with thedecrease of PMN in ascites. In patients who did notrespond, the production of GE remained elevated.Patients who developed renal insufficiency following SBPhad more marked elevation of GE in plasma (144.8± 33.43 g/liter) than those with normal renalfunction (99.5 ± 27.53 g/liter, P = 0.02).These results suggest that the measurement of GE may behelpful for the diagnosis of SBP in patients withcirrhosis and for assessing the efficacy of therapy. Inaddition, the release of GE into plasma may contributeto the impairment of renal function that follows SBP insome patients.     

Deleterious effects of digitalis on reperfusion-induced arrhythmias and myocardial injury in ischemic rat hearts: possible involvements of myocardial Na+ and Ca2+ imbalance

Summary Isolated rat hearts were made ischemic for 25 min after an initial recirculating perfusion, followed by 30 min of reperfusion. In some hearts, interventions including administration of ouabain and/or high [K⁺] in the buffer were performed during the first 10 min of reperfusion.During ischemia, intracellular Na⁺ (Na_i) increased from 15 to 64 [mol/g dry weight (dwt). During reperfusion, Na_i declined rapidly (at 10 min of reperfusion: 48 nol/g dwt, at 30 min: 25 mol/g dwt) and regular rhythm was recovered within 10 min in hearts without any intervention during reperfusion.⁴⁵Ca²⁺ uptake increased from 0.8 to 7.5 mol/g dwt after 30 min of reperfusion. Ventricular function recovered by 45 %.A 10-min perfusion with 10 or 50 M of ouabain increased Na_i (17 to 21 or 27 mol/g dwt) with increased left-ventricular (LV) contractile function, but these effects were reversed by combination of high perfusate [K⁺] (20 mM) in non-ischemic hearts.A 10-min reperfusion with ouabain retarded or stopped the decline in Na_i (at 10 min of reperfusion: 54 or 63 mol/g dwt, at 30 min: 32 or 40 mol/g dwt). These amounts of ouabain also increased the incidence of ventricular tachyarrhythmias during reperfusion to 30 % or 50 %, and increased the duration of ventricular fibrillation from 6.5 to 11.5 or 18.0 min.⁴⁵Ca²⁺ uptake reached to 8.8 or 10.0 mol/g dwt, and function recovered only 35 % or 28 %. When high perfusate [K⁺] was combined with ouabain during reperfusion, the retarded decline in Nai, augmented⁴⁵Ca²⁺ uptake, and reduced recovery of function caused by ouabain alone were attenuated. These results suggest that digitalis has toxic effects on reperfused ischemic hearts by inhibition of rapid active outward transport of previously elevated Na_i and potentiation of Ca²⁺ overload.The work was supported in part by grant HL 37936 from the National Heart, Lung and Blood Institute. J. R. Neely was deceased on November 29, 1988     

Modulation of pacemaker activity in sheep cardiac Purkinje fibers by stimulation of β-adrenoceptor subtypes

The electrophysiological effects mediated by ₁- and ₂- in spontaneously active sheep cardiac Purkinje fibers were investigated using the non-selective agonist (–)-isoproterenol (IPN) and the selective agonists (–)-noradrenaline (₁) and procaterol (₂) in the absence and presence of the selective antagonists bisoprolol (₁) and ICI 118,551 (₂).IPN (0.01 mol/l) increased the spontaneous rate by 54% and the slope of diastolic depolarization by 68% of the respective control values. Further, IPN increased the action potential duration at –20 mV (APD –20 mV) from 96 to 154 ms, reduced the APD –70 mV by 17% and the duration of the diastole by 39% and slightly hyperpolarized the maximum diastolic potential. These effects were partially inhibited by ICI 118,551 (0.03 mol/l), diminished by bisoprolol (0.1 mol/l) and almost completely blocked by the combination of both antagonists. Concentration response curves of IPN were influenced by the selective antagonists as follows: ICI 118,551 (0.03 mol/l) shifted the curves to the right by 0.2–0.4 log units and increased the slope factor. Bisoprolol (0.1 mol/l) induced a greater shift to the right by 1.1–1.5 log units. Combination of bisoprolol with ICI 118,551 shifted the curves to the right by 1.5–1.7 log units.Noradrenaline (0.3 mol/l) elicited similar actions as IPN. Bisoprolol (0.1 mol/l) shifted the concentration response curves of noradrenaline to the right by 1.1–1.9 log units. Actions of procaterol (0.1 mol/l) were weak, attained only 15–35% of the maximal effects of IPN and could be blocked by ICI 118,551 (0.03 mol/l).These results show that the increase of pacemaker activity induced by catecholamines in sheep cardiac Purkinje fibers is predominantly mediated by stimulation of ₁. However, contribution of ₂ mediated effects could be demonstrated.Supported by Ministerium für Wissenschaft und Forschung, Nordrhein-Westfalen, Projekt-Nr, 40008786.     

Increased uptake of low density lipoprotein by SV40-transformed smooth muscle cells

We compared the metabolism of low density lipoprotein (LDL) in SV40-transformed smooth muscle cells (TSMCs) to that in nontransformed smooth muscle cells (SMCs). When SMCs were incubated in medium with 100 g/ml LDL for 24 hours, they did not accumulate sudanophilic lipid droplets. On the other hand, when TSMCs were incubated in medium containing more than 100 g/ml LDL, they accumulated a large amount of lipid droplets in their cytoplasm. When cells were incubated with 200 g/ml LDL for 24 hours, cholesteryl ester levels significantly increased in TSMCs (18.3±3.53 g/mg protein), as compared with SMCs (2.40±0.85 g/mg protein). However, there was no difference in the cellular level of free cholesterol between the TSMCs and SMCs. Although the TSMCs and SMCs had a similar number of binding sites for LDL, the TSMCs demonstrated a markedly higher uptake of LDL labeled with 1,1-dioctadecyl-3,3,3,3-tetramethyl indocarbocyanine perchlorate (Dil-LDL), compared with the SMCs. SMCs that had been pretreated with 100 g/ml of unlabeled LDL for 24 hours showed a decreased uptake of Dil-LDL. In contrast, TSMCs incorporated Dil-LDL independently of the preincubation with 100 g/ml LDL. The presence of brefeldin A, which may block the transport of glycoproteins from the ER to Golgi apparatus, had less of an effect on the uptake of LDL in the TSMCs than in the SMCs. These results suggest that SV40-transformed smooth muscle cells show an increased uptake of LDL independent of the cellular cholesterol level, which may induce the accumulation of lipid droplets in their cytoplasm. A LDL receptor-independent pathway may be related to the increased uptake of LDL in SV40-transformed smooth muscle cells.     

Influence of phorbol esters on contractile force,action potential and calcium current of isolated guinea-pig heart tissues

Phorbol-12,13-dibutyrate (PDB) reduced concentration-dependently the contractile force of guineapig papillary muscles (EC₅₀ 1.07 mol/l) while phorbol-12-myristate-13-acetate (PMA) was ineffective. The protein kinase C inhibitors staurosporine (0.1 mol/l) and polymyxin B (70 mol/l) did not antagonize the negative inotropic effect of PDB. Neither PMA nor PDB, in concentrations up to 30 mol/l caused significant changes of the membrane resting potential, the maximum depolarization velocity, the action potential duration or the functional refractory period in intact papillary muscles. In isolated ventricular cardiomyocytes the inward calcium current was halved by either 1 mol/l PDB or 10 mol/l PMA. PKC inhibitors attenuated, but could not completely abolish this effect of the phorboles. It is concluded that the negative inotropic effect of PDB is caused by a reduction of the slow inward calcium current and that this inhibition is, for the greater part, not mediated by an activation of protein kinase C.     

Secretory component and lactoferrin in pure pancreatic juice in chronic pancreatitis

To evaluate pathophysiological roles of proteins in pancreatic secretion, immunoreactive lactoferrin (LF) and secretory component (SC) were measured in the first fraction of the pure pancreatic juice obtained endoscopically from 17 control, 21 suspected (SCP), 14 noncalcified (NCP), and 14 calcified chronic pancreatitis (CCP) subjects. The protein and amylase tended to decrease both in concentration and output from control to CCP. LF concentration was elevated in CCP (18.0±4.9/ml) when compared with controls (2.3±0.2g/ml), and LF output in NCP (12.3±3.8 g/min) was increased from controls (3.8±0.6 g/min). The combination of high LF concentration with low protein output was observed in 10/14 in CCP but 0/14 in NCP and can be a biochemical discriminator of CCP from NCP. SC concentrations were also elevated in NCP (8.5±2.0 g/ml) and CCP (5.6±1.6 g/ml) from controls (1.2±0.2 g/ml). SC outputs in SCP (9.8±3.1 g/min) and NCP (21.1±4.8 g/min) were increased from controls (1.7±0.3 g/min), but there was no further increase in CCP. Hypersecretion of LF and SC in chronic pancreatitis is different, especially in CCP, although the mechanisms for hypersecretion are unknown.This study was supported in part by a research grant for intractable pancreatic disease from the Ministry of Health and Welfare, Japan.     

Einfluß der Prämedikation mit Gibberellinsäure auf das Wachstum des an Mäusen subcutan transplantierten Ehrlichschen Ascitestumors

Zusammenfassung Nach einer vorherigen, 9 Tage dauernden Prämedikation mit GS von verschiedenen Konzentrationen (1000, 100, 10 und 1 g/0,5 ml) wurden den Mäusen am 10. Tag eine Suspension von Ehrlich-Ascites-Tumorzellen subcutan transplantiert. Nach weiteren 22 Tagen wurden die Tiere getötet, und der subcutan wachsende Tumor gewogen. Die Werte der Durchschnittsgewichte der Tumoren zeigten, daß die niedrigsten Konzentrationen der applizierten GS (10 und 1 g) die höchste biologische Aktivität ausübten (p=0,001).

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Influence of premedication with gibberellic acid on the growth of subcutaneously transplanted Ehrlich ascites tumor

Summary Gibberellic acid in different concentrations (1000 g, 100 g, 10 g and 1 g/0.5 ml) was administered to four groups of experimental mice for nine days. Control mice received only a placebo. On the tenth day a cell suspension of Ehrlich ascites tumor (EAT) with 5×10⁶ cells in 0.1 ml was transplanted subcutaneously in the right inguinal region of all groups of mice. The animals were killed 22 days after the transplantation and the EAT growths were weighed. A comparison of the average weight of tumors grown in the experimental mice with those of the control mice showed the slowest tumor growth was in those groups of mice (p=0.001) that were pretreated with 10 and 1 g of gibberellic acid).

     

Induction and activation of procollagenase in rabbit synovial fibroblasts after treatment with active oxygen released by xanthine/xanthine oxidase

Treatment of rabbit synovial fibroblasts with active oxygen (AO) released by xanthine/xanthine oxidase resulted in an induction of procollagenase in these cells in concentrations ranging from 12.5 g/ml xanthine plus 0.0025 U/ml xanthine oxidase to 50 g/ml xanthine plus 0.01 U/ml xanthine oxidase. Preceding this there was an accumulation of poly(ADP-ribose) for the same concentration range of xanthine/xanthine oxidase. Furthermore, it was found that AO caused activation of the latent procollagenase to the active enzyme in concentrations ranging from 0.1 g/ml xanthine plus 0.00002 U/ml xanthine oxidase to 1 g/ml xanthine plus 0.0002 U/ml xanthine oxidase. It is suggested that poly(ADP-ribosyl)ation participates in the induction of procollagenase by relaxing chromatin. Furthermore, it is proposed that AO activates latent procollagenase under physiological conditions.     

Role of histamine H3 receptors in control of mouse intestinal motility in vivo and in vitro: comparison with alpha2-adrenoceptors

We tested drugs acting at histamine H₃ receptors in mice on the gastrointestinal transit of a charcoal meal in vivo and on neurogenic contractions of isolated ileal preparations. The agonist (R)--methylhistamine (100 mol/kg) caused a maximum 25% reduction of gastrointestinal transit, an effect mimicked by immepip (100 mol/kg) and antagonized by thioperamide (20 mol/kg) or clobenpropit (20 mol/kg). In the isolated ileum, (R)--methylhistamine (10–100 M) caused a slight, thioperamide-insensitive, reduction (maximum 15%) of electrically evoked cholinergic contractions. In comparison, the ₂-adrenoceptor agonist clonidine (0.1 mol/kg) caused a 35.2% inhibition of the gastrointestinal transit and almost completely reduced (maximum 82% at 1 M) the cholinergic contraction of the isolated ileum, both effects being antagonized by idazoxan (0.4 mol/kg and 1 M, respectively). These results suggest that histamine H₃ receptors, located outside the myenteric plexus, mediate an inhibition of the gastrointestinal transit in vivo. Conversely, the presence of ₂-adrenoceptors in the cholinergic nerve endings and their inhibitory role in the control of gastrointestinal propulsion is confirmed.     

Developmental changes in the fatty (fafa) rat: Evidence for defective thermogenesis preceding the hyperlipogenesis and hyperinsulinaemia

Summary Preobese fatty rats have been identified by their lower rectal temperature. Of 51 pups born from matings of heterozygote (Fafa) parents, 16 had low rectal temperatures from day 16 onward (34.6±0.2° C v 35.4±0.3° C) and all subsequently became obese. No animal with the higher normal rectal temperature developed obesity. Hepatic fatty acid synthesis (preobese 0.6±0.1; lean 0.6±0.1 mol/ g/h), hepatic glucose-6-phosphate dehydrogenase activity (G6PDH) (preobese 0.68±0.07; lean 0.71 ±0.03 mol/g/min) and serum insulin (preobese 64 ±2; lean 58±4 U/ml) were unchanged in 18 day preobese, suckling fafa rats. 3 days after weaning hepatic lipogenesis (preobese 25.3±2.0; lean 5.4±0.7 mol/g/h) and G6PDH activity (preobese 4.5±0.5; lean 0.90±0.05 mol/g/min) had increased in both lean and preobese rats although the values attained in preobese rats were significantly greater than in lean rats. When weaning was delayed there was no enhancement in lipogenesis, G6PDH or serum insulin in the preobese rat. The results suggest that the primary genetic defect in fatty rats is not related to the increase in lipogenesis or serum insulin but may reflect a defective thermogenic process.