bluuebunny/crossref_metadata_2025 huggingface dataset:
The response of the pulmonary circulation to exercise during normoxia and hypoxia following pneumonectomy in the adult sheep
Authors: Smith Michele , Coates Geoffrey , Kay J. Michael , O'Brodovich Hugh
Published: April 2011

Pneumonectomy approximately halves the available pulmonary vascular bed. It is unknown whether the remaining lung has sufficient vascular reserve to cope with increased blood flow under stressful conditions without demonstrating abnormal pulmonary hemodynamics. To investigate this question, unanesthetized ewes with vascular catheters had hemodynamics assessed before and after a left pneumonectomy. Subsequently, on different days, the sheep were exercised on a treadmill under normoxic and hypobaric hypoxic (430 mmHg) (1 mmHg = 133.3 Pa) conditions. Pneumonectomy itself increased mean pulmonary arterial pressure by 4 mmHg. During normoxic or hypoxic exercise, the pneumonectomized sheep demonstrated a pulmonary hemodynamic response similar to normal sheep with two lungs. The pressure–flow relation for the right lung suggested the vascular reserve of the lung was not exceeded during exercise in the pneumonectomized sheep. Eighteen to 70 days after pneumonectomy there was no evidence of right ventricular hypertrophy, but there were small increases in the number of muscularized vessels less than 50 μm diameter and in the amount of muscle in normally muscularized pulmonary arteries. This study demonstrates that pneumonectomy slightly increases mean pulmonary arterial pressure. However, there is sufficient vascular reserve in the remaining lung to permit a normal hemodynamic response to exercise-induced increased blood flow even under hypoxic conditions.Key words: pulmonary hypertension, pneumonectomy, sheep.
Inhibition of chick embryo hepatic uroporphyrinogen decarboxylase by components of xenobiotic-treated chick embryo hepatocytes in culture
Authors: James C. A. , Marks G. S.
Published: April 2011

Uroporphyrinogen decarboxylase (UROG-D) activity in the 10 000 g supernatant of 17-day-old chick embryo liver homogenates was determined by measuring the conversion of pentacarboxylporphyrinogen I to coproporphyrinogen I. The optimum pH of the enzyme was found to be approximately 6.0 and enzyme activity was found to be linear with protein concentrations ranging from 0.3 to 2.0 mg/mL. At a protein concentration of 1.2 mg/mL and pH 6.0, the activity was found to be linear for a reaction time of 50 min and to be approximately 10 pmol/(mg protein∙min). This enzyme assay was used to demonstrate that a UROG-D inhibitor, previously reported to accumulate in rodent liver, also accumulates in 3,3′4,4′-tretrachlorobiphenyl (TCBP) and sodium phenobarbital (PB) treated chick embryo hepatocytes in culture. This result accords with the previous demonstration of a TCBP- and PB-induced decrease in UROG-D activity in this system. Uroporphyrin accumulation in chick embryo hepatocyte culture is interpreted as resulting from a combination of two mechanisms, viz., inhibition of UROG-D activity and uroporphyrinogen oxidation to uroporphyrin catalyzed by a cytochrome P-450 isozyme.Key words: uroporphyrinogen decarboxylase, enzyme inhibition, chick embryo hepatocytes, tetrachlorobiphenyl, porphyria.
A tribute to Peter E. Dresel, Ph.D.: (February 27, 1925 – November 15, 1987)
Authors: Man R. Y. K. , Bose D.
Published: April 2011

Dr. Peter E. Dresel was a highly respected pharmacologist who played a significant role in the development of this discipline in Canada. Peter immigrated to the United States of America from Germany at a very young age. After graduating from high school and serving meritoriously in the U.S. Army during World War II, he obtained his doctorate in pharmacology from the University of Rochester in 1952. After serving in several positions in the university and in the pharmaceutical industry, Peter was recruited in 1956 by Mark Nickerson to join the fledgling Department of Pharmacology at the University of Manitoba. Nickerson's wish to develop Peter into a neuropharmacologist was never fulfilled. Instead, Peter went on to become an outstanding cardiac pharmacologist who trained a number of students, many of whom hold prestigious positions in their field of research. Having helped shape the "Nickerson Era" in Manitoba and having established a name in the cardiovascular pharmacology scene in North America, Peter became the Head of the Department of Pharmacology at Dalhousie University in Halifax in 1976. For the next 12 years Peter showed his superb academic and administrative abilities in shaping a vigorous and productive department.Peter served The Pharmacological Society of Canada in many capacities. He was a Councillor (1966–1969), Secretary (1969–1972), Vice President (1974–1975), and ultimately President (1975–1977). In addition to serving on the editorial boards of several international journals and scientific review committees, Peter was very active in university affairs, serving in the Senate at both the University of Manitoba and Dalhousie. He was also elected President of the Associate of Academic Staff at the University of Manitoba.Peter will be remembered for his unique flair. Despite his flamboyance, he had the unique ability to make his students feel at ease. His wealth of life experiences enabled him to teach his students and colleagues more than just science. He was eclectic and provocative, loyal and compassionate. Peter was never afraid of facing a challenge, nor was he too big to admit mistakes. Above all, he was extraordinarily generous in speaking of the accomplishments of his students and colleagues. Peter Dresel lived his life to the fullest, and helped those who crossed his path to do the same. His attributes will be judged not only through his contributions to science, but also by the enrichment of all who were touched by his influence.It is only befitting to honor Peter Dresel with a Memorial Issue in this Journal, which he served so well as an Associate Editor. The response of former students and colleagues has been overwhelming, and we wish to thank them all for their contributions.
Reflected reentry, delayed conduction, and electrotonic inhibition in segmentally depressed atrial tissues
Authors: Lukas Anton , Antzelevitch Charles
Published: April 2011

Reflection is a subclass of reentrant cardiac arrhythmias in which reexcitation of the heart occurs as a result of to and fro electrotonically mediated transmission of impulses across a narrow zone of impaired conductivity. Although relatively well characterized in ventricular tissues, the reflection mechanism has not been studied in atrial tissues. In this study we examine the possibility of reflected reentry in segmentally depressed atrial tissues and evaluate conduction characteristics in these preparations. Narrow strips of atrial pectinate muscle or crista terminalis (canine and calf) were placed in a three-chambered bath and the central segment was superfused with an isotonic sucrose solution or an "ischemic" Tyrode's solution. Proximal to distal conduction across the 1.0- to 1,2-mm wide ischemic gap showed step delays as long as 210 ms. Reflected reentry was readily demonstrable when prominent step delays occurred during anterograde conduction of the impulse across the gap. Progressive acceleration of the stimulation rate resulted in progressively greater impairment of anterograde conduction until complete block occurred. The incidence and patterns of reflected reentry were therefore a sensitive function of the stimulation rate. Other features exhibited by these preparations include a slow recovery of excitability following the action potential, postrepolarization refractoriness, and electrotonic inhibition and summation. Our data suggest that the characteristics of conduction and reflection in segmentally depressed atrial tissues are qualitatively similar to those in ventricular tissues. The presence of electrotonic inhibition in atria may also help to explain the functionally inexcitable zone seen in the vortex of the leading circle model of atrial flutter.Key words: reflection, reentry, atria, conduction, electrotonic inhibition.
Effects of K-channel blockers, calcium, and verapamil suggest different pacemaker mechanisms in cultured neonatal rat and embryonic chick ventricle cells
Authors: Schanne Otto F. , Boutin L. , Derosiers J.
Published: April 2011

We compared the determinants of spontaneous activity in explanted neonatal (2-day-old) rat ventricle cells and in reaggregates derived from 15-day-old chick embryos. We studied the beating rate with an optical recording method and the underlying electrical activity with glass microelectrodes using the K current blockers cesium (Cs) and tetraethylammonium, varied Ca concentrations, and the Ca antagonist verapamil. In the rat (i) Cs increased the beating rate that was mediated by an increase in the slope of the diastolic potential, (ii) Ca increased the beating rate dramatically at low and medium concentrations to decrease it again at 8 mM Cao.2This increase in the beating rate was mediated by an increase of the slope of the diastolic depolarization. (iii) The beating rate decreased with verapamil at concentrations between 0.5 and 2.0 μM. The effects of Cs and Ca suggest that an increase in net inward current (block of IK1) underlies the positive chronotropic effect of Cs and that the pacemaker mechanism is determined by a Ca inward current or an IT1 type current modulated by variations of Cai. In the chick reaggregates (i) Cs and tetraethylammonium decreased the beating rate that was mainly brought about by a decrease in the slope of diastolic depolarization. (ii) Ca increased the beating rate but to a lesser degree than in the rat and there was no decrease of the beating rate at higher concentrations. (iii) The increase in the beating rate was not mediated by an increase in the slope of the diastolic potential but mainly by a depolarization of the maximum diastolic potential. (iv) Verapamil inhibited electrogenesis before any change in the diastolic potential was evident. The negative chronotropic effect of Cs and tetraethylammonium is compatible with the notion that a voltage- and time-dependent K current was inhibited and that this current determines the pacemaker. Moreover, the Ca component of the pacemaker mechanism in explanted rat ventricle cells resembles either that of the sinoatrial node or represents triggered activity.Key words: pacemaker mechanism, cultured cardiac cells, K-channel blocker, calcium, verapamil.
Effects of cholecystokinin octapeptide on the pancreatic exocrine secretion in the pig
Authors: Cuber Jean-Claude , Corring Tristan , Levenez Florence , Bernard Christine , Chayvialle Jean-Alain
Published: April 2011

In conscious pigs, intravenous infusion of serial doses of cholecystokinin octapeptide (CCK8; 2.9–232.3 pmol∙kg−l∙min−1) upon a background of secretin resulted in a linear increase of plasma CCK-like immunoreactivity (CCK-LI) concentration and evoked a dose-related increase of pancreatic volume and bicarbonate and protein outputs. The threshold plasma CCK-LI concentration for significant pancreatic response was 103.8 ± 10.2 pM using a CCK8 dose of 8.8 pmol∙kg−1∙min−1. The maximum pancreatic response was observed for a plasma CCK-LI level of 498.0 ± 15.3 pM using 77.2 pmol CCK8∙kg−1∙min−1. In anesthetized pigs, the threshold plasma CCK-LI concentration for pancreatic response was 1500 pM (actual CCK8 dose of 60.3 pmol∙kg−1∙min−1). The physiological relevance of this finding was assessed by comparing the food-induced increase of pancreatic secretion with that of plasma CCK-LI. Food ingestion was followed by a sharp pancreatic response and by a progressive increase of plasma CCK-LI to a peak increment of about 15 pM. Gel chromatography of portal and peripheral plasma from fed animals revealed three major peaks in the volumes of CCK33/39 and CCK8, and in a volume intermediate between CCK33/39 and CCK8. An additional minor component eluted ahead of CCK33/39. CCK8, which is one of the CCK components released after food intake, appears to be a fairly weak pancreatic stimulant in pigs.Key words: cholecystokinin, pig, pancreas, secretion.
Net appearance of amino acids in portal blood during the digestion of casein or rapeseed proteins in the pig
Authors: Galibois Isabelle , Nunes Carlos Simoes , Rérat Alain , Savoie Laurent
Published: April 2011

The kinetics of appearance of amino acids (AA) in portal blood following the ingestion of casein or rapeseed protein were compared. Six pigs, fitted with permanent catheters in the portal vein and in the carotid artery, as well as with an electromagnetic flow probe around the portal vein, received three 800 g test meals, one containing 12% rapeseed proteins (RA12) and the others containing 12% and 24% casein (CA12 and CA24), at 1-week intervals and according to a double Latin square design. Portal and arterial blood samples were collected and portal blood flow rate was recorded for 8 h after the test meals. At the end of measurement, an average of 76.1 ± 5.6% (mean ± SEM) of total AA from the CA24 diet had appeared in portal blood, compared with 94.3 ± 10.4% for the CA12 diet and 103.5 ± 12.6% for the RA12 diet. Similar results were obtained for essential AA. Differences were found in the kinetics of appearance of individual AA. Eight hours after the meal, 79% of lysine, 84% of methionine, and 73% of valine from the CA24 diet had appeared in portal blood compared, respectively, with 100, 89, and 83% from the CA12 diet and 99, 86, and 106% from the RA12 diet. Arginine from rapeseed had a net appearance level lower (82%) than the overall mixture of essential AA. With casein diets, the net appearance of arginine reached 97% (CA12) and 82% (CA24). Following the ingestion of rapeseed proteins, there seemed to be a significant appearance of endogenous AA in portal blood. The results indicate that both the composition and the amount of dietary protein have important effects on the sequence and rate of AA absorption.Key words: amino acids, digestion, absorption, casein, rapeseed.
The use of a cell-free perfusate in the perfused rat hindquarter: methodological concerns
Authors: McDermott John C. , Hutber Adrian , Tan Meng H. , Bonen Arend
Published: April 2011

The viability of using a cell-free perfusate in a rat hindlimb preparation to assess skeletal muscle glycogenesis was investigated. A perfusate containing 10 mM glucose and 10 μCi (1 Ci = 37 GBq) of D-[5-3H]glucose was recycled for a 60-min period. In agreement with other studies using more complex media, oxygen uptake of the preparation indicated adequate tissue oxygenation (8 μmol∙min−1∙g−1).Skeletal muscle fiber type heterogeneity in basal glycogen synthesis from glucose was shown (slow oxidative > fast oxidative glycolytic > fast glycolytic fibres). Insulin (4.2 mU/mL) markedly stimulated glycogenesis from D-[5-3H]glucose in the soleus (slow oxidative fiber), red gastrocnemius (fast oxidative glycolytic fiber), and white gastrocnemius muscles (p < 0.05). A recent report indicates that tissue edema in this preparation did not affect insulin responsiveness of the tissue. In contrast, our observations indicate that glucose uptake was enhanced by insulin when edema was absent (p < 0.05), but not when edema was present (p < 0.05). In addition, the presence of tissue edema negated insulin-mediated glycogenesis in slow oxidative and fast oxidative glycolytic muscle (p < 0.05 compared with control) but not in fast glycolytic muscle (p < 0.05). These data warrant caution when using a cell-free media in the perfused rat hindquarter; however, in the absence of edema, normal responses of glucose metabolism are observed.Key words: glycogenesis, insulin, edema.
Species differences in the positive inotropic response to DPI 201-106, a novel cardiotonic agent
Authors: Haleen Stephen J. , Steffen Robert P. , Weishaar Ronald E.
Published: April 2011

The positive inotropic activity of the novel cardiotonic DPI 201-106 was investigated in rat and guinea pig isolated hearts. For comparative purposes, the adenylate cyclase stimulant forskolin and the sodium channel agonist veratridine were also evaluated in both species. DPI 201-106 and veratridine produced greater inotropic effects in rat hearts than in guinea pig hearts, whereas forskolin produced comparable effects. In both species the inotropic response to DPI 201-106 and veratridine, but not forskolin, was reversed by the sodium channel antagonist tetrodotoxin. These results confirm that the positive inotropic effect of DPI 201-106 is due to stimulation of the sodium channel and demonstrate for the first time that species differences exist in the inotropic response to this novel cardiotonic drug.Key words: cardiac muscle, contractility, cardiotonic drug, sodium channel, isolated heart.
The effect of repeated intermittent hypoxia on pulmonary vasoconstriction in the newborn
Authors: Belik Jaques , Sienko Anna , Light R. Bruce
Published: April 2011

The effect of repeated intermittent hypoxia upon the basal pulmonary vascular tone in the newborn period is unknown. We therefore studied the central hemodynamic response to seven repeated intermittent hypoxic challenges in acutely prepared piglets under 2 weeks of age. Catheters were placed in the aorta, pulmonary artery, and atria, and an electromagnetic flow probe was positioned around the main pulmonary artery. Each hypoxic challenge (Fio2 = 0.14) lasted 5 min, and was separated by an equal duration of ventilation with air. Nine control animals were ventilated with air for 90 min, a period of time equivalent to the seven challenges in the experimental group, and subjected to one hypoxic challenge at the end. Hypoxia uniformly induced pulmonary vasoconstriction. Repeated intermittent hypoxic challenges produced a progressive increase in pulmonary artery pressure and vascular resistance, both during air ventilation and hypoxia. For each challenge, the vascular resistance value achieved during hypoxia was directly related to the immediately preceding air ventilation one, and the magnitude of hypoxic pulmonary vasoconstriction, defined as the incremental change in resistance from air to hypoxia, was not different from the first to the last challenge in the experimental group. In the control group the pulmonary vascular tone did not change during the 90 min of air ventilation, and the single hypoxic challenge induced an increase in pulmonary vascular pressure and resistance similar in magnitude to the first challenge in the experimental group. Indomethacin administration to five experimental animals, after the last challenge, reversed the increase in air ventilation pulmonary artery pressure and vascular resistance. Plasma levels of thromboxane B2 and 6-keto-PGF1α were also measured by an enzyme immunoabsorbent assay in half the experimental animals. Surgical stress was associated with a significant rise in both prostaglandin metabolites. Repeated hypoxic challenges led to a further increase in thromboxane B2 and also in the ratio of this metabolite and 6-keto-PGF1α (p < 0.05). The percentage increase in the latter was linearly correlated with the increase in pulmonary arterial pressure and vascular resistance from the first to the last hypoxic challenge. These data indicate that repeated intermittent hypoxia in the newborn pig increases the pulmonary vascular resistance on air ventilation. This phenomenon is possibly related to the release of the potent pulmonary vasoconstrictor thromboxane A2, and may play a role in the pathogenesis of the persistent pulmonary hypertension in human infants who underwent repeated perinatal hypoxic insults.Key words: persistent pulmonary hypertension syndrome, hypoxic pulmonary vasoconstriction, newborn, prostaglandins.
3,5-Diethoxycarbonyl-2,6-dimethyl-4-ethyl-1,4-dihydropyridine inactivates rat liver cytochrome P-450c, but not its orthologue, rabbit lung form 6
Authors: Riddick D. S. , Mackie J. E. , Massey T. E. , Marks G. S.
Published: April 2011

Various rat liver cytochrome P-450 (P-450) isozymes are targets for mechanism-based inactivation by 3,5-diethoxycarbonyl-2,6-dimethyl-4-ethyl-1,4-dihydropyridine (4-ethyl DDC). Unlike rat liver, which contains multiple P-450 isozymes, rabbit lung contains only three major isozymes referred to as forms 2, 5, and 6. We have examined the ability of 4-ethyl DDC to destroy P-450 heme in hepatic and pulmonary microsomes from untreated and β-naphthoflavone (βNF)-treated rabbits. This compound destroyed 31% of the P-450 in either hepatic microsomal preparation, but was ineffective at lowering P-450 and heme levels in pulmonary microsomes when examined at a range of concentrations (0.45 – 5.0 mM). These data suggest that rabbit pulmonary P-450 forms 2, 5, and 6 are not targets for destruction by 4-ethyl DDC, despite the ability of this compound to inactivate rat liver P-450c, the orthologue of rabbit lung form 6.Key words: 3,5-diethoxycarbonyl-2,6-dimethyl-4-ethyl-1,4-dihydropyridine, cytochrome P-450, mechanism-based inactivation, rabbit pulmonary microsomes.
The inhibitory effect of halothane on the emetic response in the ferret
Authors: Zunini Graciela S. , Roth Sheldon H. , Lucier Gregory E.
Published: April 2011

Emesis and nausea are often associated with anaesthesia and continue to be a common clinical problem. Past clinical studies have demonstrated that halothane produces a higher incidence of vomiting compared with other anaesthetics, but some investigators have described an antiemetic effect. The purpose of this study was to investigate the effects of various doses of halothane on the emetic response in the decerebrate ferret. Following a control emetic response, a maximum of six increasing cumulative concentrations of halothane were delivered. At the end of each delivery period, the supradiaphragmatic vagal communicating branch, which has been shown to reproducibly elicit vomiting, was electrically stimulated and the emetic response was monitored. An increase in halothane concentration produced a marked depression of tongue, abdominal muscle, and diaphragm EMG activity as well as a decrease in central venous pressure. Licking, a prodromal response comparable to nausea in the human, appeared to be most sensitive. An increase in latency of the emetic response occurred as the concentration of halothane was increased. All phases of the response were observed at concentrations below 0.6 vol% halothane. At 0.6 vol% halothane, 75% of the animals vomited. At higher concentrations, the emetic response was completely abolished. One hour post-halothane, all latencies had returned to near control values. The methods utilized in this study provided a model that was not complicated by a large number of variables usually present in clinical studies. These data demonstrate that halothane exerts an inhibitory, concentration-dependent, and reversible effect on the emetic response in the ferret and provide further support that halothane alone does not possess emetic properties at clinical concentrations.Key words: vomiting, anaesthetic, decerebrate ferret, retching, vagus.
Bifemelane induces translocation of protein kinase C in the CA3, but not the CA1, region of guinea-pig hippocampus
Authors: Fujii Takeshi , Kuraishi Yasushi , Okada Toshikazu , Satoh Masamichi
Published: April 2011

We made use of the [3H]phorbol 12,13-dibutyrate binding assay to investigate the effects of bifemelane on the subcellular distribution of protein kinase C in the CA3 and CA1 regions of guinea-pig hippocampal slices. Bifemelane, a drug that augments the long-term potentiation in the CA3 region, significantly induced the translocation of [3H]phorbol 12,13-dibutyrate binding activity from the cytosol to the membrane in a dose-dependent manner (10−8 to 10−6 M) and with no effects on total binding activity in the CA3 region. Bifemelane, at a concentration of 10−6 M, was without effect on the subcellular distribution of [3H]phorbol 12,13-dibutyrate binding activity in the CA1 region. These observations suggest that bifemelane acts directly on the hippocampus to induce translocation of protein kinase C in the CA3 region. Such an effect may be associated with the bifemelane-induced augmentation of the long-term potentiation in this region of the brain.Key words: bifemelane, protein kinase C, hippocampal slice, translocation, CA3.
Pulmonary vascular resistance in adult rats exposed to hypoxia in the neonatal period
Authors: Hakim T. S. , Mortola J. P.
Published: April 2011

Newborn rats were exposed to hypoxia (10% O2 + N2) from 24 h to day 6 of neonatal life and then returned to room air until 45 days of age (experimental). The rats were anaesthetized, heparinized, and exsanguinated. The chest was opened and the lungs were perfused with diluted autologous blood at a constant flow rate (Q). The pulmonary arterial pressure (Pa) and venous pressure (Pv) were monitored. The properties of the pulmonary vasculature were assessed by measuring baseline vascular resistance, PVR = (Pa−Pv)/Q, segmental pressure gradients (double occlusion technique), pressure–flow relationship, hypoxic pressor response (HPR, 3% O2), and the response to 0.5 μg bolus of angiotensin II (AII). These were compared with similar measurements on age-matched control animals never exposed to hypoxia. The perfusate hematocrit and gases were not significantly different between the two groups. The PVR normalized to body weight was 30% higher in the experimental groups (p < 0.005). The double occlusion results (obtained at a flow rate of 13 mL/min) revealed that this increase in resistance was primarily due to the increase in the postcapillary resistance. HPR was primarily in the upstream segment in both groups but was larger in the experimental group. In contrast, the response to AII occurred in both the upstream as well as in the downstream vascular segments and did not differ between the two groups. We conclude that adult rats exposed to hypoxia in the neonatal period have elevated pulmonary vascular resistance and increased vascular reactivity to hypoxia.Key words: resistance, angiotensin, lung development, pulmonary hypertension.
The inotropic effect of digoxin on an isolated rat heart in hypercapnia and (or) hypoxia
Authors: Allam M. , Saunier C. , Sautegeau A. , Hartemann D.
Published: April 2011

The explanation for the increased frequency of troubles with digoxin therapy in patients with chronic pulmonary diseases is debated. The reported effects of hypoxia in vivo on myocardial levels of digoxin are contradictory, and there have been few studies on the effects of hypercapnia. In the past, it has been shown in rat myocardial tissue at rest in vitro that hypoxia decreased and hypercapnia acidosis increased the digoxin uptake. We performed a new study in vitro in an isolated beating rat heart perfused at constant flow (37 °C) and stimulated at a constant frequency (6 Hz). The performances were recorded with an intraventricular balloon equipped with a tip-manometer catheter. The action of digoxin was studied by recording systolic pressure (PS) and diastolic pressure (PD), the left ventricular developed pressure (LVDP = PS − PD), the (dP/dt)max, and the ratio (dP/dt)max/PS. First, the heart was perfused for 30 min with a modified Tyrode's solution perfusate aerated with carbogen (pH = 7.40; [Formula: see text]; [Formula: see text]) (1 mmHg = 133.32 Pa). Various parameters of contractions were recorded (initial control values). Then the heart was perfused for 15 min with Tyrode's solution aerated either with a hypoxic gas mixture (pH = 7.41; [Formula: see text]; [Formula: see text]), a hypercapnic gas mixture (pH = 7.08; [Formula: see text]; [Formula: see text]), or a hypoxic–hypercapnic gas mixture (pH = 7.09; [Formula: see text]; [Formula: see text]). Control hearts were continuously perfused with Tyrode's solution aerated with carbogen. During heart perfusion with hypercapnic, hypoxic, or hypoxic–hypercapnic Tyrode's solution, a decrease in LVDP and (dP/dt)max was observed. Finally, the heart was perfused with the same Tyrode's solution plus 1.75 × 10−5 M digoxin. The increase in myocardial contractility produced by digoxin was enhanced by hypercapnia and abolished by hypoxia. The addition of hypercapnia to hypoxia in Tyrode's solution seems to enhance the depressor action of the hypoxia.Key words: isolated heart, digoxin, hypoxia, hypercapnia, myocardial contractility.
Transferrin delays oxygen radical induced cardiac-contractile failure
Authors: Tiede R. , Sareen S. , Singal P. K.
Published: April 2011

The role of iron-loaded transferrin in xanthine–xanthine oxidase (X–XO) induced cardiac injury in isolated perfused rat hearts was examined. X (2 mM) – XO (10 U/L) perfusion resulted in contractile failure, a rise in resting tension, an increase in lipid peroxidation, and myocardial cell damage. The addition of transferrin (2.4 μM) into the X–XO medium had a protective effect, as indicated by an increase in time to contractile failure, a lesser rise in resting tension, a decrease in MDA values, and lesser damage compared with the X–XO perfused controls. Ultrastructural studies revealed localization of transferrin along the capillary basement membrane. In contrast, addition of transferrin and Desferal (desferrioxamine mesylate, 3 mM, an iron chelator) into X–XO medium caused a rapid contractile failure as well as a rise in resting tension, and in these hearts transferrin was localized inside the myocytes. These findings suggest that a vascular supply of iron protein chelators may have a beneficial effect against myocardial cell injury caused by a vascular source of oxygen radicals.Key words: oxy-radical injury, myocardial failure, lipid peroxidation, heart cell damage, iron binding proteins.
Increased sympathetic innervation in the cerebral and mesenteric arteries of hypertensive rats
Authors: Mangiarua Elsa I. , Lee Robert M. K. W.
Published: April 2011

The density of catecholamine-containing nerve fibers was studied in the cerebral and mesenteric arteries from normotensive Wistar–Kyoto rats (WKY), spontaneously hypertensive rats (SHR), and stroke-prone SHR (SHRSP) in the growing (SHR, WKY) and adult (SHR, SHRSP, WKY) animals. Cerebral arteries from SHR showed an increased adrenergic innervation from day 1. The nerve plexuses reached an adult pattern earlier in SHR than in WKY. The arteries from adult SHR and SHRSP (22 weeks old) showed a markedly higher nerve density than WKY. There was a positive linear correlation between blood pressure and nerve density for four cerebral arteries. The mesenteric arteries were not innervated at birth. However, hyperinnervation of these arteries in the SHR was already present at 10 days of age as compared with WKY. Sympathectomy with anti-nerve growth factor and guanethidine caused a complete disappearance of fluorescent fibers in the mesenteric arteries from SHR and WKY, and in the cerebral arteries of WKY. The same procedure caused only partial denervation of the cerebral arteries from hypertensive animals. We postulate that the increase in nerve density in the cerebral arteries from the hypertensive rats may contribute to the development of arterial hypertrophy in chronic hypertension through the trophic effect of the sympathetic innervation on vascular structure.Key words: sympathetic innervation, cerebral artery, mesenteric artery, spontaneously hypertensive rat, neonatal rat.
Cardiac dysfunction in isolated perfused hearts from spontaneously diabetic BB rats
Authors: Rodrigues Brian , McNeill John H.
Published: April 2011

The purpose of this investigation was to examine cardiac function and biochemistry in spontaneously diabetic BB rats, a strain in which diabetes occurs spontaneously and closely resembles insulin-dependent diabetes in humans. The study involved two groups: nondiabetic littermates of BB rats and BB diabetic rats treated daily with a very low insulin dose such that the rats were severely hyperglycemic and hyperlipidemic. The hearts from these two groups were isolated and heart function (using isolated perfused working hearts) and biochemistry were examined 6 weeks after the onset of diabetes. BB diabetic rats exhibited a lower calcium-stimulated myosin ATPase activity and depressed left ventricular developed pressure, cardiac contractility, and ventricular relaxation rates compared with BB nondiabetic littermates. These results suggest that the chronically diabetic state in the BB rat produces cardiac changes similar to those demonstrable after chemical diabetes induced by alloxan or STZ, or that seen during human diabetes mellitus.Key words: diabetes, cardiac function, Wistar BB rat, myosin ATPase, cardiomyopathy.
8-Bromo-cyclic GMP inhibits the calcium channel current in embryonic chick ventricular myocytes
Authors: Wahler Gordon M. , Rusch Nancy J. , Sperelakis Nicholas
Published: April 2011

Superfusion with 8-bromo-cyclic GMP or intracellular injection of cyclic GMP inhibits calcium-dependent slow action potentials in embryonic chick or guinea pig ventricular cells, suggesting that cyclic GMP inhibits calcium currents. Recently, cyclic GMP has been shown to reduce cyclic AMP-stimulated calcium currents in voltage-clamped ventricular myocytes. Since earlier results in intact cells had suggested that cyclic GMP might inhibit basal (i.e., unstimulated by cyclic AMP) calcium currents, we directly investigated the effect of 8-bromo-cyclic GMP on basal calcium channel currents (using barium as the charge carrier) in voltage-clamped ventricular myocytes isolated from embryonic chick hearts. Superfusion with 1 mM 8-bromo-cyclic GMP (without prior cyclic AMP elevation) progressively decreased peak calcium channel currents (−68% at 15 min after the onset of drug exposure). In contrast, the currents were unchanged during 15 min superfusion with control solution, or 1 mM 8-bromo-GMP (the noncyclic inactive analog of 8-bromo-cyclic GMP). The present results in voltage-clamped embryonic chick heart cells indicate that cyclic GMP can inhibit basal calcium channel currents, apparently through a cyclic AMP-independent mechanism.Key words: cyclic GMP, calcium channels, calcium current, heart.
Metoprolol suppresses the development of ethanol-induced cardiac hypertrophy in the rat
Authors: Adams M. A. , Hirst M.
Published: April 2011

Subacute, severe intoxication with ethanol stimulates the peripheral sympathetic nervous system in the rat and enhances the excretion of adrenaline and noradrenaline. In association with this effect there is a rapid development of cardiac hypertrophy, with proportional heart weight increasing by 12% within 48 h. At this time adrenal medullary adrenaline content was depressed by more than 35%, whereas nonadrenaline content of the adrenal and heart were not affected. Metoprolol (20 mg/kg, t.i.d.) was without effect when used alone and had little if any impact on the ethanol-induced changes. Metoprolol (100 mg/kg, t.i.d.) reduced adrenal catecholamine content, but not cardiac noradrenaline content, and diminished cardiac weight in control animals. The combination of ethanol with the high dose of metoprolol enhanced the loss of medullary catecholamine and reduced cardiac noradrenaline content, whereas cardiac weight was the same as in control animals. A correlation between sympathetic activation and increasing cardiac mass and its antagonism by metoprolol implies a β-adrenoceptor mediated link in the cardiac hypertrophy induced by ethanol.Key words: cardiac hypertrophy, ethanol, catecholamines, metoprolol.
Kinetics, distribution, and biotransformation of the chemical HI-6 in the rat, dog, and rhesus monkey
Authors: Ecobichon D. J. , Comeau A. M. , O'Neil W. M. , Marshall W. D.
Published: April 2011

Disposition of the bis-pyridinium mono-oxime, HI-6, following intramuscular injection in rats (200 mg/kg bw), beagle dogs (10 and 50 mg/kg bw), and rhesus monkeys (50 mg/kg bw) revealed that the oxime was absorbed rapidly and completely from the site of injection, was distributed rapidly in the tissues, and that tissue concentrations decreased below the limits of detection by 4 h after treatment. No overt signs of toxicity were observed in any species at the concentrations given. Tissue analysis for HI-6 and degradation products was conducted by extraction followed by ion-pair, reverse phase, HPLC chromatography. The estimated plasma half-life values were 20, 40–55, and 25–30 min for rats, dogs, and monkeys, respectively. HI-6 and the degradation products were excreted via the urine. A marked species difference in disposition was observed in that HI-6 selectively accumulated in the diaphragmatic muscle of the rat to a level 10- to 20-fold higher than the level in blood plasma, whereas in the dog and monkey, diaphragmatic concentrations were comparable with those in the plasma. Three degradation products of HI-6 were detected in the plasma of the three species. One excreted product formed spontaneously since it was also detected in buffered solutions used for abiotic stability studies. The second product, the picolinic acid analog of HI-6, appeared to be metabolically formed in vivo. A third product remains unidentified.Key words: oxime (HI-6), disposition, elimination, biotransformation, mammalian (rat, dog, monkey).
Glucoregulatory response to moderate exercise in long-term islet cell autografted dogs
Authors: Portis Andrew J. , Warnock Garth L. , Finegood Diane T. , Belcastro Angelo N. , Rajotte Ray V.
Published: April 2011

The glucoregulatory response to moderate treadmill exercise ([Formula: see text]60% maximum heart rate; 60 min at 100 m/min, 12% grade) was examined in six controls and six pancreatectomized dogs that had been normoglycemic and insulin independent for more than 1 year since autograft of isolated islets of Langerhans (Tx). There were no significant intergroup differences in plasma glucose levels during exercise, but return to baseline after exercise was delayed in Tx (p < 0.05). In Tx, the initially suppressed insulin levels rose above baseline from 30 to 60 min. Within Tx, exercise-induced levels of plasma glucagon and epinephrine were more variable than control and strongly correlated (r = 0.81, p < 0.001), perhaps indicating that the A cells within the grafted islets were regulated by circulating β-adrenergic agonists. We conclude that the isolated islets were removed from direct central control. In Tx dogs, the variable counterregulatory responses and the diminished recovery of plasma glucose after exercise indicate reliance on alternative glucoregulatory mechanisms.Key words: pancreatic transplantation, islets of Langerhans, exercise, glucose.
Sympathetically mediated hypermetabolic response to cerebral ischemia in the rat
Authors: O'shaughnessy Celestine T. , Rothwell Nancy J. , Shrewsbury-Gee Joanne
Published: April 2011

Cerebral ischemia, induced in rats by occlusion of the middle cerebral artery resulted in infarcts affecting the basal ganglia and adjacent frontoparietal cortex. Resting oxygen consumption was similar for sham-operated and ischaemic rats immediately after surgery but was elevated in the latter group (peak value 18–21 % above controls) 5–6 h post occlusion. By 24 h, these values had returned to control levels. The increase in [Formula: see text] was inhibited by injection of the β-adrenergic antagonist propranolol but was unaffected by injection of the cyclooxygenase inhibitor ibuprofen. The thermogenic activity of brown adipose tissue was assessed from in vitro binding of guanosine diphosphate to mitochondria isolated from intact and surgically denervated lobes of sham-operated and ischemic rats, 6 h after surgery. Brown adipose tissue specific guanosine diphosphate (GDP) binding was elevated by 86% in intact tissue from ischemic compared with sham-operated rats but was identical in denervated tissue from the two groups. Brown adipose tissue activity correlated with resting oxygen consumption in the ischemic group (r = 0.85, p < 0.01) but not in controls (r = –0.35, NS). Thus occlusion of the middle cerebral artery in the rat may provide a representative model for both stroke and head injury in man. It is associated with a transient increase in metabolic rate and by sympathetically mediated activation of brown adipose tissue in the rat.Key words: cerebral ischemia, rat, metabolic rate, brown adipose tissue, sympathetic nervous system.
Inhibition of Na transport by 2-chloroadenosine: dissociation from production of cyclic nucleotides
Authors: Husted Russell F. , Clancy Gerard P. , Adams-Brotherton Abigail , Stokes John B.
Published: April 2011

The adenosine analogue 2-chloroadenosine (2-CA) is often used to determine the biologic effects of adenosine because 2-CA is less susceptible to degradation than adenosine. We studied the effects of 2-CA on primary cultures of rat inner medullary collecting ducts because there is good evidence that adenosine can influence cell function through its effects on second messengers. 2-CA inhibited Na+ transport across the apical membrane and increased cAMP content of the cells. The major adenosine receptors in these cells appear to be the stimulatory (A2) type. Stimulation of cAMP by 2-CA was more potent when applied to the apical membrane than to the basolateral membrane, an effect opposite to that of vasopressin. These results imply that adenosine receptors are more numerous or more effective on the apical membrane than on the basolateral membrane. Inhibition of Na+ transport was probably not mediated by an adenosine receptor as evidenced by (i) a lack of effect of adenosine and other adenosine analogues on Na+ transport; (ii) a lack of effect of nonmetabolizable cyclic nucleotides on Na+ transport; and (iii) a clear discrepancy in the temporal course of 2-CA effects on a second messenger system (cAMP) and 2-CA inhibition of Na+ transport. Dipyridimole, an inhibitor of adenosine transport, also reduced Na+ transport. Taken together, the data suggest that 2-CA inhibits Na+ transport by interfering with adenosine transport or metabolism.Key words: cAMP, cGMP, 2-chloroadenosine, vasopressin, Na+ transport, dipyridimole, adenosine metabolism.
Calcium ions inhibit the allosteric interaction between the dihydropyridine and phenylalkylamine binding site on the voltage-gated calcium channel in heart sarcolemma but not in skeletal muscle transverse tubules
Authors: Murphy Brian J. , Tuana Balwant S.
Published: April 2011

Calcium channel blockers bind with high affinity to sites on the voltage-sensitive Ca2+ channel. Radioligand binding studies with various Ca2+ channel blockers have facilitated identification and characterization of binding sites on the channel structure. In the present study we evaluated the relationship between the binding sites for the Ca2+ channel blockers on the voltage-sensitive Ca2+ channel from rabbit heart sarcolemma and rabbit skeletal muscle transverse tubules. [3H]PN200-110 binds with high affinity to a single population of sites on the voltage-sensitive Ca2+ channel in both rabbit heart sarcolemma and skeletal muscle transverse tubules. [3H]PN200-110 binding was not affected by added Ca2+ whereas EGTA and EDTA noncompetitively inhibited binding in both types of membrane preparations. EDTA was a more potent inhibitor of [3H]PN200-110 binding than EGTA. Diltiazem stimulates the binding of [3H]PN200-110 in a temperature-sensitive manner. Verapamil inhibited binding of [3H]PN200-110 to both types of membrane preparations in a negative manner, although this effect was of a complex nature in skeletal muscle transverse tubules. The negative effect of verapamil on [3H]PN200-110 binding in cardiac muscle was completely reversed by Ca2+. On the other hand, Ca2+ was without effect on the negative cooperativity seen between verapamil and [3H]PN200-110 binding in skeletal muscle transverse tubules. Since Ca2+ did not affect [3H]PN200-110 binding to membranes, we would like to suggest that Ca2+ is modulating the negative effect of verapamil on [3H]PN200-110 binding through a distinct Ca2+ binding site. The differential effect of Ca2+ on the negative cooperativity between verapamil and [3H]PN200-110 binding in rabbit heart and skeletal muscle membrane may reflect molecular and functional differences between voltage-sensitive Ca2+ channels in these two types of tissue.Key words: Ca2+ channel, sarcolemma, calcium channel blockers.
Suppression of gill withdrawal reflex behaviours in Aplysia: the role of acetylcholine
Authors: Cawthorpe David , Lukowiak Ken
Published: April 2011

Acetylcholine (ACh) dissolved in seawater and perfused through the isolated gill of the Aplysia californica produced suppression of the gill withdrawal reflex (GWR) evoked by tactile stimulation of the gill. This suppression was reversible upon washout and was blocked by co-perfusion of curare and α-bungarotoxin. Co-perfusion of atropine did not block the suppression of the GWR produced by ACh. We concluded that the suppressive effects produced by perfusion of ACh through the gill occur as a result of the action of ACh at the nicotinic-like receptors. The role of ACh suppression in the mediation of gill reflex behaviours is discussed.Key words: Aplysia, gill withdrawal reflex, suppression, acetylcholine.
Modulation by β-adrenoceptors and angiotensin II receptors of splanchnic nerve evoked catecholamine release from the adrenal medulla
Authors: Foucart Sylvain , Champlain Jacques de , Nadeau Réginald
Published: April 2011

In the present study, we have evaluated the effect of both facilitatory β2-adrenoceptor and angiotensin II receptor on the release of adrenal catecholamines induced by electrical stimulation of the splanchnic nerve in anaesthetized and vagotomized dog. In these experiments, individual or combined treatments with the β2-adrenoceptor antagonist ICI 118551 (0.3 mg/kg i.v.), the converting enzyme inhibitor captopril (2 mg/kg i.v.), or the angiotensin II receptor antagonist saralasin (2 μg∙kg−1∙min−1 i.v.) were found to significantly decrease the release of adrenal catecholamines during splanchnic nerve stimulation (5-V pulses of 2 ms duration for 3 min at 1 Hz) whatever the order of administration of the drugs. On the other hand, the infusion of angiotensin II (20 ng∙kg−1∙min−1) was shown to potentiate the release of adrenal catecholamines in response to electrical stimulation, and this effect was totally blocked by treatment with saralasin (4 μg kg−1∙min−1 i.v.). This facilitating angiotensin mechanism differed from β-adrenoceptor facilitating mechanism, since following β-blockade with ICI 118551, angiotensin II infusion still significantly potentiated the release of catecholamines during splanchnic nerve stimulation. These observations thus suggest that both facilitating β2-adrenoceptors and angiotensin II receptors can independently modulate the release of adrenal catecholamines.Key words: adrenal catecholamines, β2-adrenoceptors, angiotensin II receptors, adrenal medulla, facilitating sympathetic mechanisms, receptor interactions.