bluuebunny/crossref_metadata_2025 huggingface dataset:
Fentanyl decreases catecholamine metabolism measured by in vivo voltammetry in the rat locus coeruleus
Authors: Milne Brian , Quintin Luc , Gillon Jean Yves , Pujol Jean-François
Published: April 2011

The objective of this study was to investigate under controlled conditions the effects of fentanyl on the rat locus coeruleus catechol oxidation current. Using differential normal pulse voltammetry combined with electrochemically treated carbon fiber electrodes to measure the catechol oxidation current, catecholamine metabolism can be reliably monitored. Male Sprague–Dawley rats weighing 500–600 g had carbon fiber electrodes implanted into the locus coeruleus under halothane – O2 – air anesthesia with controlled ventilation and muscle relaxation. Experiments consisted of four groups of rats given the following treatments: (A) saline (n = 6); (B) fentanyl, 10 μg∙kg−1 i.v. (n = 6); (C) naloxone, 800 μg∙kg−1 i.v. followed 2 min later by fentanyl, 10 μg∙kg−1 (n = 5); (D) clonidine, 200 μg∙kg−1 i.p. (n = 6). There was no significant change in the catechol oxidation current following saline. Fentanyl produced a significant (ANOVA, p < 0.05) decrease in the catechol oxidation current (maximum 32 min postinjection was 75.8 ± 4.6% of baseline). This decrease was prevented by a prior injection of naloxone. Clonidine produced a significant decrease in catechol oxidation current (maximum 40 min postinjection was 54.1 ± 7.0% of baseline). Systolic blood pressure was significantly decreased following clonidine and there were no significant changes in arterial blood gases throughout the experiments. The α2-adrenergic agonist clonidine and the opioid fentanyl produced a decrease in locus coeruleus catechol oxidation current measured by in vivo voltammetry, which monitors catecholamine turnover.Key words: catecholamine, clonidine, fentanyl, opiates, locus coeruleus, in vivo voltammetry.
Influence of gramicidin S on cardiac membrane Ca2+/Mg2+ ATPase activities and contractile force development
Authors: Zhao Dayuan , Dhalla Naranjan S.
Published: April 2011

The effects of gramicidin S (GS), an antibiotic, on the rat heart membrane ATPases and contractile activity of the right ventricle strips were investigated. GS inhibited sarcolemmal Ca2+-stimulated ATPase (IC50 = 3 μM), Ca2+/Mg2+ ATPase which is activated by millimolar Ca2+ or Mg2+ (IC50 = 3.4 μM), and sarcoplasmic reticulum Ca2+-stimulated ATPase (IC50 = 6 μM). The type of inhibition for the sarcolemmal Ca2+/Mg2+ ATPase by GS was apparently uncompetitive, while that for Ca2+-stimulated ATPases in sarcolemma or sarcoplasmic reticulum was of mixed type. Other ATPases, including mitochondrial ATPase, sarcolemmal Na+–K+ ATPase, and myofibrillar ATPase, were not inhibited by this agent. GS also decreased the rat right ventricle maximum force development (half-maximal inhibitory concentration was 2–4 μM), maximum velocity of contraction, and maximum velocity of relaxation. The resting tension was increased by GS to over 200%. The contractile actions of GS were mostly irreversible upon washing the muscle 3 times over a 10-min period. Decreased Ca2+, Mg2+, Na+, K+ concentrations in the perfusate increased the effects of GS. These findings showed that GS was a potent inhibitor of divalent cation ATPases of heart sarcolemma and sarcoplasmic reticulum and it is suggested that these membrane effects may explain the cardiodepressant action of this agent.Key words: gramicidin S, rat heart sarcolemma, rat heart sarcoplasmic reticulum, Ca2+/Mg2+ ATPase, Ca2+-stimulated ATPase, rat heart contraction.
ACTH receptors in nervous tissue. High affinity binding–sequestration of [125I][Phe2,Nle4]ACTH 1–24 in homogenates and slices from rat brain
Authors: Hnatowich M. R. , Queen G. , Stein D. , LaBella F. S.
Published: April 2011

We have demonstrated specific, high affinity binding of a biologically active Tyr23-monoiodinated derivative of ACTH, [125I][Phe2,Nle4]ACTH 1–24, in rat brain homogenates. Similarly, in metabolically inhibited and noninhibited rat whole brain slices there is a specific "binding–sequestration" process that is dependent on time, protein concentration, and pH. In homogenates, binding curves were best described by a two-site model and provided the following parameters: [Formula: see text], [Formula: see text]; [Formula: see text], [Formula: see text]. In metabolically viable brain slices, concentration–competition curves of [125I][Phe2,Nle4]ACTH 1–24 binding–sequestration can be described by three components ([Formula: see text], [Formula: see text]; [Formula: see text], [Formula: see text]; [Formula: see text], [Formula: see text]). Metabolic inhibition, by removal of glucose and addition of 100 μM ouabain, abolishes the lowest affinity, highest capacity binding–sequestrian component only ([Formula: see text], [Formula: see text]; [Formula: see text], [Formula: see text]). The two binding–sequestration parameter estimates obtained from metabolically inhibited tissue slices are not significantly different from those of the two higher affinity components obtained with noninhibited tissue. Thus, metabolic inhibition permits demonstration of ACTH receptor binding only, unconfounded by sequestration or internalization of ligand: receptor complexes. Binding–sequestration of [125I][Phe2,Nle4]ACTH 1–24 exhibited brain regional differences in site densities with the following rank order: cortex > hypothalamus > hippocampus > striatum > cerebellum > midbrain > brainstem. The specificity of [125I][Phe2,Nle4]ACTH 1–24 binding in homogenates and binding–sequestration in tissue slices was assessed by testing a number of peptides and other compounds, including opioid peptides and opiate drugs. In homogenates, except for ACTH 1–24, the most potent competitors of [125I][Phe2,Nle4]ACTH 1–24 binding were vasoactive intestinal polypeptide, dynorphin 1–13, and growth hormone releasing factor, all approximately equipotent to each other with a mean Ki of 5.3 nM.Key words: ACTH, receptor, brain, vasoactive intestinal peptide, dynorphin.
pH shifts evoked by neuronal stimulation in slices of rat hippocampus
Authors: Walz Wolfgang
Published: April 2011

Extracellular pH was measured with ion-selective microelectrodes in 500-μm thick slices of the CA1 region of the rat hippocampus. The center of the slice was 0.24 pH units more acidic than the surface, thus creating a decreasing pH gradient from the surface to the center, most likely owing to increased anaerobic metabolism. Stimulation at various frequencies created a transient alkaline shift of 0.03 pH unit, followed by a sustained acidification (0.15 pH unit above baseline). The same pattern was seen in both cell body and dendritic layers. The presence of the alkaline shift in slices in vitro is especially significant, implying that it is not due to alterations in blood flow. The [Formula: see text] transport inhibitor SITS and the carbonic anhydrase inhibitor acetazolamide increased the alkaline shift to 0.06 and 0.23, respectively. The acid shift was influenced by the Na+–H+ transport inhibitor amiloride, with a reduction of about 50%. Possible mechanisms for these stimulus-evoked changes as discussed. The most likely cause for the alkaline shift is bicarbonate accumulation in the extracellular space. Hydrogen ion and lactic acid release are seen as the major factors contributing to the sustained acid shift.Key words: acetazolamide, acidosis, amiloride, hippocampal slice, pH.
The effect of inhibitors of endogenous opioid degradation, bacitracin, bestatin, captopril, and D-phenylalanine, on digoxin-induced arrhythmias in guinea pigs
Authors: Rabkin Simon W. , Redston Mark
Published: April 2011

The purpose of this study was to investigate the effect of inhibition of endogenous opioid degradation on digitalis-induced arrhythmias, utilizing the inhibitors bacitracin, bestatin, captopril, and D-phenylalanine. Guinea pigs, anesthetized with pentobarbital, 50 mg/kg i.p., and breathing spontaneously received intracerebroventricular (i.c.v.) injection of bacitracin (6.8 mg/kg), bestatin (1 mg/kg), captopril (2 mg/kg), D-phenylalanine (1.2 mg/kg) or the diluent, saline. Digitalis arrhythmias were induced by a 50 μg/kg i.v. bolus of digoxin followed by 500 μg∙kg−1∙h−1 i.v. Bacitracin and bestatin, but not captopril or D-phenylalanine, significantly (p < 0.05) altered the relationship between the digoxin dose and the first occurrence of arrhythmias, i.e., digoxin-induced ventricular arrhythmias became manifest at lower digoxin doses. The mean digoxin dose and ED50s, at which arrhythmias first occurred, were significantly (p < 0.05) reduced by bacitracin and bestatin. The findings were similar for fatal arrhythmias, although D-phenylalanine appeared to decrease the digoxin dose at the development of fatal arrhythmias. The opioid antagonist naloxone, in a 50 μg/kg bolus and 50 μg∙kg−1∙h−1 i.c.v., completely prevented these effects of bacitracin and reduced the effect of bestatin. The relationship to arrhythmias could not be ascribed to an effect on blood pressure, as the blood pressure response to digoxin was the same in bestatin, D-phenylalanine, and control groups. To examine whether systemic administration of an inhibitor of opioid degradation had similar effects, a second protocol was selected with systemic administration of bacitracin because it altered the dose effect relationship after i.c.v. administration and systemic concentrations could be readily attained. Bacitracin, in a 13.5 mg/kg i.v. bolus and 135 mg∙kg−1∙h−1 i.v., was followed by 100 μg/kg digoxin i.v. every 15 min. Bacitracin significantly (p < 0.05) reduced the digoxin dose at the development of arrhythmias. This was reversed by naloxone, given as 2 mg/kg i.v. plus 10 mg∙kg−1∙h−1. Thus, these data indicate that inhibitors of degradation of some opioid potentiate digitalis arrhythmias in a manner that is inhibited by naloxone, and provide evidence that implicates a role for endogenous opioids in digitalis arrhythmias.Key words: digitalis arrhythmias, aminopeptidase inhibitors.
Caffeine treatment inhibits drug-induced calcium release from sarcoplasmic reticulum and caffeine contracture but not tetanus in frog skeletal muscle
Authors: Koshita Makoto , Oba Toshiharu
Published: April 2011

Effects of pretreatment with caffeine on Ca2+ release induced by caffeine, thymol, quercetin, or p-chloromercuriphenylsulfonic acid (pCMPS) from the heavy fraction of sarcoplasmic reticulum (SR) were studied and compared with those effects on caffeine contracture and tetanus tension in single fibers of frog skeletal muscle. Caffeine (1–5 mM) did induce transient Ca2+ release from SR vesicles, but subsequent further addition of caffeine (10 mM, final concentration) induced little Ca2+ release. Ca2+ release induced by thymol, quercetin, or pCMPS was also inhibited by pretreatment with caffeine. In single muscle fibers, pretreatment with caffeine (1–5 mM) partially reduced the contracture induced by 10 mM caffeine. However, tetanus tension was almost maximally induced by electrical stimulus in caffeine-treated fibers. These results indicate that SR, which becomes less sensitive to caffeine, thymol, quercetin, or pCMPS by pretreatment with caffeine, can still respond to a physiological signal transmitted from transverse tubules.Key words: Ca2+ release, sarcoplasmic reticulum, caffeine, tetanus, skeletal muscle.
Endothelin is a potent constrictor of the lamb ductus arteriosus
Authors: Coceani Flavio , Armstrong Craig , Kelsey Lois
Published: April 2011

Endothelin was tested on isolated ductus arteriosus preparations from mature fetal Iambs. At low [Formula: see text] (18–24 Torr; 1 Torr = 133.3 Pa), the compound constricted the vessel dose-dependently over the range from about 10−10 to 10−7 M. The contraction was sustained and did not subside even after an extended period of washing. Endothelin was also effective on tissues ([Formula: see text], 217–231 Torr; indomethacin, 2.8 × 10−6 M) that had been completely relaxed with CO (CO/O2 ratio, 0.28). CO treatment interferes with a cytochrome P-450 mechanism, which is considered crucial for the contractile response of the vessel to oxygen. These findings are consistent with a role of endothelin in the closure of the ductus arteriosus at birth.Key words: ductus arteriosus closure, oxygen, cytochrome P-450.
Positive inotropic effect of the thromboxane analog U-46619 on guinea pig left atrium: mediation by specific receptors and association with increased phosphoinositide turnover
Authors: Sakuma Ichiro , Gross Steven S. , Levi Roberto
Published: April 2011

U-46619, a stable epoxymethano analog of thromboxane A2 elicited a direct positive inotropic effect on guinea pig left atrium paced at a constant rate (EC50 = 2.5 nM). This novel observation contrasts with previous reports of a decrease in myocardial contractility by thromboxane mimetic compounds in coronary-perfused preparations, an action recognized as secondary to vasoconstriction. The positive inotropic effect of U-46619 was competitively antagonized by the specific thromboxane receptor blocker L-655,240 (pA2 = 8.02; identical to that reported in smooth muscle), but was unaffected by blockers of α1-, β1-, and H1-receptors and by cyclooxygenase and lipoxygenase inhibitors. Increased tissue levels of inositol phosphates, but not cAMP, were associated with the positive inotropic action of U-46619, in analogy to the actions of α1- and H1-receptor agonists. However, the inotropic effect of U-46619 and the concomitant increase in phosphoinositide breakdown were both selectively antagonized by L-655,240. Thus, U-46619 acts on specific thromboxane receptors in guinea pig left atrium and elicits a positive inotropic effect that probably results from an increase in phosphoinositide metabolism.Key words: thromboxane analog U-46619, positive inotropic effect, guinea pig left atrium, phosphoinositide turnover, compound L-655-240.
Control of low density lipoprotein receptor gene expression in steroidogenic cells
Authors: Takagi Koichiro , Strauss III Jerome F.
Published: April 2011

Low density lipoprotein (LDL)-carried cholesterol is a primary substrate for steroid hormone synthesis by luteinized human granulosa cells. Chorionic gonadotropin and 8-bromo-cAMP both increase LDL receptor levels in granulosa cells by stimulating accumulation of the receptor mRNA. LDL and 25-hydroxycholesterol reduce LDL receptor expression, but this suppressive effect is partially overcome by 8-bromo-cAMP. Using fusion gene constructs containing the LDL receptor gene promoter transfected into JEG-3 cells, a cyclic AMP responsive enhancer could not be identified in the LDL receptor gene upstream promoter in transfection studies. We suggest that the LDL receptor gene in human steroidogenic cells is under negative control by a sterol effector, but that a cyclic AMP triggered process overcomes, to some extent, the sterol-mediated suppression. The detailed mechanisms by which sterol and cyclic AMP modulate LDL receptor gene expression remain to be elucidated.Key words: low density lipoproteins, low density lipoprotein receptors, cholesterol, steroidogenesis, gonadotropins.
Core threshold temperatures for sweating
Authors: Mekjavić Igor B. , Bligh John
Published: April 2011

To detect shifts in the threshold core temperature (Tc) for sweating caused by particular nonthermal stresses, it is necessary to stabilize or standardize all other environmental and physiological variables which cause such shifts. It is, however, difficult to cause progressive changes in Tc without also causing changes in skin temperature (Tsk). This study compares the technique of body warming by immersion in water at 40 °C, and subsequent body cooling in water at 28 °C, to determine the core threshold for sweating, with one by which Tc was raised by cycling exercise in air at 20 °C, and then lowered by immersion in water at 28 °C. The first of these procedures involved considerable shifts in Tsk upon immersion in water at 40 °C, and again upon transfer to water at 28 °C; the second procedure caused only small changes in Tsk. The onset of sweating at a lower esophageal temperature (Tes) during immersion in water at 40 °C (36.9 ± 0.1 °C) than during exercise (37.4 ± 0.3 °C) is attributed to the high Tsk since Tes was then unchanged. Likewise, the rapid decline in the sweat rate during immersion at 28 °C had the same time course to extinction after the pretreatments. This related more to the Tsk, which was common, than to the levels or rates of change of Tes, which both differed between techniques. Tes fell most rapidly, and thus sweating was extinguished at a lower Tes, following 40 °C immersion than following exercise. These differences in the rate of fall of Tes cannot be wholly accounted for by differences in the rates of heat production and of heat loss. A principal contributory factor could be a persistent peripheral vasodilatation after immersion in water at 40 °C, resulting in a greater indwelling of cool venous blood. The conclusions to be drawn from this study are (i) that the second of the techniques for raising and lowering body temperature (exercise in air followed by immersion in water at 28 °C) is preferable to the first technique (immersion in water at 40 °C and then in water at 28 °C) in the assessment of the Tc threshold for sweating, and (ii) that there must be a doubt about the meaningfulness of Tes as a valid measure of Tc in such circumstances since it is more sensitive than is Tc generally to the temperature of the venous return from peripheral tissues.Key words: temperature regulation, sweating rate, shivering, core threshold temperatures, exercise, water immersion.
Does in vitro activation of postsynaptic α2-adrenoceptor utilize intracellular Ca2+ for contraction in dog saphenous vein?
Authors: Guan Y. Y. , Kwan C. Y. , Daniel E. E.
Published: April 2011

Dog saphenous vein spiral strips were employed to determine whether an intracellular source of Ca2+ is used for contraction upon activation of the α2-adrenoceptor by B-HT 920 in Ca2+-free Krebs solution containing 50 μM EGTA. The studies were carried out in parallel with the activation of the α1-adrenoceptor by phenylephrine (Phe) under the condition that B-HT 920 (10−5 M) and Phe (2 × 10−6 M) gave rise to a similar level of responses in Ca2+-containing Krebs solution. A similar level of responses to these agonists at equieffective concentrations in Ca2+-free medium were also observed. Such responses to Phe and B-HT 920 were inhibited by 10−7 M rauwolscine and 10−7 M prazosin, respectively, and were not affected by 10−7 M nifedipine or 5 mM Mn2+. The responses to B-HT 920 (10−5 M) and submaximal concentration of Phe (2 × 10−6 M) in Ca2+-free medium were additive. However, if the vascular strips were first contracted maximally with 10−4 M Phe in Ca+2-free medium to deplete the intracellular Ca store, subsequent addition of B-HT 920 failed to induce additional response. Our results strongly suggest that activation of α2-adrenoceptor in dog saphenous vein in Ca2+-free medium indeed utilizes intracellular Ca2+ for contraction. We also found that the failure of earlier studies to demonstrate the contractile effects of B-HT 920 in dog saphenous vein was due to experimental artifacts derived from the use of high concentration of EGTA and artificial pH-buffering reagent.Key words: adrenoceptor, saphenous vein, vascular muscle, calcium.
Pharmacology of HI-6, an H-series oxime
Authors: Rousseaux C. G. , Dua A. K.
Published: April 2011

HI-6 is an oxime experimentally developed for reactivation of previously untreatable soman-phosphorylated acetylcholinesterase. It has been shown to be effective in restoring acetylcholinesterase activity after poisoning with other "nerve agents" namely VX and sarin; however, its antidotal qualities for the treatment of organophosphorus pesticide poisoning are not well known. HI-6, and other H-series oximes, apparently act in a number of ways: reactivation of acetylcholinesterase, blockage of ganglia and muscarinic receptors, stimulation of vasopressor and respiratory centre receptors, chemical combination with agents, restoration of neuromuscular transmission, retardation of the formation of the aged inhibitor–enzyme complex, and (or) inhibition of the release of acetylcholine.Key words: HI-6, H-series oxime, acetylcholinesterase, soman, mechanisms.
Use of the doubly labeled water method for measurement of energy expenditure, total body water, water intake, and metabolizable energy intake in humans and small animals
Authors: Roberts S. B.
Published: April 2011

The basis of the doubly labeled water method is measurement of the differential rates of disappearance of two isotopes of water (H218O and either 2H2O or 3H2O, administered at the start of the study) from body water. Published studies indicate that, in its current forms, this technique can be used to provide accurate and reasonably precise information on carbon dioxide production, total body water, and water intake in free-living humans and many small animals. Total energy expenditure can be calculated from carbon dioxide production with little loss of precision. Metabolizable energy intake can also be predicted, as the sum of total energy expenditure plus an estimate for the change in body energy stores during the measurement, but this prediction is unlikely to be accurate and precise unless the subject is in approximate energy balance.Key words: doubly labeled water, energy metabolism, energy expenditure, water intake, body composition.
Bronchodilator activity of atrial natriuretic peptide in guinea pigs
Authors: Potvin W. , Varma D. R.
Published: April 2011

Atrial natriuretic peptide (ANP) produced concentration-dependent relaxation of isolated guinea pig tracheal chains contracted with histamine, serotonin, carbachol, and arachidonic acid. ANP was a full agonist. ANP was two-to three-fold less potent when compared with isoprenaline in relaxing histamine-, serotonin-, and arachidonic acid-contracted tracheal chains. However, ANP was 20-fold less potent than isoprenaline in relaxing carbachol-contracted tracheal chains. The relaxant potencies of isoprenaline and sodium nitroprusside were similar regardless of the agent used to induce the tone. ANP was less potent and efficacious than isoprenaline in inhibiting the serotonin-, histamine-, and carbachol-induced increases in pulmonary inflation pressure in pentobarbitone-anesthetized guinea pigs. Neither ANP nor isoprenaline inhibited the arachidonic acid-induced increase in pulmonary inflation pressure. ANP decreased and isoprenaline increased arterial pressure. The data suggest that ANP possesses limited bronchodilator activity especially in vivo.Key words: bronchodilatation, atrial natriuretic peptide, isoprenaline, arachidonic acid, bronchoconstrictors, guinea pig trachea, pulmonary inflation pressure.
The relative changes in isometric force and work during fatigue and recovery in isolated toad sartorius muscle
Authors: Stevens E. Don , Syme D. A.
Published: April 2011

Toad sartorius muscle was subjected to sinusoidal varying length changes at 2 Hz to measure work. Both isometric tetanic force and work per cycle were measured before, during, and after a 3-min fatigue. Both isometric tetanic force and positive work, the work done by the muscle during the shortening part of the cycle, rapidly decreased in parallel in the first 40 s of fatigue. Thereafter, force continued to decrease, but at a slower rate, to about 10% of prefatigue values, whereas positive work levelled off at about 30% of prefatigue values. Negative work, the work done on the muscle during the lengthening part of the cycle, increased during fatigue to the extent that net work became negative. This was due to a prolonged relaxation, which resulted in active force still being generated while the muscle was being stretched. Work and force recovered at about the same rate. Isometric force measurements alone do not give any clear indication that net work will be negative under a particular set of experimental conditions.Key words: toad, muscle, fatigue, work, force.
Hypotensive properties of antibodies directed against an endogenous pressor peptide isolated from rat blood
Authors: Todd Daniel G. , McCumbee William D. , Wright Gary L. , Kopp William , Reichenbecher Vernon E.
Published: April 2011

Hypertensive factor (HF), a compound isolated from the erythrocytes of rats and tentatively identified as a peptide, has been shown to influence tissue calcium metabolism and induce prolonged blood pressure elevation. In the present study, we investigated the biological properties of antibodies directed against this peptide. Partially purified antibody preparations significantly decreased HF stimulation of lanthanum-resistant calcium uptake in rat aortic tissue in vitro. Infusion of the antibody preparation into spontaneously hypertensive (SH) or normotensive Sprague–Dawley rats resulted in a rapid decline in mean blood pressure of 54 and 34 Torr (1 Torr = 133.332 Pa), respectively. In contrast, infusion of the serum immunoglobulin preparations from controls (unimmunized and ovalbumin-immunized rabbits) had no significant effect on the blood pressure of SH or normotensive rats. The systolic blood pressure of SH rats was reduced for at least 72 h following a single injection of the antibody preparations, whereas the blood pressure of normotensive rats had returned to normal levels within 24 h following antibody injection. The results indicate that the anti-HF antibody preparation antagonizes the stimulation of calcium uptake by the peptide and acutely lowers blood pressure in SH and normotensive rats.Key words: antibodies, blood pressure regulation, hypertensive factor, spontaneously hypertensive rat.
Dietary sodium restriction and blood pressure response to sympathetic blockade in young versus adolescent spontaneously hypertensive rats
Authors: Leenen Frans H. H. , Klement Giannoula
Published: April 2011

The effects of dietary sodium restriction on the maintenance of blood pressure (BP) by sympathetic tone were evaluated in young versus more mature spontaneously hypertensive rats (SHR) and Wistar–Kyoto rats (WKY). Sympathetic activity was assessed by BP responses to α1-receptor blockade (prazosin), central inhibition of sympathetic outflow (clonidine), and by ganglionic blockade (hexamethonium). On regular sodium intake, SHR showed elevated BP and increased BP responses to sympathetic blockade at both 10 and 16 weeks of age. Sodium restriction to 9 or 17 μmol Na+/g food prevented or blunted development of hypertension in SHR when started at 4 weeks of age but did not affect BP when started at 10 weeks of age. Sodium restriction initiated in young SHR also prevented development of increased BP responses to sympathetic blockade. However, sodium restriction in more mature SHR did not decrease the increased BP responses to sympathetic blockade. We conclude that prevention of development of sympathetic hyperactivity in young SHR represents a major mechanism in the antihypertensive effect of sodium restriction in young SHR.Key words: dietary sodium, blood pressure, spontaneously hypertensive rats, age, sympathetic blockade.
Relationship between intracellular ATP and the sodium pump activity in dog renal tubules
Authors: Ammann H. , Noël J. , Boulanger Y. , Vinay P.
Published: April 2011

To examine the potential effect of the cellular ATP concentration and of the phosphate potential on the function of the sodium pump in intact renal cells, the ATP content of dog cortical tubules was first modified by a 30-min preincubation with one of the following effectors: 5 or 10 mM fructose, 2.5 mM adenosine 5′-monophosphate (AMP), or 2.5 mM adenosine in the presence of substrates (10 mM glutamine + 1 mM glutamate with either 10 mM lactate (low ATP) or 10 mM pyruvate (high ATP)). The tubules were then incubated in Krebs–Henseleit saline using two different phosphate concentrations and the same substrate mixture. The ATP content in tubular cells was modified by these treatments, ranging from 2.2 to 5.7 mM. The oxygen uptake by the tubules was measured before and after application of a small amount of nystatin (0.05 mM, 6 μmol/g wet wt.), added to impose an identical and submaximal increment of work to the Na+–K+ ATPase in tubules, irrespective of their ATP condition. This manoeuvre was followed by the addition of 1 mM ouabain to inhibit the sodium pump and quantify the respiration related to the activity of the Na+ pump. No significant effect of the ATP content on the respiratory cost of the Na+–K+ ATPase activity was noted when the [ATP] was above the normal concentration of ~3.0 mM before or after introduction of nystatin. In a second group of experiments, tubules were treated with 0.1 mM digitonin (13 μmol/g wet wt.) and resuspended in intracellular-like and sodium-free medium. The respiration was measured before and after the addition of increasing Mg-ATP concentrations (0–12 mM). A fixed quantity of Na+ (20 mM) was then introduced before ouabain was applied. The oxygen uptake was measured in these three conditions. We observed a fixed increment of ouabain-sensitive respiration upon stimulation of the pump activity by sodium at ATP concentrations ranging from 2 to 7 mM. The same observation applied when the free energy released from ATP hydrolysis ranged from −50 to −56 kJ∙mol−1 and when the [ATP]/[ADP]∙[Pi] ratio ranged from 1.5 to 7.5 mM−1. These results suggest that the Na+:ATP stoichiometry of the Na+–K+ ATPase is not modified by [ATP] in dog cortical tubules when the ATP content is at or above the physiological value. Furthermore, the stoichiometry of the pump does not appear to change when the phosphate potential and (or) the free energy released from ATP hydrolysis are altered.Key words: Na+–K+ ATPase, metabolic cost of transport, kidney, digitonin, nystatin, ouabain.
Effect of metabolic acidosis on glucose reabsorption in rats with acute hyperglycemia
Authors: Magner P. O. , Halperin M. L.
Published: April 2011

The rate of reabsorption of glucose in the kidney is a factor to consider with respect to the degree of hyperglycemia in poorly controlled diabetics. The rate of reabsorption of glucose in the proximal tubule is driven by the electrochemical gradient for sodium across the luminal membrane. This gradient in the proximal tubule is also used to reabsorb a number of other substances, quantitatively the most important being bicarbonate. We wished to explore the hypothesis that acidosis, by reducing the filtered load of bicarbonate and therefore the reabsorption of bicarbonate in the proximal tubule, might permit an increased rate of reabsorption of glucose. Hyperglycemia was induced in rats by the infusion of hypertonic glucose. Reabsorption of glucose was measured by clearance methods and factored for glomerular filtration rate (GFR), which has a direct effect on the reabsorption of glucose. The reabsorption of glucose was increased in the kidney when the reabsorption of bicarbonate in the proximal tubule was decreased by either HCl-induced acidosis or the administration of a carbonic anhydrase inhibitor. This effect was independent of a change in GFR and the fractional excretion of Na, factors that may also lead to changes in the reabsorption of glucose by the kidney.Key words: diabetes mellitus, hyperglycemic hyperosmolar nonketotic coma, diabetic ketoacidosis, proximal convoluted tubule, hyperglycemia, glucosuria, osmotic diuresis.
Neural network control of simple limb movements
Authors: Kwan Hon C. , Yeap Tet H. , Jiang Bai C. , Borrett Donald
Published: April 2011

It is possible to embed the control and computation of a simple single-joint movement at different speeds by a small nonlinear network of neuron-like elements. The network "learns" by appropriate adjustment of the strengths of interconnection, or synaptic weights, between the neuron-like elements. The learning of a few movement trajectories is generalized to the learning of a family of unlearned trajectories. These observations are in support of our hypothesis that relaxation of a network from an initial state to a final equilibrium state is both causal and computational to movement generation and control.Key words: control of movement, neural network, learning, nonlinear dynamics.
Absence of prejunctional sympathetic effect of amiodarone in hearts of open-chest anesthetized dogs
Authors: Lamontagne Daniel , Yamaguchi Nobuharu , Lambert Chantal , Champlain Jacques de , Nadeau Réginald
Published: April 2011

The effect of amiodarone (30 mg/kg p.o. each day for 3 weeks) on noradrenaline (NA) overflow into coronary sinus (CS) blood during left stellate stimulation (15 V, 2-ms square waves, 30 s duration at 1, 2, 4, and 8 Hz in random order) was investigated in an open-chest dog preparation. CS blood samples were taken before and during the stimulation period for plasma NA and hematocrit determinations. CS blood flow was monitored (extracorporal circulation with an electromagnetic flow meter) and used for NA output computation. The right atrium was paced throughout the experimental period. However, because AV block occurred at a high pacing rate in some amiodarone-treated dogs, pacing rate was lower in that group than in control dogs (132 ± 13 vs. 161 ± 10 min−1, ns). Mean arterial pressure was also lower in the treated group (95 ± 9 vs. 110 ± 13 mmHg, ns) but increased in every dog upon stimulation (p < 0.05). Basal left ventricular dP/dtmax was comparable in the two groups of dogs and increased in a similar fashion upon stimulation (p < 0.05). The increase in plasma NA concentration upon stimulation was comparable between the control and the amiodarone-treated group (0.38 ± 0.08 vs. 0.40 ± 0.12 ng/mL at 1 Hz and 12.7 ± 3.1 vs. 11.3 ± 2.3 ng/mL at 8 Hz, ns). The increase in NA output was also comparable (7.0 ± 1.6 vs. 10.7 ± 5.4 ng/min at 1 Hz and 356 ± 124 vs. 334 ± 102 ng/min at 8 Hz, ns). Amiodarone did not alter the myocardial NA content. We conclude that amiodarone, administered orally for 3 weeks, does not interfere with neural NA release, or with the positive inotropic response, following sympathetic nerve stimulation in dogs.Key words: amiodarone, noradrenaline release, antiadrenergic effect, sympathetic nerve stimulation.
Interaction of season and estradiol in the regulation of gonadotropin secretion in the adult ram
Authors: Sanford Lee M. , Robaire Bernard
Published: April 2011

The effects of season and estradiol on the secretion of gonadotropic hormones in adult Dorset × Leicester × Suffolk rams were studied. Control groups of intact and castrate rams, and castrate rams given estradiol replacement (~ 11.5 pg/mL) via polydimethylsiloxane capsules (sc) were assessed for 1 year, beginning in August. Mean concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin (PRL) were determined every 2 weeks for all three groups of rams and measurements of testosterone concentration and scrotal circumference were taken on the intact rams. Pulsatile LH release and the LH response to a 2-μg dose (iv) of gonadotropin-releasing hormone (GnRH) were assessed for all rams when the testes of intact rams were redeveloped (late October), regressed (early February, late April), and redeveloping (early August). Season directly affected LH-pulse amplitude, which increased only in the control castrate rams between February and April. In October, LH-pulse frequency was the same in both groups of castrate rams, while in April, frequency in the estradiol-treated castrate rams was suppressed to intact ram values. Pituitary responsiveness to exogenous GnRH did not change throughout the year in either of the castrate groups, but along with LH-pulse amplitude, it was increased in August in the intact rams. Although FSH secretion was 14-fold higher in the control castrate rams than in the intact rams, seasonal-directional changes in mean concentration were similar. FSH concentration in the estradiol-treated castrate rams was stable throughout the year. PRL secretion never differed between the control castrate and intact rams but was enhanced in the estradiol-treated castrate rams, particularly during long days.Key words: season, estradiol, gonadotropins, adult ram.
The role of ATP in energy-deprivation contractures in unloaded rat ventricular myocytes
Authors: Nichols C. G. , Lederer W. J.
Published: April 2011

Energy-deprivation contractures were investigated in unloaded rat ventricular myocytes. Application of 2 mM cyanide in the presence of 10 mM 2-deoxyglucose (metabolic blockade) led to a rapid shortening "contracture" (maximum speed 1.5 ± 0.2% control cell length/s). Cells shortened to a constant length of 69 ± 1.6% of the control length. Removal of cyanide caused cells to shorten further ("recontracture"), before relaxing towards the control length. Cells shortened to 57 ± 2.0% during the recontracture. Similar behaviour was observed in zero extracellular [Ca2+]. Cells permeabilized with saponin (0.1% w/v) responded to the removal of ATP from the bathing solution, and to readdition of ATP, as intact cells did to complete metabolic blockade and its removal. In these permeabilized cells, the extent and speed of contracture shortening were similar at pCa = 7 and pCa > 9. When the bath concentration of ATP ([ATP]b) was lowered to zero, shortening stopped at about 70% of the control length. However, when [ATP]b was lowered to an intermediate level (4–20 μM), cells contracted to lengths as short as 30% of the control length. Similarly, when [ATP]b was restored from zero to an intermediate concentration (4–20 μM), recontracture shortening continued without relaxation. The peak speed of this Ca2+-independent shortening showed a sigmoidal dependence on pMgATP (pMgATP0.5 = 4.0). Phosphocreatine (10 mM) shifted the ATP dependence of Ca2+-independent shortening to lower [ATP]b (pMgATP0.5 = 5.0), suggesting that gradients of [ATP] could exist between the bath and the myofilaments. Ca2+-independent shortening was inhibited by the chemical phosphatase 2,3-butanedione monoxime (BDM), although BDM did not relax cells from the shortened state during energy deprivation. Using a simple model, we show that the results can be explained by cross-bridge cycling occurring independently of Ca2+ over a "window" range of [MgATP] (0.1–100 μM). Therefore, when [MgATP] falls, cross-bridge cycling occurs and the cell shortens. As [MgATP] falls to very low levels ([MgATP] < 1 μM), shortening ceases as the rate of cross-bridge cycling declines. Recontracture occurs on restoring ATP production, because stiffness falls and Ca2+-independent cross-bridge cycling initially increases. As [MgATP] rises above 100 μM, Ca2+-independent cross-bridge cycling ceases and the cell relaxes towards the control length. We conclude that energy-deprivation contractures, and recontractures, can result from changes in [MgATP] and do not necessarily require changes in [Ca2+]i.Key words: rigor, contracture, heart, 2,3-butanedione monoxime, phosphocreatine, ADP.
The cardiac contractile function and hemodynamic control in rats after chronic adriamycin treatment
Authors: Gorodetskaya E. A. , Dugin S. F. , Golikov M. A. , Kapelko V. I. , Medvedev O. S.
Published: April 2011

Cardiac contractile function and hemodynamic parameters of control and adriamycin-treated (2 mg/kg once a week for 10 weeks) rats were studied both in the anesthetized (hexenal, 20 mg/kg) and conscious state. Radiolabelled microspheres (diameter, 15 μm) were used to measure systemic and regional hemodynamics. No significant differences between the control and adriamycin-treated groups in cardiac contractile function, total peripheral resistance, and regional blood flow (except muscles) was found in anesthetized animals. In the conscious state, a significantly higher (+70%) total peripheral resistance combined with lower blood flow in the skin and spleen was observed in adriamycin-treated rats. The response of the heart rate to changes in the arterial pressure induced by nitroglycerin and phenylephrine injection was greatly diminished after adriamycin treatment. Isoprenaline (0.64 μg∙kg−1∙min−1) increased left ventricular contractile indices approximately twofold and heart rate by 30% in the control group, while in adriamycin-treated rats only minor changes in these parameters were observed. However, cardiac output rose by 36% and total peripheral resistance fell by 36% in these animals. Results show that prolonged adriamycin treatment leads to decreased inotropic response to β-adrenoceptor stimulation and reduced baroreflex control. These changes occur in the stage preceding congestive heart failure.Key words: adriamycin, baroreflex control, microspheres, contractility.
Mechanics of vomiting: a minireview
Authors: Brizzee Kenneth R.
Published: April 2011

In a cineradiographic analysis of the vomiting reflex in response to i.v. administration of an emetic drag (lanatoside C, 12 mg/kg) in cats, it was shown that the vomiting act is preceded by cyclic periods of abnormal peristaltic activity of the small bowel and inhibition of gastric peristalsis. It was further observed that massive antiperistalsis of the upper small bowel with reflux into the stomach is a common occurrence in the period immediately preceding vomiting. The emetic act itself is composed of phases of esophageal dilation, gastric emptying, gastric reflux, and esophageal collapse in cyclic repetition. The response of the esophagus and the stomach during emesis is passive, with external pressures and forces apparently providing the expulsive forces, the gastric bolus being contained by contraction of the pylorus and probably an upper esophageal or pharyngeal barrier. Earlier studies were conducted in cats in which observations were made on changes in thoracic venous pressure, abdominal venous pressure, and arterial blood pressure associated with vomiting induced by Veratrum alkaloids. Retching was characterized by a growing series of brief negative inthrathoracic pressure pulses mirrored by positive pressure pulses in the abdomen. Expulsion then occurred and was followed with a sudden reversal of intrathoracic pressure from negative to positive. Expulsion involved a more sustained abdominal contraction, but both retching and expulsion were brought about by the same set of muscles, according to their EMG profiles. From results observed following phrenicotomy and spinal cord section at T5, it was concluded that the diaphragm, acting together with the inspiratory muscles against a closed glottis, is responsible for the negative intrathoracic pressure that occurs in retching. It was also concluded that the abdominal musculature is responsible for the positive pressure generated in the abdomen during retching and expulsion, and which in the latter phase is transmitted into the thorax by an upward shift of the diaphragm.Key words: emesis, cineradiography, peristalsis, motility, tachyarrythmia.
Respiratory muscle control during vomiting
Authors: Miller Alan D.
Published: April 2011

The changes in thoracic and abdominal pressures that generate vomiting are produced by coordinated action of the major respiratory muscles. During vomiting, the diaphragm and external intercostal (inspiratory) muscles co-contract with abdominal (expiratory) muscles in a series of bursts of activity that culminates in expulsion. Internal intercostal (expiratory) muscles contract out of phase with these muscles during retching and are inactive during expulsion. The periesophageal portion of the diaphragm relaxes during expulsion, presumably facilitating rostral movement of gastric contents. Recent studies have begun to examine to what extent medullary respiratory neurons are involved in the control of these muscles during vomiting. Bulbospinal expiratory neurons in the ventral respiratory group caudal to the obex discharge at the appropriate time during (fictive) vomiting to activate either abdominal or internal intercostal motoneurons. The pathways that drive phrenic and external intercostal motoneurons during vomiting have yet to be identified. Most bulbospinal inspiratory neurons in the dorsal and ventral respiratory groups do not have the appropriate response pattern to initiate activation of these motoneurons during (fictive) vomiting. Relaxation of the periesophageal diaphragm during vomiting could be brought about, at least in part, by reduced firing of bulbospinal inspiratory neurons.Key words: brain stem, bulbospinal respiratory neurons, vomiting center critique, diaphragm, abdominal muscles.
Conditioned taste aversion and motion sickness in cats and squirrel monkeys
Authors: Fox Robert A. , Corcoran Merylee , Brizzee Kenneth R.
Published: April 2011

The relationship between vomiting and conditioned taste aversion was studied in intact cats and squirrel monkeys and in cats and squirrel monkeys in which the area postrema was ablated by thermal cautery. In cats conditioned 7 – 12 months after ablation of the area postrema, three successive treatments with xylazine failed to produce either vomiting or conditioned taste aversion to a novel fluid. Intact cats, however, vomited and formed a conditioned aversion. In squirrel monkeys conditioned 6 months after ablation of the area postrema, three treatments with lithium chloride failed to produce conditioned taste aversion. Intact monkeys did condition with these treatments. Neither intact nor ablated monkeys vomited or evidenced other signs of illness when injected with lithium chloride. When the same ablated cats and monkeys were exposed to a form of motion that produced vomiting prior to surgery, conditioned taste aversion was produced and some animals vomited. These findings confirm other studies indicating motion can produce vomiting in animals with the area postrema destroyed and demonstrate that motion-induced conditioned taste aversion can be produced after ablation of the area postrema. The utility of conditioned taste aversion as a measure of subemetic motion sickness is discussed by examining agreement and disagreement between identifications of motion sickness by conditioned taste aversion and vomiting. It is suggested that a convincing demonstration of the utility of conditioned taste aversion as a measure of nausea requires the identification of physiological correlates of nausea, and caution should be exercised when attempting to interpret conditioned taste aversion as a measure of nausea.Key words: area postrema, conditioned taste aversion, motion sickness, nausea, emesis.
Application of the isobologram technique for the analysis of combined effects with respect to additivity as well as independence
Authors: Pöch G. , Reiffenstein R. J. , Unkelbach H.-D.
Published: April 2011

Combined actions of two substances with similar effects are frequently expressed by pairs of doses that produce a fixed response, usually 50%, in so-called isobolograms (ED50 isobolograms). In addition to the dose scales in such graphs we propose the addition of effect scales, where possible, to indicate the effect at certain doses, e.g., the ED30. We further propose to construct isoboles for expected independent interaction, in addition to the additivity line, for which purpose a simple procedure is delineated. In practice, an independent isobole for 50% effect passes through the point formed by the ED30s of A and of B in ED50 isobolograms. Thus, the ED30s constitute the "zenith" of an independent isobole in ED50 isobolograms. It is shown that theoretical independent isoboles can either represent additive, overadditive, or underadditive interactions, depending on the steepness of the dose–response curves of the components. Hence, drugs with shallow dose–response curves exhibit overadditive independent effects, compounds with exponentially steep curves show additive independent interactions. Substances with very steep dose–response curves, producing lethal effects, exhibited marked underadditive effects which could be ascribed largely to an independent mechanism of action of the components. Hence, the inclusion of independent isoboles into conventional isobolograms provides new insights into the mechanisms of interactions and into the actions of the components. Interactions can thus be characterized better and more completely, and misinterpretations appear less likely than with conventional isoboles.Key words: isobolograms, method, effect scales, independence.