bluuebunny/crossref_metadata_2025 huggingface dataset:
Physiological properties of sympathetic preganglionic neurones in the thoracic intermediolateral nucleus of the cat
Authors: Backman Steven B. , Henry James L.
Published: April 2011

Extracellular spikes were recorded from cell bodies of sympathetic preganglionic neurones in spinal segments T1–T3 of the cat. Each neurone was identified by its antidromic response to electrical stimulation of the sympathetic chain and was found in histological sections to lie within the intermediolateral nucleus. Physiological properties studied in detail included basal activity, spike configuration, and latency of antidromic activation. Also studied, in tests with paired stimuli, were the threshold interstimulus interval evoking two responses, as well as changes in amplitude and latency of the second spike which occurred at intervals near this threshold. Approximately 60% of the units studied were spontaneously active, the rest were silent. Spontaneous activity was characterized by a slow ([Formula: see text] (SD) spikes/s), irregular pattern of discharge. With approximately one-third of the cases there was a periodic pattern of discharge in phase with oscillations in blood pressure. This correlation of phasic activity suggests that many of the units studied were involved specifically in cardiovascular function. Silent and spontaneously active units could not be differentiated on the basis of latency of antidromic activation or threshold interstimulus interval; mean latency for the two groups was 7.2 ± 4.9 ms, mean threshold interval was 6.4 ± 4.7 ms. Thus, with the exception of basal activity, the physiological properties studied failed to indicate more than a single population of neurones. These results therefore suggest that the sympathetic preganglionic neurones in the intermediolateral nucleus subserving varied autonomic functions share overlapping physiological properties, and that functional differentiation of these neurones may be based on differences in synaptic inputs.
Effect of 5-isosorbide mononitrate on isosorbide dinitrate-induced relaxation of rabbit aortic rings
Authors: Bennett Brian M. , Tam Glen S. , Alstyne Katherine Van , Brien James F. , Nakatsu Kanji , Marks Gerald S.
Published: April 2011

The ability of isosorbide dinitrate (ISDN) and its two metabolites, 5-isosorbide mononitrate (5-ISMN) and 2-isosorbide mononitrate (2-ISMN), to relax phenylephrine-contracted rabbit aortic rings was compared. The three organic nitrates demonstrated similar efficacy. ISDN was found to be the most potent (median effective dose (ED50); 1.5 × 10−7 ± 1.1 × 10−7 M), followed by 2-ISMN (ED50, 1.8 × 10−6 ± 9 × 10−7 M) and 5-ISMN (ED50, 8.2 × 10−6 ± 3.6 × 10−6 M). The log dose–response curve of ISDN in rabbit aortic rings was constructed in the absence and presence of three fixed concentrations of 5-ISMN (5 × 10−6, 10−5, and 3 × 10−5 M). No shift in the ISDN dose–response curve at high ISDN concentrations was noted in the presence of 5-ISMN. Using the isobolographic method with fixed ISDN/5-ISMN ratio mixtures, no evidence for an antagonistic effect of 5-ISMN on ISDN-induced vasodilation was obtained. Analysis of the fixed ISDN/5-ISMN ratio mixture responses by the median–effect plot showed no antagonistic effect. It is concluded that (a) in rabbit aortic rings 5-ISMN, the major metabolite of ISDN, is not an antagonist of ISDN at a "nitrate receptor," and (b) no support is provided for the hypothesis that the accumulation in plasma of metabolites (e.g., 5-ISMN) with longer half-lives than the parent drug explains tolerance to organic nitrates.
Occurrence of intramitochondrial Ca2+ granules in a hypertrophied heart exposed to adriamycin
Authors: Singal Pawan K. , Forbes Michael S. , Sperelakis Nick
Published: April 2011

Left ventricular hypertrophy was produced in rabbits by narrowing the abdominal aorta in the subdiaphragmatic region. Six weeks after the surgery, sham control as well as hypertrophied animals were treated with adriamycin. Myocardial cell damage resulting from a total cumulative dose of 5 mg/kg of adriamycin was seen only in hypertrophied hearts. Alterations in muscle cells of these hearts included prominent "contraction bands" and perinuclear edema. Mitochondria were characterized by swelling and accumulation of electron-opaque granules. Energy-dispersive x-ray analysis of the mitochondria revealed the presence of calcium in these granules. The study confirms that the hypertrophied heart is more vulnerable to adriamycin-induced cell damage and this may be due to an increased susceptibility of these hearts to the occurrence of Ca2+ overload in the cell.
Norepinephrine-stimulated vascular prostacyclin synthesis. Receptor-dependent calcium channels control prostaglandin synthesis
Authors: Stewart Duncan , Pountney Elaine , Fitchett David
Published: April 2011

Norepinephrine-stimulated prostacyclin synthesis was studied in rat aortic rings by measuring 6-keto-prostaglandin F1α (6-keto-PGF1α) by radioimmunoassay. Norepinephrine (10−6 M) results in a 10- to 20-fold increase in 6-keto-PGF1α synthesis by rat aortic rings (54 ± 11 to 437 ± 260 pg∙mg wet weight−1∙20 min−1). The maximal stimulation of 6-keto-PGF1α synthesis was observed with a norepinephrine concentration of 10−5 M at a mean effective concentration (EC50) of 9.5 ± 3.2 × 10−7 M which is similar to the contractile response (Emax = 10−5 M, EC50 = 6.5 ± 1.8 × 10−7 M). Potassium chloride (30 mM), although causing a similar maximal contractile response as 10−6 M norepinephrine, did not increase 6-keto-PGF1α synthesis. Norepinephrine-stimulated 6-keto-PGF1α synthesis was dependent upon extracellular calcium. Norepinephrine stimulation in Ca2+-free medium did not lead to a significant increase in 6-keto-PGF1α synthesis. However, on the introduction of Ca2+, 6-keto-PGF1α synthesis was restored to its initial level. Phentolamine (10−6 M) (an α-adrenergic antagonist) and trifluroperazine (2.5 × 10−4 M) (a calmodulin inhibitor) completely inhibited norepinephrine-stimulated 6-keto-PGF1α synthesis, whereas verapamil 3 × 10−6 M (a calcium channel blocking drug) only partially inhibited synthesis (control, 74 ± 12; norepinephrine, 437 ± 260; norepinephrine + verapamil, 123 ± 8 pg∙mg wet weight−1∙20 min−1). Norepinephrine-stimulated prostacyclin synthesis is probably α-receptor mediated and appears to depend upon the opening of receptor-operated Ca2+ channels. The operation of potential-dependent Ca2+ channels (by 30 mM KCl) in contrast, although known to be associated with an increase of intracellular Ca2+, does not stimulate PG synthesis.
Branching characteristics of coronary arteries in rats
Authors: Zamir M. , Phipps S. , Langille B. L. , Wonnacott T. H.
Published: April 2011

The purpose of this study is to examine quantitatively the branching characteristics of the coronary arteries. Branching angles and vessel diameters were measured in a total of 175 arterial bifurcations in the coronary beds of rats, and the results are compared with those of 350 bifurcations in other parts of the cardiovascular system of the same species. Significant differences are found in the values of branch diameters and branching angles, both being found generally lower in the coronary bed than in other parts of the system. On statistical grounds these differences are found to have very high significance levels, with P values less than 0.02 in the case of branching angles and much less than 0.001 in the ease of branch diameters. On physiological grounds, the differences are such as to place the coronary arteries further away from the "theoretical optimum" than are vessels in other parts of the cardiovascular system. The theoretical optimum represents branching angles and branch diameters which make arterial bifurcations more efficient physiologically.
Hepoxilin A, hydroxyepoxide metabolite of arachidonic acid, stimulates transport of 45Ca across the guinea pig visceral yolk sac
Authors: Derewlany L. O. , Pace-Asciak C. R. , Radde I. C.
Published: April 2011

The effect of hepoxilin A, a newly isolated hydroxyepoxide metabolite of arachidonic acid, on calcium transport across the visceral yolk sac membrane of the guinea pig was investigated in vitro in Ussing chambers. While 1-14C-labelled hepoxilin A itself was not transported across the membrane, it increased the rate of transport of calcium toward the side to which hepoxilin A was added. The degree of increase in calcium transport was similar whether hepoxilin A was added to the maternal side or to the fetal side of the membrane. The observed effect was dependent on the concentration of hepoxilin A over a narrow range (0.5–1.0 × 10−6 M). It was also dependent on the time of incubation reaching maximal effect by 25 min. We have recently observed that hepoxilin A is formed from platelet-derived 12-hydroperoxyeicosatetraenoic acid (12-HPETE) through hernin and hemoglobin catalysis as well as during perifusion of 12-HPETE through isolated pancreatic islets. The present study suggests that hepoxilin A, if formed in vivo, could play a role in the mobilization of calcium.
Effects of diltiazem on atrioventricular conduction and arterial blood pressure: correlation with plasma drug concentrations
Authors: Clozel Jean-Paul , Billette Jacques , Caillé Gilles , Théroux Pierre , Cartier Richard
Published: April 2011

Atrial and atrioventricular conduction variables were studied at control and at the end of each of six consecutive 45-min diltiazem administration periods in eight closed chest-anesthetized dogs. Diltiazem was given as a bolus (50 μg/kg, i.v.) followed by an infusion (0.5 μg∙kg−1∙min−1); doses were doubled in subsequent periods. The plasma concentrations, measured by gas–liquid chromatography, ranged from 8 to 1400 ng/mL and correlated strongly with the doses (r = 0.92; p < 0.01). The Wenckebach cycle length, basic conduction time, and functional refractory period of the atrioventricular (AV) node increased proportionally with plasma concentration (respective r = 0.90, 0.89, 0.80; p < 0.01). The minimum mean plasma concentrations affecting these variables significantly were 37, 83, and 175 ng/mL, respectively. Second or third degree AV blocks developed in all dogs for plasma concentrations between 379 and 1400 ng/mL. In four dogs which were given isoproterenol (0.2 μg∙kg−1∙min−1), these blocks disappeared within 1 min. Atrial conduction time and functional refractory period were slightly but significantly shortened by diltiazem with mean plasma concentrations of 175 ng/mL and over. His–Purkinje intervals were not significantly changed by diltiazem. Systolic and diastolic arterial pressures were decreased by diltiazem (r = −0.64, r = −0.79; p < 0.01) starting with a mean plasma concentration of 83 ng/mL. We conclude that AV nodal conduction variables are progressively prolonged with increasing plasma concentrations of diltiazem; plasma concentrations affecting blood pressure and AV nodal variables overlap; and the AV blocks produced by toxic concentrations of diltiazem can be corrected by isoproterenol.
Effects of exercise frequency, intensity, and duration on revascularization in the transition zone of infarcted rat hearts
Authors: Przyklenk K. , Groom A. C.
Published: April 2011

In the rat model of chronic myocardial infarction the border or "transition zone," extending 225–525 μm from the margin of the scar, is supplied by significantly fewer capillaries and characterized by an altered capillary-fiber geometry when compared with healthy rat myocardium. Four weeks of daily voluntary running can, under certain conditions, promote capillary growth and a shift in capillary-fiber geometry, such that a normal capillary supply is restored to the transition zone. However, the importance of exercise frequency, intensity, and duration for capillary growth in the transition zone has not been determined. One week after surgical occlusion of the left coronary artery, rats were divided into four groups following different protocols of voluntary exercise (running): A (2 h/day, 6 days/week for 4 weeks), B (2 h/day, 3 days/week for 4 weeks), C (2 h/day, 6 days/week for 2 weeks, followed by 2 weeks sedentary), and D (2 h/day, 6 days/week for 2 weeks). Significant improvements in capillary supply to the transition zone were associated with voluntary exercise, three separate factors being of importance, (i) An intermediate total distance run; rats that ran 5–10 km in the month restored a normal number of capillaries and a normal capillary-fiber geometry in the transition zone, whereas rats that ran either <5 or >10 km showed no significant improvements. (ii) A balance between exercise frequency and mean distance ran per 2-h exercise period; rats in group B (3 days/week) had to run twice the daily distance of those in group A (6 days/week) to obtain the same improvement in capillary supply. (iii) Regular reinforcement of the exercise periods throughout the experiment; animals in groups B and D demonstrated significant increases in capillary supply in the transition zone, while those in group C did not. Although exercise stimulates capillary growth and a shift in capillary-fiber geometry in the transition zone, the mechanisms underlying these improvements are, as yet, unknown.
The recovery of organelle transport and microtubule integrity in myelinated axons that are frozen and thawed
Authors: Smith R. S. , Kendal W. S.
Published: April 2011

Myelinated axons of Xenopus laevis were rapidly frozen in liquid nitrogen and thawed in a potassium glutamate based medium. Organelles within isolated, thawed axons were visualized by light microscopy. After thawing, organelles were stationary for about 5 min. Following this quiescent period, organelles exhibited a low frequency oscillation in the longitudinal direction of the axon; some of the organelles then began to move in either the anterograde or retrograde directions. Electron microscopic examination of axonal cross sections showed that few microtubules were present immediately after thawing, but the numbers of microtubules recovered to approximately normal levels with a time course closely resembling that of the recovery of organelle transport. The effects of colchicine and taxol on the recovery of organelle transport and the microtubule content of axons was consistent with the hypothesis that the recovery in microtubule numbers was related to the recovery of organelle transport. Vanadate ions inhibited the recovery of organelle transport at concentrations known to inhibit dynein ATPase.
Effects of prostaglandins and luteinizing hormone-releasing hormone on phosphatidic acid – phosphatidylinositol labeling in rat granulosa cells
Authors: Minegishi Takashi , Leung Peter C. K.
Published: April 2011

In cultures of rat granulosa cells, luteinizing hormone-releasing hormone (LHRH) increases 32P incorporation into both phosphatidylinositol (PI) and phosphatidic acid (PA). After 20 min, the level of radioactivity was three- to four-fold (p < 0.01) above control in the PI and PA fractions, respectively. The stimulatory effect of LHRH on 32P incorporation was limited to PI and PA. Similar to the effects of LHRH, a rapid and marked increase of 32P incorporation into both PI and PA is observed upon addition of prostaglandin F2α (PGF2α) (10−5 M) to rat granulosa cells. Incorporation of radioactivity into PA was already increased (p < 0.05) by 2 min following PGF2α addition, while the increase in 32P-labeled PI became significant (p < 0.01) by 5 min. In contrast to PGF2α, the labeling of PI and PA following the addition of PGE2 (10−5 M) was not significantly different from control levels during the entire 10 min of incubation. The sensitivity of the increased PA–PI labeling induced by LHRH and PGF2α is compared in another experiment. After 20 min incubation 10−6 M LHRH increased PI and PA labeling by six-and four-fold, respectively. Although the effect of PGF2α is less than that of LHRH, 10−5 M PGF2α significantly (p < 0.01) increased PI and PA labeling by three- and two-fold, respectively. By contrast, 10−6 M PGE2 failed to affect 32P incorporation into the various phospholipid fractions, but a small enhancement (p < 0.05) of PI and PA labeling was observed only at 10−5 M PGE2. These data further support the hypothesis that LHRH and PGF2α share a common mechanism in ovarian cells involving phospholipid metabolism.
The effects of hydrogenated coconut oil, safflower oil, and evening primrose oil on development of hypertension and sodium handling in spontaneously hypertensive rats
Authors: Soma Masayoshi , Manku Mehar S. , Horrobin David F.
Published: April 2011

Spontaneously hypertensive rats (SHR) were fed a basal regular diet (BD) or three different fat supplemented diets which contained 10% hydrogenated coconut oil (HCO), 10% safflower oil (SFO), or 10% evening primrose oil (EPO). The rats received these four different diets from 4 weeks to over 24 weeks of age. The development of hypertension in SHR was significantly retarded in the EPO-supplemented animals. The blood pressure was lower in the SFO group animals as compared with the BD and HCO groups, but this did not reach significance. Sodium excretion rate in young SHR was increased in the EPO group compared with the HCO and SFO groups, and the urinary K/Na ratio was decreased in the EPO group compared with the HCO and EPO groups. Water intake and urine volume were increased in the SFO group as compared with the HCO and EPO groups. Sodium concentration in erythrocytes was decreased in the rats receiving SFO. Pressor responses to norepinephrine and angiotensin II were enhanced in the EPO and SFO groups as compared with the basal chow group. These data suggest that a dietary supplementation of EPO which contains a substantial amount of gamma-linolenic acid consistently lowers blood pressure in SHR. The mechanism is uncertain, but the effects on sodium handling may in part be responsible for the retardation of the development of hypertension. There was a difference between the EPO and the SFO groups in sodium–water handling, and to some extent in the blood pressure development in SHR.
In vitro effects of hypoxia and (or) hypercapnic acidosis on the myocardial uptake of digoxin
Authors: Sautegeau A. , Clozel J. P. , Saunier C. , Hartemann D.
Published: April 2011

A recent study has shown in the conscious dog that hypoxia associated with respiratory acidosis could increase the in vivo distribution of digoxin in the myocardium. The aim of the present study was to evaluate in vitro the effects of hypoxia and (or) hypercapnic acidosis on the digoxin uptake. For this purpose, rat myocardium was incubated for 180 min with radiolabelled [3H]digoxin. The uptake of digoxin which was expressed in nanograms of digoxin bound per 100 mg of myocardium was decreased by hypoxia and increased by hypercapnic acidosis. The association of hypoxia and hypercapnic acidosis had no effect on the digoxin uptake, suggesting that in vitro hypoxia acts in an opposite way to hypercapnia.
A comparative study of the inhibition of hepatic aldehyde dehydrogenases in the rat by methyltetrazolethiol, calcium carbimide, and disulfiram
Authors: Brien J. F. , Tam G. S. , Cameron R. J. , Steenaart N. A. E. , Loomis C. W.
Published: April 2011

Methyltetrazolethiol (1-methyl-5-mercapto-1,2,3,4-tetrazole, MTT) is a heterocyclic substituent of the cephalosporin antibiotics, cefamandole, cefoperazone, and moxalactam. Pretreatment of rats with MTT has been reported to increase blood acetaldehyde concentration after ethanol administration. The time course of MTT-induced inhibition of hepatic aldehyde dehydrogenases (ALDH) was determined in adult, male Sprague–Dawley rats in comparison with the hepatic ALDH inhibition induced by calcium carbimide (calcium cyanamide, CC) and disulfiram (D). The apparent onset of maximal inhibition of hepatic low Km ALDH occurred at 2 h for 50 mg/kg MTT (subcutaneous, s.c.) and 7 mg/kg CC (oral) and at 24 h for 300 mg/kg D (oral). The relative magnitude of maximal inhibition of low Km ALDH was CC > D > MTT. The relative duration of enzyme inhibition was D > MTT > CC. High Km ALDH was only inhibited by CC. Hepatic low Km ALDH was selectively inhibited by s.c. and oral administration of 125 mg/kg MTT. For s.c. administration of 125 mg/kg MTT, the magnitude of maximal enzyme inhibition and the duration of inhibition were greater than for the 50 mg/kg dose. Oral administration of 125 mg/kg MTT produced similar inhibition of hepatic low Km ALDH compared with s.c. administration of the same dose. The time course of blood ethanol and acetaldehyde concentrations was determined for the intravenous infusion of two 0.3-g/kg doses of ethanol to rats that were pretreated orally with saline (1 h), MTT (125 mg/kg, 2 h), or CC (7 mg/kg, 1 h). The relative increase in blood acetaldehyde concentration compared with saline pretreatment was CC > MTT. The elimination of ethanol from blood was slower in the MTT- and CC-pretreated animals, and this effect was more pronounced for CC pretreatment. Overall, the data demonstrate that the characteristics of hepatic ALDH inhibition for MTT are different from those of the known ALDH inhibitors, CC and D.
Interaction of 2′,3′-di-O-nitro-5′-(N-ethylcarboxamido)adenosine with adenosine receptors in intestinal smooth muscle
Authors: Baer H. P. , Vriend R. , Murji A.
Published: April 2011

The adenosine derivative, 2′3′-di-O-nitro-(5′-N-ethylcarboxamido)adenosine (DINECA), caused relaxation in several isolated smooth muscle preparations including guinea pig taenia caeci, beef coronary arteries, and rabbit small intestine. In rabbit small intestine the response profile of DINECA action differed from that of established adenosine receptor agonists and, in contrast with the latter, its relaxant effect was only partially reversed by the antagonist 8-p-sulfophenyltheophylline. Concentration–response curves to 5′-(N-ethylcarboxamido)adenosine (NECA), but not those to DINECA, were significantly shifted to the right by 100 μM of 8-sulfophenyltheophylline. Tissues exposed previously to DINECA became refractory to adenosine, an effect not observed with tissues exposed to NECA, suggesting that DINECA became bound to adenosine receptors. Adenylate cyclase from neuroblastoma cells, containing Ra-type adenosine receptors, was stimulated by 2-chloroadenosine and NECA but not by DINECA. The results suggest that most of the smooth muscle relaxant actions of DINECA are not due to interaction with adenosine receptors but are probably due to its function as a nitrate. However, DINECA appears to interact with adenosine receptors, causing long lasting inhibition of adenosine action in rabbit intestine. Such actions may contribute to the overall response to DINECA application in vivo, although lowering of blood pressure due to the high reactivity of the vasculature to nitrates may be the initial and major effect.
Ca2+ channel antagonist actions in bladder smooth muscle: comparative pharmacologic and [3H]nitrendipine binding studies
Authors: Yousif F. B. , Bolger G. T. , Ruzycky A. , Triggle D. J.
Published: April 2011

The actions of a series of 15 Ca2+ channel antagonists including D-6(X), nifedipine, and diltiazem were examined against K+ depolarization and muscarinic receptor induced responses in guinea pig bladder smooth muscle. Responses of bladder are very dependent upon extracellular Ca2+ and sensitive to the Ca2+ channel antagonists, the tonic component more than the phasic component of response. Regardless of stimulant, K+ or methylfurmethide (MF), or component of response, the same rank order of antagonist activities is expressed, suggestive of a single structure–activity relationship and the existence of a single category of binding site which may, however, exist in several affinity states. High affinity binding of [3H]nitrendipine (KD = 1.1 × 10−10 M) occurs in bladder membranes, and similar high affinity binding was found in microsomal preparations from other smooth muscles including guinea pig and rat lung, rat vas deferens, uterus, and stomach. [3H]nitrendipine binding in the bladder was sensitive to displacement by other 1,4-dihydropyridines, paralleling their pharmacologic activities and showing excellent agreement with binding data previously obtained for guinea pig ileal smooth muscle. Comparison of pharmacologic data for inhibition of K+- and MF-induced responses by a common series of Ca2+ channel antagonists in bladder and ileum revealed excellent correlations. Neither pharmacologic nor binding studies suggest significant differences in Ca2+ channel antagonist properties in smooth muscle from bladder and intestine.
The effect of growth hormone on biogenic amines in the hepatic portal circulation of the dog
Authors: Hussain M. N. , Sirek A. , Cukerman E. , Sirek O. V.
Published: April 2011

The effects of a spike concentration of growth hormone (GH) on hepatic portal and peripheral levels of free serotonin and catecholamines were studied by improved radioenzymatic methods in trained, conscious, normal, adult dogs fitted with an indwelling portal catheter. An injection of ovine GH (6 or 100 μg/kg) into a cephalic vein produced in the hepatic portal circulation a transient, statistically significant rise of serotonin and a concomitant significant reduction in the concentration of dopamine, norepinephrine, and epinephrine. No change was found in the peripheral circulation, partly because the amines were conjugated to sulfates and glucuronides and these derivatives are not detectable by our assays. Thus, a pulse of GH not only stimulates the release of pancreatic hormones and glucose turnover, but also affects the portal profile of glucoregulatory bioamines. The present investigation lends further support to our view that the splanchnic area represents an endocrine system whose preferential target is the liver.
Acetaminophen toxicity in lymphocytes heterozygous for glutathione synthetase deficiency
Authors: Spielberg Stephen P.
Published: April 2011

We have studied the effects of acetaminophen metabolites generated by a murine hepatic microsomal system on lymphocytes from two subjects heterozygous for glutathione synthetase deficiency. Heterozygous cells exhibited greater dose-related toxicity than controls. Following a 2-h incubation with acetaminophen and the microsomal system, cells were washed and incubated for 16 h in the presence or absence of N-acetylcysteine, the standard antidote for acetaminophen toxicity. In control cells, glutathione content was replenished to nearly base-line values and toxicity was prevented. N-Acetylcysteine thus prevented toxicity even after covalent binding of acetaminophen metabolites had occurred. Heterozygous cells failed to use N-acetylcysteine as efficiently to resynthesize glutathione, and the cells were not protected from acetaminophen toxicity. Heterozygotes may be at increased risk of toxicity from drugs whose metabolites are detoxified by glutathione conjugation.
In situ molecular weight determination of rat brain [3H]phenytoin binding sites
Authors: Spero Lawrence
Published: April 2011

Using irradiation inactivation analysis of specific [3H]phenytoin binding to rat brain we have demonstrated that there are two different binding sites involved, with molecular weights of 73 238 ± 1535 (higher affinity site) and 108 121 ± 6935 (lower affinity site).
Weaning and metabolic regulation in the rat
Authors: Angel Joseph F. , Back Donald W.
Published: April 2011

Premature weaning of rats to high carbohydrate diets causes a variety of short- and long-term changes in lipid metabolism, but the mechanisms involved are unclear. It is likely that interaction of diet with certain emerging hormonal control patterns during weaning might condition metabolic control and (or) subsequent adaptations in the adult organism. This implies that the adaptive responses of infant animals to diet may differ from those of the mature organism. For example, premature weaning leads to early appearance of rat liver malic enzyme (ME), even when fat supplies as much as 65% of the dietary energy; the same diet suppresses ME activity in 45-day-old rats. The levels of plasma glucagon and thyroid hormones are elevated during the weaning period. Several studies have shown that triiodothyronine evokes hepatic ME in suckling rats. Conversely, glucagon infusion into prematurely weaned rats suppresses the early appearance of the enzyme. Premature weaning, regardless of fat intake, leads to a rapid decline in plasma glucagon levels. Since glucagon is known to antagonize the actions of triiodothyronine on liver ME, the interaction of diet with glucagon and thyroid hormones is conceivably part of the mechanism responsible for the early appearance of hepatic malic enzyme, whereby the decline of plasma glucagon permits triiodothyronine to act on liver ME. Insulin probably exerts a permissive action subsequently. The manner in which these events relate to the long-term consequences of premature weaning is unknown.
The role of diet during development on the regulation of adult cholesterol homeostasis
Authors: Innis Sheila M.
Published: April 2011

Atherosclerosis is believed to begin early in life and to develop over several decades. Elevated plasma cholesterol is a major contributing factor. Studies in animals have shown that manipulation of cholesterol metabolism during its development in pre-and early post-natal life can permanently alter cholesterol synthesis and catabolism to favour lower plasma cholesterol levels in the adult faced with a high dietary cholesterol intake. Although the mechanisms and pathways involved are likely to be different, "metabolic training" can occur as a result of both the diet fed to the mother during gestation and lactation and from the diet fed to the animal itself in early life. The presence of cholesterol itself in the suckling diet does not appear to confer any lasting improvement to cholesterol handling in either man or animals. Although much research is still required to define the time in development for effective training of specific steps in cholesterol metabolism and the primary site and mechanism of permanently altered metabolism, significant progress has been made. These studies will form the basis of this review.
The 13th J. A. F. Stevenson Memorial Lecture Sexual differentiation of the brain: possible mechanisms and implications
Authors: Gorski Roger A.
Published: April 2011

The mammalian brain appears to be inherently feminine and the action of testicular hormones during development is necessary for the differentiation of the masculine brain both in terms of functional potential and actual structure. Experimental evidence for this statement is reviewed in this discussion. Recent discoveries of marked structural sex differences in the central nervous system, such as the sexually dimorphic nucleus of the preoptic area in the rat, offer model systems to investigate potential mechanisms by which gonadal hormones permanently modify neuronal differentiation. Although effects of these steroids on neurogenesis and neuronal migration and specification have not been conclusively eliminated, it is currently believed, but not proven, that the principle mechanism of steroid action is to maintain neuronal survival during a period of neuronal death. The structural models of the sexual differentiation of the central nervous system also provide the opportunity to identify sex differences in neurochemical distribution. Two examples in the rat brain are presented: the distribution of serotonin-immunoreactive fibers in the medial preoptic nucleus and of tyrosine hydroxylase-immunoreactive fibers and cells in the anteroventral periventricular nucleus. It is likely that sexual dimorphisms will be found to be characteristic of many neural and neurochemical systems. The final section of this review raises the possibility that the brain of the adult may, in response to steroid action, be morphologically plastic, and considers briefly the likelihood that the brain of the human species is also influenced during development by the hormonal environment.
Rat skeletal muscle triacylglycerol utilization during exhaustive swimming
Authors: Spriet Lawrence L. , Peters Sandra J. , Heigenhauser George J. F. , Jones Norman L.
Published: April 2011

The utilization of triacylglycerol in slow oxidative, fast oxidative–glycolytic, and fast glycolytic skeletal muscle fiber types was examined in rats subjected to a prolonged exhaustive swim. Significant reductions of intramuscular triacylglycerol occurred following 2 h and 40 min of swimming in all muscles containing a predominance of slow oxidative and fast oxidative–glycolytic fibers, which possess a high capacity for free fatty acid oxidation. Triacylglycerol content in the soleus decreased by 48%, and reductions of 41, 29, and 27% were measured in the red vastus lateralis, red gastrocnemius, and plantaris muscles, respectively. In the white vastus lateralis and white gastrocnemius muscles (fast glycolytic fibers) triacylglycerol concentrations were unaffected. In all muscles the variability of intramuscular triacylglycerol measurements between animals was 20–50% and the within animal variance (right vs. left hindlimb) was similar. Analytical repeatability was approximately 10% in all muscles and significantly less than the between- and within-animal variances. It was concluded that a real biological variation exists in the triacylglycerol content of all rat skeletal muscles and that intramuscular triacylglycerol is an important energy source during prolonged exercise of moderate intensity.
Analgesia and autonomic function following intrathecal administration of morphine and norepinephrine to the rat
Authors: Loomis C. W. , Cervenko F. W. , Jhamandas K. , Sutak M. , Milne B.
Published: April 2011

The acute intrathecal (i.t.) administration of 10, 25, 50, and 100 μg morphine and 7.5, 10, 15, and 30 μg (−)norepinephrine (NE) to the rat produced dose-dependent, long-lasting analgesia as assessed by the tail-flick and hot-plate tests. For i.t. morphine, maximum analgesia was observed 30–60 min after drug administration. The duration of analgesia in the tail-flick test ranged from 30 to 150 min; the duration of analgesia in the hot-plate test ranged from 60 to 120 min. For i.t. NE, maximum analgesia was observed 15–60 min after drug infusion. The duration of NE-induced analgesia in the hot-plate test ranged from 45 to 120 min and was 120 min in the tail-flick test. The effects of acute i.t. and intravenous (i.v.) infusions of morphine (10 μg) and NE (15 μg) on heart rate, blood pressure, arterial pH, partial pressure of oxygen [Formula: see text], partial pressure of carbon dioxide [Formula: see text], and standard bicarbonate were determined over 45 min in rats anesthetized with α-chloralose (70 mg/kg). Morphine significantly decreased [Formula: see text] throughout the experiment but did not affect blood pressure, heart rate, pH, [Formula: see text] and standard bicarbonate. A significant increase in blood pressure (137% of control) was observed 2.5 min after i.t. administration of NE. Intravenous NE produced a marked increase in blood pressure (246% of control) followed by a compensatory decrease in heart rate. There were no significant changes in blood gases with i.t. and i.v. NE. The data suggest that i.t. morphine and NE can produce effective analgesia with minimal effects on cardiovascular and respiratory function.
The metabolic response of the kidney to acute sodium lactate alkalosis
Authors: Lemieux Guy , Junco Eduardo , Perez Raphael , Lemieux Christiane , Allignet Elizabeth
Published: April 2011

In vivo studies were performed in the dog to verify if sodium lactate had an important effect on the metabolism of glutamine by the kidney. The animals were infused with 0.6 M sodium lactate to induce acute metabolic alkalosis with plasma bicarbonate of 29.7 mM. During these experiments, it was demonstrated that the renal uptake of glutamine increased by 46%, while the renal production of ammonia was unchanged. The renal production of alanine rose from 6.0 to 16.8 μmol/min. Plasma concentration of lactate increased from 1.3 to 19.2 mM, while that of pyruvate increased from 0.075 to 0.454 mM. In the renal tissue, α-ketoglutarate, malate, oxalocacetate, lactate, pyruvate, citrate, and alanine increased significantly. Similar changes were found in the liver and skeletal muscle. The observed changes are best described by transamination of pyruvate and glutamate under the influence of alanine aminotransferase (GPT). It can be calculated that this reaction was responsible for 76% of the production of ammonia from glutamine, the latter being necessary to provide glutamate for the synthesis of alanine. Dogs infused with 0.3 M sodium bicarbonate instead of sodium lactate with the same degree of acute metabolic alkalosis, showed a depression of 40% in the renal uptake of glutamine with a 38% decrease in renal ammoniagenesis and a 20% fall in the production of alanine. The present studies demonstrate that the production of ammonia from glutamine is not necessarily related to changes in acid–base balance, but may be associated with biochemical alterations related to the synthesis of alanine by the kidney.
The influence of D2O, perchlorate, and variation in temperature on the potential-dependent contractile function of frog skeletal muscle
Authors: Foulks James G. , Morishita Lillian
Published: April 2011

D2O and perchlorate manifest opposing effects on the contractile function of skeletal muscle (amplitude of twitches and maximum K contractures, potential dependence of contraction activation and inactivation), and when combined the influence of one may effectively antagonize that of the other. The ratio of perchlorate concentrations required to produce effects of equal intensity (e.g., twitch enhancement and restoration of maximum K contractures in media lacking divalent cations or containing a depressant concentration of a cationic amphipath) in H2O and D2O solutions was generally rather constant. These findings are compatible with the view that both agents can influence contractile function by virtue of their effects on solvent structure. In the absence of divalent cations, the effects of reduced temperature resemble those of D2O whereas the effects of increased temperature resemble those of the chaotropic anion. However, in other media, variation in temperature was found to result in additional nonsolvent effects so that low temperature could oppose rather than enhance the effects of D2O. These observations are discussed in terms of a model which postulates a role for solvent influences on the kinetics of two separate potential-dependent conformational transitions of membrane proteins which mediate the activation and inactivation of contraction in skeletal muscle.
The use of 8-phenyltheophylline as a competitive antagonist of adenosine and an inhibitor of the intrinsic regulatory mechanism of the hepatic artery
Authors: Lautt W. Wayne , Legare Dallas J.
Published: April 2011

Reduction of portal blood flow results in compensatory vasodilation of the hepatic artery, the hepatic arterial buffer response. The hypothesis tested is that the regulation of the buffer response is mediated by adenosine, where the local concentration of adenosine in the region of the hepatic arterial resistance vessels is regulated by washout of adenosine into portal venules that are in intimate contact with hepatic arterioles. In anesthetized cats, portal flow was reduced to zero by complete occlusion of all arterial supply to the guts. The resultant dilation of the hepatic artery compensated for 23.9 ± 4.9% of the decrease in portal flow. Dose–response curves were obtained for the effect of intraportal adenosine infusion on hepatic arterial conductance in doses that did not lead to recirculation and secondary effects on the hepatic artery via altered portal blood flow. The dose to produce one-half maximal response for adenosine is 0.19 mg∙kg−1∙min−1 (intraportal) and the estimated maximal dilation is equivalent to an increase in hepatic arterial conductance to 245% of the basal (100%)) level. The adenosine antagonist, 8-phenyltheophylline, produced dose-related competitive antagonism of the dilator response to infused adenosine (but not to isoproterenol) and a similar, parallel antagonism of the hepatic arterial buffer response. If supramaximal blocking doses were used, the hepatic artery showed massive and prolonged constriction with blood flow decreasing to zero. The data strongly support the hypothesis that intrinsic hepatic arterial buffer response is mediated entirely by local adenosine concentration. This hypothesis is contrary to the popular views that the hepatic artery is controlled either by myogenic responses to change in portal pressure or by metabolic feedback from the parenchymal cells.
Histamine—whither now?
Authors: Code Charles F.
Published: April 2011

This review presents, from the author's viewpoint, avenues of histamine research likely to produce new information. One potentially useful approach may be to attempt to relate histamine's function to its occurrence in different body tissues such as the pituitary and hypothalamus, the gastrointestinal mucosa, and the bone marrow and white blood cells. Prospects also seem bright for quantitative studies of histamine metabolites in blood and urine and possible changes in the relative amounts of these metabolites in a variety of diseases.
Noradrenergic alpha2 binding sites in vagal dorsal motor nucleus and nucleus tractus solitarius: autoradiographic localization
Authors: Robertson H. A. , Leslie R. A.
Published: April 2011

The distribution in the canine medulla oblongata of binding sites for p-[3H]aminoclonidine, a ligand specific for alpha2-adrenergic receptors, was studied with light microscopic autoradiographic methods. Specific labelling was determined using unlabelled phentolamine as a displacer. The greatest density of sites was localized in the dorsal motor nucleus of the vagus nerve, the area postrema, and in several regions of the nucleus tractus solitarius. Less dense binding of the radioligand was also seen in the inferior olivary nucleus. Dorsomedial regions of the nucleus tractus solitarius were the most densely labelled in this nucleus, and dorsolateral and ventral regions were much less densely labelled. The region of the nucleus tractus solitarius shown in this study to be heavily labelled with alpha2-adrenergic binding sites has been implicated in the autonomic control of blood pressure. The dorsal motor nucleus of the vagus, together with the nucleus tractus solitarius, may thus represent the site of the antihypertensive action of the drug clonidine, an alpha2-adrenoreceptor agonist.
Cholesterol feeding impairs endothelium-dependent relaxation of rabbit aorta
Authors: Jayakody R. L. , Senaratne M. P. J. , Thomson A. B. R. , Kappagoda C. T.
Published: April 2011

Experiments were designed to assess the effect of cholesterol feeding on the endothelium-mediated relaxation of the rabbit aorta to acetylcholine. Age-matched male New Zealand white rabbits were fed either a 2% cholesterol diet or standard rabbit chow. The animals were anaesthetized with sodium pentobarbitone and sacrificed after 4 and 8 weeks on these diets. Rings were prepared from the proximal thoracic aorta and examined in tissue baths. These rings were contracted first with norepinephrine (−6 log mol/L) and acetylcholine was added to demonstrate the endothelium-mediated relaxation. The endothelium-dependent relaxation was significantly less in aortas from rabbits fed the 2% cholesterol diet than in aortas from animals fed the conventional diet. This impairment of relaxation was apparent after both 4 and 8 weeks of cholesterol feeding. In both groups of animals no relaxation was seen in rings from which the endothelium was removed. These results show that cholesterol feeding leads to an impairment of endothelium-mediated relaxation of the rabbit aorta to acetylcholine.
Biliary excretion of inorganic electrolytes: its role in hepatic bile formation
Authors: Tavoloni Nicola
Published: April 2011

To define the role of inorganic electrolyte secretion in hepatic bile formation, the effects of secretin, glucagon, and differently structured bile acids on bile flow and composition were studied in the dog, guinea pig, and rat. In the dog and guinea pig, secretin (2.5–10 clinical units∙kg−1∙30 min−1) increased bile flow and bicarbonate concentration in bile, a finding consistent with the hypothesis that the hormone stimulates a bicarbonate-dependent secretion possibly at the level of the bile ductule–duct. In the rat, secretin (5–15 CU∙kg−1∙30 min−1) failed to increase bile secretion. Glucagon (1.25–300 μg∙kg−1∙30 min−1) increased bile flow in all the three species, and produced no changes in biliary bicarbonate concentrations in the dog and rat. In the guinea pig, however, glucagon choleresis was associated with an increase in bicarbonate concentration in bile, similar to that observed with secretin. The choleretic activities of various bile acids (taurocholate, chenodeoxycholate, glycochenodeoxycholate, tauroursodeoxycholate, and ursodeoxycholic acid, infused at 30–360 μmol∙kg−1∙30 min−1) were similar in the rat (6.9–7.2 μL/μmol), but different in the guinea pig (11–31 μL/μmol). In the latter species, the more hydrophobic the bile acid, the greater was its choleretic activity. In all instances, bile acid choleresis was associated with a decline in the biliary concentrations of chloride, but with no major change in bicarbonate levels. The prominent finding of these studies is that, regardless of whether bile flow was stimulated by hormones or different bile acids, bicarbonate concentrations in bile were always similar to or higher than those in plasma. This is construed to support the view that bicarbonate is transported into bile, possibly at multiple sites within the biliary tree. Its excretion most likely provides the driving force for hormone-induced choleresis, and may in part account for the flow of bile associated with bile acid secretion.
Blood pressure responsiveness during the development of hypertension in the conscious spontaneously hypertensive rat
Authors: Toal Corey B. , Leenen Frans H. H.
Published: April 2011

Blood pressure responsiveness to iv noradrenaline and angiotensin II was studied in conscious, freely moving, age-matched spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats from 4 to 16 weeks of age. At 4 and 6 weeks the SHR showed small, but nonsignificant increases in responsiveness compared with WKY to both noradrenaline and angiotensin II. At 8 weeks they exhibited similar responses to the WKY. Subsequently, at 12 and 16 weeks decreased responsiveness to noradrenaline (nonsignificant) and angiotensin II (p < 0.05 at 12 and 16 weeks) was observed in SHR versus WKY. At 16 weeks of age, hexamethonium caused potentiation of the blood pressure response to noradrenaline and angiotensin II, but to the same degree in the two strains. Captopril at this age did not elicit potentiation to noradrenaline or angiotensin II in either strain. These results indicate that there is no rise in blood pressure responsiveness to circulating pressor agents, parallel to the development of hypertension in SHR. Increased receptor occupancy or more active attenuating reflexes in SHR versus WKY appear not to be involved in the absence of hyperresponsiveness in intact consious SHR at 16 weeks of age.