bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of nitrovasodilator- and acetylcholine-induced relaxation and cyclic GMP accumulation by the cytochrome P-450 substrate, 7-ethoxyresorufin
Authors: Bennett Brian M. , McDonald Bernard J. , Nigam Rita , Long Patrick G. , Simon W. Craig
Published: April 2011

We examined the effect of the cytochrome P-450 substrate, 7-ethoxyresorufin (7-ER), and its corresponding product, resorufin, on nitrovasodilator- and endothelium-dependent relaxation of isolated rat aorta. The EC50 value for glyceryl trinitrate (GTN) induced relaxation was increased over 100-fold by 7-ER and less than 3-fold by resorufin. The EC50 value for sodium nitroprusside (SNP) induced relaxation was increased approximately 12-fold by 7-ER, acetylcholine (ACh) induced relaxation was abolished, and relaxation induced by isopropylnorepinephrine was not significantly affected. GTN-, SNP-, and ACh-induced increases in cyclic GMP accumulation were inhibited by 7-ER, as were basal cyclic GMP levels in endothelium-intact, but not endothelium-denuded tissues. 7-ER decreased GTN biotransformation in intact aorta and decreased the regioselective formation of glyceryl-1,2-dinitrate. The activation by GTN and SNP of aortic guanylyl cyclase in broken cell preparations was not affected by 7-ER, indicating that the inhibitory effect of 7-ER is probably not due to a direct interaction with guanylyl cyclase. The inhibitory effect of 7-ER on GTN-induced relaxation was not altered by the addition of superoxide dismutase, suggesting that 7-ER does not act by increasing superoxide anion concentration (which would serve to increase the degradation of nitric oxide (NO) formed during vascular GTN biotransformation). Our data provide further evidence for the role of the cytochrome P-450 – cytochrome P-450 reductase system in the biotransformation of GTN to an activator (presumably nitric oxide) of guanylyl cyclase. The data are consistent with a mode of action of 7-ER involving either competitive inhibition of vascular cytochrome P-450 or uncoupling of vascular cytochrome P-450 reductase from cytochrome P-450. The data also suggest that the cytochrome P-450 system facilitates NO release from SNP and that 7-ER has an inhibitory effect on endothelial nitric oxide synthase.Key words: glyceryl trinitrate, nitrovasodilators, cytochrome P-450, vascular smooth muscle, 7-ethoxyresorufin, endothelium, cyclic GMP.
Blood pressure and heart rate response to vasoactive agents in conscious diabetic rats
Authors: Yu Zhen , McNeill John H.
Published: April 2011

Blood pressure and heart rate responses to different vasoactive agents were observed in conscious streptozotocin-diabetic rats. An indwelling femoral artery catheter was used for direct measurement of arterial pressure and heart rate. The femoral vein was cannulated for drug administration. In a resting state diabetic rats showed lower heart rates and lower systolic blood pressure. The vasodepressor response to both acetylcholine and sodium nitroprasside was decreased, while the heart rate increase induced by the baroreceptor reflex was not altered. Both the increase in blood pressure and the reflex bradycardia to norepinephrine were decreased in the diabetic group. When the change in heart rate was plotted against blood pressure in response to norepinephrine, there was no difference in the two groups of animals. The vasodepressor response to isoproterenol, hydralazine, and verapamil in diabetic rats was unchanged. The results demonstrate a decreased vascular responsiveness in diabetic rats to norepinephrine, acetylcholine, and nitroprusside. The diabetes-induced vascular system changes require further study to understand the mechanisms involved.Key words: diabetes, blood pressure, acetylcholine, sodium nitroprusside, norepinephrine, isoproterenol, hydralazine, verapamil.
Changes in blood flow distribution during the perinatal period in fetal sheep and lambs
Authors: Bendeck Michelle P. , Langille B. Lowell
Published: April 2011

We have measured total blood flows and blood flows per 100 g tissue to major tissues at 120 and 140 days gestation in fetal sheep and at 3 and 21 days of age in lambs (gestation period = 144 ± 2 days). Between 120 and 140 days gestation, flow per 100 g tissue increased by 74, 150, and 317% in the renal, intestinal, and hepatic arterial beds, but no further significant change in flow was observed at 3 or 21 days postpartum. Blood flows per 100 g to cerebral hemispheres and cerebellar tissues also increased dramatically during late gestation (142 and 121%, respectively), but declined sharply by 3 days postpartum (73 and 75%, respectively). Brain blood flows at 21 days postpartum remained substantially below late gestational levels. Adrenal blood flows per 100 g more than doubled during late gestation, fell by more than half at birth, and only partially recovered by 21 days of age. Blood flows to carcass tissues did not change in late gestation, fell at birth, then partially recovered. Pre- and post-natal increases in brain blood flows were almost entirely attributable to increased perfusion rather than tissue growth, whereas large perinatal increases in flow to the diaphragm paralleled tissue growth. Tissue growth and increased perfusion per 100 g contributed almost equally to increased blood flows to kidneys postnatally, and to adrenal glands and the gastrointestinal tract prenatally.Key words: blood flow, perinatal, birth, fetus, sheep.
Dose-dependent, mechanism-based inactivation of cytochrome P450 monooxygenases in vivo by 1-aminobenzotriazole in liver, lung, and kidney of untreated, phenobarbital-treated, and β-naphthoflavone-treated guinea pigs
Authors: Knickle Leah C. , Bend John R.
Published: April 2011

The mechanism-based inactivation of the cytochrome P450 (P450) dependent monooxygenase system was studied in vivo in liver, lung, and kidney of untreated, phenobarbital-treated, and β-naphthoflavone-treated guinea pigs 24 h after administration of 1-aminobenzotriazole (1 – 100 mg/kg, i.p.). Microsomal isozyme-selective or -specific monooxygenase activities were inhibited in a dose-dependent manner in all three organs. In the liver of untreated and phenobarbital-treated animals, 7-pentoxyresorufin O-depentylation (catalyzed primarily by P450 2Bx, an orthologue of rabbit P450 2B4/rat 2B1) was inhibited more than 7-ethoxyresorufin O-deethylation (P450 1A1), 4-aminobiphenyl N-hydroxylation (P450 1A2), erythromycin N-demefhylation (P450 3A), or benzphetamine N-demethylation; in β-naphthoflavone-treated animals, 4-aminobiphenyl N-hydroxylation activity was preferentially inhibited. In lung, the order of inactivation of monooxygenase activities was 4-aminobiphenyl N-hydroxylation (4Bx, the orthologue of rabbit 4B1) > 7-pentoxyresorufin O-depentylation activity (2Bx) > 7-ethoxyresorufin O-deethylation (1A1; for example 72, 53, and 29% inactivation, respectively, in phenobarbital-treated animals at 100 mg/kg). In all three tissues the loss in spectrally assayed P450 content corresponds quite well to the inhibition of monooxygenase activities. Thus, these studies show that 1-aminobenzotriazole is an effective inactivator of the pulmonary, hepatic, and renal P450 systems in guinea pigs following i.p. administration, and that P450 1A2 (liver) and P450 4Bx (lung), isozymes efficient for the oxidation of primary aromatic amines, are preferentially inactivated.Key words: cytochrome P450, 1-aminobenzotriazole, mechanism-based inhibition, lung, liver.
Nucleotide requirement and effects of fatty acids on protein synthesis and degradation in brown adipose tissue mitochondria
Authors: Desautels M. , Dulos R. A.
Published: April 2011

The objective of this work was to evaluate whether changes in respiratory status of isolated brown-fat mitochondria influence synthesis and degradation of proteins within the organelles. Mitochondrial protein synthesis is subject to regulation, as a 24-h fast in mice reduced [35S]methionine incorporation without affecting the stability of the newly synthesized proteins. Proteins synthesized in isolated mitochondria were labile and degraded in a process stimulated by ATP. ATP hydrolysis was required within the organelle, as ATP-stimulated protein breakdown was inhibited by atractyloside, an inhibitor of adenine nucleotide transport, and by arsenate and vanadate, which inhibit ATPases. Additions of ATP and ADP were equally effective at reducing mitochondrial oxygen consumption. However, ATP added exogenously was better at supporting protein synthesis and degradation than ATP generated by oxidative phosphorylation when mitochondria were incubated with ADP, substrates, and Pi. GDP also reduced oxygen consumption and stimulated degradation of mitochondrial translation products. Addition of fatty acids in the presence or absence of carnitine–CoA increased mitochondrial respiration but had no effect on protein synthesis or degradation. Addition of carbonyl cyanide m-chlorophenylhydrazone (mCCP) had no effect on ATP-stimulated protein degradation. These results indicate that synthesis and stability of mitochondrial translation products are not significantly influenced by changes in the activity of the uncoupling protein brought about by additions of adenine nucleotides and fatty acids.Key words: mitochondrial biogenesis, bioenergetics, ATP-dependent proteolysis, body weight regulation, thermoregulation, uncoupling protein.
Intracellular calcium disruption as a secondary event in acetaminophen-induced hepatotoxicity
Authors: Grewal Kuldip K. , Racz William J.
Published: April 2011

To examine a role for disturbances in intracellular calcium homeostasis in acetaminophen-induced hepatotoxicity, freshly isolated mouse hepatocytes were incubated with 1.0 mM acetaminophen for 1.5 h to allow for covalent binding and initiation of cell damage. The hepatocytes were then washed and the cells incubated in fresh medium containing either 2.0 mM N-acetylcysteine or 1.5 mM dithiothreitol for the duration of a 4-h incubation period. These agents were used as tools in the elucidation of the biochemical events responsible for acetaminophen-induced cell necrosis. The reduced protein sulfhydryl content, cytosolic [Ca2+], and plasma membrane integrity were quantitated. Acetaminophen produced protein sulfhydryl depletion, an increased cytosolic [Ca2+], and cell injury; however, cytotoxicity preceded the increase in [Ca2+]. Both N-acetylcysteine and dithiothreitol restored the acetaminophen-induced protein sulfhydryl loss. Dithiothreitol prevented both further cell injury and an increase in the cytosolic [Ca2+]. However, cell death and a subsequent increase in cytosolic [Ca2+] proceeded unabated following N-acetylcysteine addition. Although both agents restored protein sulfhydryl content, in view of their contrasting ultimate effects on cell viability the role of reduced protein sulfhydryl depletion in acetaminophen-induced hepatic injury requires further investigation. The increase in cytosolic [Ca2+] with acetaminophen alone and with subsequent N-acetylcysteine addition was determined to be a secondary event in cell injury because cytotoxicity occurred by 1.5 h; however, the increase in cytosolic [Ca2+] was not observed until 2.5 h. Additional evidence for changes in cytosolic [Ca2+] as a secondary event was obtained by incubating the hepatocytes with acetaminophen in the presence of fura 2. Measurement of the fluorescent signal indicated that fura 2 effectively chelated the cytosolic Ca2+ yet did not prevent cell toxicity.Key words: acetaminophen, hepatotoxicity, N-acetylcysteine, dithiothreitol, calcium ion.
Gastric ulceration: critical events at the neutrophil–endothelium interface
Authors: Wallace John L.
Published: April 2011

Neutrophil adherence to the vascular endothelium and the subsequent release of oxygen-derived free radicals and proteolytic enzymes has been implicated as a critical event in the pathogenesis of various forms of gastrointestinal ulceration. This paper reviews the evidence that events at the neutrophil-endothelium interface are important in the pathogenesis of gastric ulceration induced by nonsteroidal anti-inflammatory drugs (NSAIDs). Endothelial injury occurs within minutes of NSAID administration and appears to be attributable to neutrophil adherence and activation. Neutrophil adherence in response to NSAIDs may occur as a consequence of inhibition of endothelial prostaglandin synthesis, but it appears to involve a lipoxygenase product, such as leukotriene B4. Prevention of neutrophil adherence to the vascular endothelium results in near-complete prevention of experimental NSAID gastropathy. Depletion of circulating neutrophils also results in reduced susceptibility to NSAID-induced mucosal injury. As prostaglandins are potent inhibitors of neutrophil adherence and activation, it is possible that the neutrophil–endothelium interface represents one of the most important targets of action of these compounds in terms of their ability to prevent or reduce the severity of NSAID-induced ulceration.Key words: ulcer, mucosal blood flow, prostaglandin, neutrophil, leukotriene.
Convergence of ventrolateral medullary and aortic baroreceptor inputs in nucleus of the solitary tract
Authors: Roder Stefanie , Ciriello John
Published: April 2011

Experiments were done in α-chloralose anesthetized rats to investigate the effect of stimulating the intermediate region of the ventrolateral medulla (VLM) on the response of single units in nucleus of the solitary tract (NTS) that altered their rate of discharge during aortic baroreceptor stimulation. Of 178 units recorded within NTS, 65 responded orthodromically to VLM stimulation. An additional 16 units were activated antidromically by VLM stimulation. The interaction between the aortic depressor nerve and VLM orthodromic inputs was investigated in 38 units that received converging inputs from VLM and the aortic depressor nerve. A conditioning stimulus applied to VLM, regardless of whether the NTS unit was excited by (n = 13) or did not respond to (n = 9) VLM stimulation, decreased the excitatory response of the unit to aortic depressor nerve stimulation. These data suggest that VLM neurons are involved in the modulation of aortic baroreceptor afferent information at the level of the NTS and that this interaction of inputs in NTS may involve both postsynaptic and presynaptic mechanisms.Key words: ventrolateral medulla, aortic depressor nerve, A1 noradrenergic cell group, C1 adrenergic cell group, baroreceptor reflex, vagal bradycardia, central regulation of circulation.
Atrial and arterial baroreceptor influences on the circulatory response to acute changes in renal perfusion
Authors: Ashton N. , Rankin A. J.
Published: April 2011

We have recently reported a neurally mediated reflex increase in hindlimb vascular resistance associated with an acute decrease in renal perfusion pressure in the chloralose–urethane-anesthetized rabbit. The present study was designed to investigate the influence of this reflex in the body's integrated response to circulatory disturbances by investigating the influence of carotid baroreceptor and left atrial receptors on this reflex and assessing the effect of acute changes in renal perfusion on the heart. Interaction of the renal-generated reflex with carotid baroreceptors was investigated by independent perfusion of the carotid sinus region. Responses in hindlimb perfusion pressure, at constant flow, to changes in renal perfusion were greatest with the carotid sinus perfusion pressure (CSP) low (27 ± 4 mmHg (1 mmHg = 133.3 Pa) increase in hindlimb pressure at low CSP vs. 19 ± 3 mmHg increase at normal CSP) and were inhibited with maximum carotid stimulation. Partial mitral obstruction, resulting in left atrial distension and atrial receptor stimulation, attenuated the hindlimb vascular response. The increase in hindlimb pressure under control conditions was 34 ± 10 mmHg compared with 20 ± 5 mmHg during atrial receptor stimulation. However, acute reduction of renal perfusion pressure did not result in any changes in heart rate, cardiac output, or inotropic state. It appears that both atrial and arterial baroreflexes modify the reflex change in hindlimb vascular resistance associated with acute alterations of renal perfusion.Key words: afferent renal nerves, baroreceptors, atrial receptors, vascular resistance.
Effect of insulin on the altered thyroid function and adrenergic responsiveness in the diabetic rat
Authors: Katovich Michael J. , Marks Kelly S. , Sninsky Charles A.
Published: April 2011

We have previously reported the tail skin temperature response to isoproterenol as being significantly attenuated in male rats 4 weeks after the induction of diabetes with streptozotocin. The current study evaluated the time course of this altered adrenergic responsiveness and the role of thyroid hormone and insulin treatment in the tail skin temperature response. In the first study, the tail skin temperature response to isoproterenol was monitored weekly, for 6 weeks. The tail skin temperature response was similar in control and diabetic animals after 1 week of streptozotocin treatment. However, after 2, 4, 5, and 6 weeks of diabetes the tail skin temperature response was significantly reduced. Total T3, T4, and free T4 concentrations were also significantly reduced in these diabetic animals. In a second study, the effects of graded doses of insulin treatment on thyroid hormone levels was assessed. The reduced thyroid hormone concentrations observed in untreated streptozotocin-diabetic rats were restored towards control levels in animals receiving the lowest dose of insulin (1 U/day), whereas higher doses of insulin were required to more closely restore euglycemia and lower glycated hemoglobin. A subsequent study, utilizing a 1-U/day dose of insulin, resulted in a normalization of the tail skin temperature response to isoproterenol, during 8 weeks of treatment in the treated diabetic rat. In a final study utilizing the spontaneous BB diabetic rat maintained on daily insulin treatment, no differences in the tail skin temperature response or thyroid hormone levels were observed. Collectively, these results suggest that treatment with doses of insulin that do not completely normalize blood glucose and glycated hemoglobin nearly restore thyroid status and reduce β-adrenergic responsiveness associated with the diabetic state.Key words: β-adrenergic responsiveness, tail skin temperature, streptozotocin, BB rat, diabetes, insulin.
Pulmonary mechanical and vascular responses after acute hyperbaric oxygen exposure
Authors: Amin Hesham M. , Cigada Marco , Hakim Tawfic S. , Camporesi Enrico M.
Published: April 2011

Pulmonary mechanical and vascular responses were studied in Sprague–Dawley rats exposed to hyperbaric oxygen (HBO, 100% O2 at 2.8 atm (1 atm = 101.325 kPa) for 6 h). Two groups of animals were examined after HBO exposure: group HBO comprised rats examined immediately after exposure and group R consisted of rats left recovering while breathing air for 24 h before being studied. Both groups were compared with control rats, group C, not exposed to HBO. Pulmonary mechanical responses were measured by quantitating static lung compliance (Cs), wet to dry weight ratio (W/D) of lung tissue, and surface tension (ST) of broncho-alveolar lavage as a measurement of lung surfactant. Cs and W/D did not change significantly after exposure to HBO. ST was slightly lower in group R compared with group C (18.46 ± 1.46 vs. 22.47 ± 0.91 dynes/cm (1 dyne = 10 μN); p < 0.05). The effects of HBO on the pulmonary vasculature were studied in an isolated perfused lung preparation. Pulmonary vascular responses to hypoxia were recorded repeatedly over a period of 1 h. The percent increase in pulmonary vascular resistance (PVR) with hypoxia was blunted in group HBO and returned to the normal level in group R (8.2 ± 2.4% in group HBO vs. 44.2 ± 7.2% in group C and 42.9 ± 11.2% in group R; p < 0.001). In a subgroup of rats, to assess the vascular smooth muscle contractility, 0.1 mL of KCl (15 mmol/L) was added to the perfusate and the pulmonary vascular responses were also recorded. The vascular response to KCl was less in group R (86.6 ± 10.1% in R vs. 162.6 ± 12.2% in C and 179.0 ± 23.2% in HBO; p < 0.01). Our study shows that acute HBO exposure induces only minor pulmonary mechanical changes, while pulmonary vascular responses are markedly altered.Key words: hyperbaric oxygen, oxygen toxicity, lung mechanics, surfactant, pulmonary vasculature.
Comparison of core threshold temperatures for forehead sweating based on esophageal and rectal temperatures
Authors: White Matthew D. , Mekjavić Igor B.
Published: April 2011

A protocol incorporating successive hot and cold water immersions, causing respective warming and cooling of the body, has been used to determine the core threshold for sweating. Disparate results have been reported for the core threshold of sweating, and these have been attributed to the possible existence of core temperature gradients during such a protocol. Spatial and temporal core temperature (Tc, °C) gradients during dynamic changes in body temperature may give rise to different values of core temperature thresholds for sweating, depending on the Tc measurement site. In addition, during such an immersion protocol skin temperature transients may influence expression of thresholds using esophageal temperature (Tes). With these considerations, the effects of Tc gradients and skin temperature on Tc thresholds for sweating were examined. Subjects (n = 22) were immersed to the neck in 40 °C water until Tes reached 38.5 °C (phase 1), followed immediately by cooling in 30.6 °C water until extinction of sweating was observed (phase 2). Cooling was continued in the latter bath after the sweating extinction until total immersed time reached 50 min or until shivering was initiated (phase 3). During the trials continuous assessment was made of rectal temperature (Tre) and Tes, mean unweighted skin temperature (Tsk, °C), forehead sweating rate ([Formula: see text], g∙m−2∙min−1) oxygen consumption ([Formula: see text], L∙min−1), and surface heat flux ([Formula: see text], W∙min−2). With the current protocol it appeared inappropriate to determine the Tc thresholds for onset of sweating, as sweating was initiated prior to any significant displacement of Tc, but was most likely influenced by Tsk and its rate of change. During the transfer to the 30.6 °C bath Tes followed a similar profile and rate of response as Tsk, suggesting it was affected by transient Tsk changes, whereas the rate of Tre response was significantly different than rates of skin and esophageal temperatures. Significantly different rates of Tes and Tre gave Tc gradients during such a protocol and it is concluded that this may confound determination of Tc thresholds using such a protocol.Key words: temperature regulation, hypothermia, hyperthermia, water immersion.
Whole-cell Cl− currents in a human peripheral airway epithelial cell line
Authors: Wang Xiaodong , Fedorko Ludwik , Marunaka Yoshinori , O'Brodovich Hugh
Published: April 2011

We have used the whole-cell patch-clamp technique to identify and characterize Cl− currents in a cell line derived from human peripheral airway epithelium (NCI-H-441-4). The permeability sequence and relative selectivity for different anions was Br− (1.4) ~ I− (1.3) > Cl− (1.0) > F− (0.6) > gluconate (0.4) > glutamate (0.2). The current–voltage relationship displayed rectification in the outward direction. Diphenylamine-2-carboxylate (10−4 M) applied intracellularly blocked the outward-rectified current, while extracellularly applied diphenylamine-2-carboxylate had no effect on Cl− current. This current was also blocked by extracellularly applied 5-nitro-2-(3-phenylpropylamino)benzoate (NPPB), with an estimated IC50 of 15.2 μM. Dibutyryl-cyclic AMP (10−4 M) increased outward current, whereas pretreatment with 100 ng/mL pertussis toxin almost completely abolished the Cl− current. Pertussis toxin inhibition of this current could be partially reversed by dialysis of the cell interior with the activated αi–2 subunit of Gi protein. This cell line provides an opportunity to study directly the regulation of Cl− channels in cells derived from the peripheral human lung airways.Key words: chloride secretion, whole-cell patch clamp, GTP binding protein, cyclic AMP, pertussis toxins, 5-nitro-2-(3-phenylpropylamino)benzoate, diphenylamine-2-carboxylate, cell line H441.
Fatty Acids: Evolution in Relation to Neurobiology
Authors: Clandinin M. T.
Published: April 2011

Metabolism of long-chain polyunsaturated fatty acids derived from 18:2ω−6 and 18:3ω−3 by chain elongation – desaturation is essential for synthesis of complex structural lipids, leukotrienes, thromboxanes, and prostaglandins. These essential fatty acids are required for normal function in developing tissues and appropriate maturation of a wide variety of physiological processes. During development, fetal accretion of long-chain metabolites of ω−6 and ω−3 fatty acids may result from maternal or placental synthesis and transfer or, alternatively, from the metabolism of 18:2ω−6 and 18:3ω−3 to longer chain homologues by the fetus. After birth the infant must synthesize or be fed the very long chain polyunsaturated fatty acids of C20 and C22 type derived from 18:2ω−6 and 18:3ω−3.Metabolism of ω−6 and ω−3 fatty acids utilizes the same enzyme system and is competitive. When levels of dietary ω−3 and ω−6 C18 fatty acids are altered, the levels of metabolites of these precursor fatty acids change in specific brain membranes, influencing membrane lipid dependent functions. For example, a diet unbalanced in very long chain ω−3 and ω−6 fatty acids may increase brain membrane ω−3 fatty acid content when 20:5ω−3 is fed, while decreasing membrane fatty acid content of the ω−6 series of competing fatty acids. As 20:4ω−6 is quantitatively and qualitatively important to brain phospholipid, significant reduction in brain levels of 20:4ω−6 may be less than optimal. The impact of these compositional changes on brain function is not yet clear.The authors in this symposium address how this general area of essential fatty acid metabolism is relevant to the evolution of man, growth and development of fish, function of the retina and neural tissue, cognitive development of infants, and infant nutrition.
Chronic leukotriene inhibition in the rat fails to modify the toxicological effects of a cyclooxygenase inhibitor
Authors: Ford-Hutchinson A. W. , Tagari P. , Ching S. V. , Anderson C. A. , Coleman J. B. , Peter C. P.
Published: April 2011

A 5-week study was carried out in rats using a leukotriene biosynthesis inhibitor (MK-886; 3-[1-(4-chlorobenzyl)-3-t-butylthio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid) at a dose of 300 mg∙kg−1∙day−1, this being sufficient to produce > 90% inhibition of ex vivo leukotriene B4 synthesis in rat blood, and a cyclooxygenase inhibitor (indomethacin, 4 and 6 mg∙kg−1∙day−1) to ascertain whether inhibition of leukotriene biosynthesis would potentiate or inhibit the toxicity associated with the administration of nonsteroidal anti-inflammatory drugs (NSAIDs), in particular the gastrointestinal damage. Treatment with indomethacin alone or in combination with MK-886 resulted in the toxicity normally associated with NSAIDs, including gastrointestinal lesions. No toxicity was associated with the administration of MK-886 alone, and MK-886 had no significant effect on the incidence of gastrointestinal lesions produced by indomethacin. These results indicate that leukotrienes are not significant mediators of NSAID-induced gastroenteropathy in the rat.Key words: nonsteroidal anti-inflammatory drugs, gastric damage, gastropathy, leukotrienes, prostaglandins.
Effect of increases in myocardial epinephrine content on epinephrine release from the dog heart
Authors: Péronnet F. , Boudreau G. , Champlain J. de , Nadeau R. A.
Published: April 2011

The effect of short-term (10 min) and prolonged (180 min) epinephrine (E) infusion (92.5 ng∙kg−1∙min−1) on E content of the myocardium and on the subsequent release of E from the heart during stimulation of the left stellate ganglion (4 and 10 Hz, 4 V, 2 ms, 1 min) was studied in anesthetized dogs. The E content in the free wall of the left ventricle significantly increased 1.7- and 4.2-fold following short-term and prolonged E infusion, respectively, compared with a control group infused with saline. Tissue norepinephrine (NE) content was not modified by E infusion. The plasma E concentration gradient across the heart indicated a significant release of E during electrical stimulation of the left stellate ganglion, which was related to the amount of E stored in the tissue (e.g., control, 126 ± 60; 10-min infusion, 279 ± 105; 180-min infusion, 1487 ± 287 pg∙mL−1; at 10 Hz). NE release from the heart also tended to increase with the amount of E stored in the myocardium and released upon electrical stimulation of the left stellate ganglion, although the difference did not reach statistical significance. These results provide further direct evidence that blood-borne E can be taken up and stored in sympathetic nerve endings and can be released as a cotransmitter with NE. Locally released E could favor NE release.Key words: norepinephrine, sympathetic system, neuronal uptake, desipramine, cotransmitter, β2 facilitation.
Effect of adrenal demedullation and (or) physical training on glucose tolerance in the rat
Authors: Jean Christine , Tancrède Gilles , Nadeau André
Published: April 2011

Physical training increases insulin sensitivity by mechanisms not yet fully understood. Because exercise also modulates adrenergic system activity, the present study was designed to ascertain whether the improved glucose homeostasis observed in trained rats is influenced by epinephrine secretion from the adrenal medullae. Male Wistar rats previously submitted to adrenal demedullation or sham operated were kept sedentary or trained on a treadmill over a 10-week period. An intravenous glucose tolerance test (IVGTT) was done 64 h after the last bout of exercise. Basal plasma glucose levels were reduced by physical training (p < 0.005) and by adrenal demedullation (p < 0.001). Adrenodemedullated rats had lower (p < 0.005) plasma glucose levels than sham-operated animals over the whole glucose tolerance curve. Trained animals had lower (p < 0.01) plasma glucose levels than sedentary rats throughout the IVGTT, except at 45 min. The glucose disappearance rate measured after the glucose bolus injection was increased by training (p < 0.05), whereas it was not modified by adrenal demedullation. Basal plasma insulin levels were reduced (p < 0.001) by physical training but unaffected by adrenal demedullation. During the IVGTT, adrenodemedullated rats had higher (p < 0.01) plasma insulin levels at 2, 4, and 6 min, whereas trained animals had lower (p < 0.05) plasma insulin levels throughout the test. Moreover, insulin in adrenodemedullated and trained rats had returned to basal levels at 30 min. The area under the curve for insulin was diminished by physical training (p < 0.001) but was not modified by adrenal demedullation. In the basal state and during the IVGTT, the sedentary adrenodemedullated rats had higher (p < 0.05) plasma glucagon levels compared with the other groups of animals. Pancreatic insulin content was not modified by adrenal demedullation but was diminished (p < 0.01) by physical training. The pancreatic glucagon content was not altered by adrenal demedullation or physical training. Because adrenal demedullation abolished the exercise-induced increase in epinephrine secretion, the results of the present study suggest that the enhanced insulin sensitivity induced by physical training is not caused by an increase in epinephrine secretion from the adrenal medullae.Key words: adrenal demedullation, physical training, glucose tolerance, insulin sensitivity, catecholamines.
Myocardial energetics and blood flow in acute rapid ventricular pacing
Authors: Simmons William W. , Moe Gordon W. , Grima Etienne A. , Howard Robert J. , Armstrong Paul W.
Published: April 2011

The mechanism whereby chronic rapid ventricular pacing induces severe heart failure is unclear, but the phenomenon is associated with a reduction in left ventricular ATP levels. Accordingly, the current study was undertaken to evaluate the acute effects of rapid ventricular pacing on hemodynamics, left ventricular adenine nucleotide levels, myocardial blood flow, and oxygen consumption. Anesthetized dogs (n = 7) were studied in sinus rhythm and during 30 min of pacing at 250 beats/min. Pacing caused a significant (means ± SD, all p < 0.001) decrease in cardiac output (3.0 ± 0.6 to 2.0 ± 0.6 L/min) and peak left ventricular systolic pressure (133 ± 14 to 82 ± 10 mmHg (1 mmHg = 133.3 Pa)) and an increase in pulmonary wedge pressure (10 ± 2 to 18 ± 3 mmHg). Following pacing, the peak first derivative of left ventricular pressure and the relaxation time constant, τ, remained unchanged compared with baseline values. Myocardial blood flow and oxygen consumption both increased by 70% with pacing. The transmural distribution of myocardial blood flow and myocardial lactate consumption remained unchanged. There was no change in left ventricular ATP or ADP levels with the observed increase in myocardial oxygen consumption. Therefore, the hemodynamic deterioration associated with acute rapid ventricular pacing, in contrast to that of chronic pacing, is not associated with perturbed myocardial energetics.Key words: canine, ventricular pacing, ATP, ADP, myocardial blood flow, ventricular function.
Stretching releases Ca2+ from intracellular storage sites in canine cerebral arteries
Authors: Tanaka Yoshio , Hata Shinzo , Ishiro Hiromi , Ishii Kunio , Nakayama Koichi
Published: April 2011

Mechanical stretch applied to canine cerebral artery produced myogenic contraction. The contraction of the artery in response to quick stretch was dependent on not only the transmembrane influx of Ca2+ through 1,4-dihydropyridine-sensitive Ca2+ channels but also the release of Ca2+ from intracellular storage sites: the stretch-produced contractile component that was resistant to 0.1 μM nicardipine, a Ca2+-channel antagonist, was inhibited by about 50% after treatment with ryanodine, and was almost completely suppressed by 0.1 mM 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate, a putative phospholipase C inhibitor, or by lowering the temperature from 35 to 20 °C. The results suggest that in addition to transmembrane influx of Ca2+ through L-type Ca2+ channels, the release of Ca2+ from both ryanodine-sensitive and -insensitive intracellular storage sites, which increases intracellular Ca2+, accounts for the stretch-induced contraction of canine basilar artery. It seems also possible that inositol 1,4,5-trisphosphate is a common mediator for the release of Ca2+ from both types of intracellular storage sites.Key words: stretch-induced contraction, cerebral artery, phospholipase C, ryanodine, Ca2+ storage sites, inositol 1,4,5-trisphosphate, Ca2+ release, Ca2+-channel antagonist.
Studies on the action of interleukin-1 on term human fetal membranes and decidua
Authors: Alnaif B. , Benzie R. J. , Gibb W.
Published: April 2011

Recent studies have indicated the possible importance of cytokines in the onset of term and preterm labor. To examine this further, the effect of interleukin-1β (IL-1β), interleukin-1α (IL-1α), and interleukin-6 (IL-6) on prostaglandin output by dispersed cells from human amnion, chorion laeve, and decidua obtained at term (38–40 weeks gestation) was examined. During the first or second 24 h of culture no significant effect of these interleukins on prostaglandin output was observed. The reason for this apparent refractoriness was further investigated by studying the distribution of IL-1 receptors in frozen sections of undisrupted fetal membranes and decidua at term. Whole-tissue autoradiography indicated that receptors were present in chorion–decidua but not in amnion. By using emulsion autoradiography, IL-1 receptors were found in high concentrations in chorion laeve and were absent in amnion and at low levels in the decidua. These studies indicate that under normal circumstances in human pregnancy at term IL-1 did not stimulate prostaglandin production by dispersed cells. In the case of amnion, this may be due to the absence of receptors, and therefore it would appear that the IL-1 receptor must first be induced in this tissue before it can respond to this cytokine. Furthermore, although chorion laeve expresses the IL-1 receptor, dispersed cells from this tissue did not respond to the cytokine by increasing prostaglandin output.Key words: labor, prostaglandins, interleukin-1, interleukin-1 receptor, fetal membranes, decidua.
Calcium-sensitive potassium current in isolated canine coronary smooth muscle cells
Authors: Buljubasic N. , Marijic J. , Kampine J. P. , Bosnjak Z. J.
Published: April 2011

This study characterizes K+ current in canine coronary artery and investigates its role in regulation of vascular smooth muscle tone during the resting and activated state. Isolated rings and whole-cell K+ current as well as single K+ channels were studied. Tetraethylammonium (<3 mM) did not increase the resting tension in isolated rings; however, 0.3 mM tetraethylammonium increased tension in vessels that were precontracted by elevated [K+]o or 5-hydroxytryptamine (5-HT). The whole-cell K+ current showed voltage and Ca2+ dependency and sensitivity to tetraethylammonium (31 ± 7, 72 ± 2, and 83 ± 4% depression by 1, 10, and 30 mM tetraethylammonium, respectively). A large-conductance (100 pS) K+ channel was identified in cell-attached patches with open-time distribution fitted with two exponentials. Calcium ionophore A23187 (10 μM) increased the probability of opening, mean open time, and amplitude of this channel in cell-attached patches, suggesting Ca2+ dependency. A23187 shifted the plot of unitary current as a function of pipette potential to the right, suggesting A23187-induced cell hyperpolarization. In inside-out patches, increase in cytoplasmic-side [Ca2+] from 10−7 to 10−6 M increased both the frequency of channel opening and duration of the open state, without changing its conductance. Tetraethylammonium (1 mM) on the cytoplasmic side caused a reversible decrease in the current amplitude. Charybdotoxin (100 nM) decreased the probability of opening and mean open time and increased mean closed time, while apamin (100 nM) did not significantly affect channel kinetics. In summary, this study demonstrates the existence and important functional role of a large-conductance, Ca2+-sensitive K+ channel in regulation of membrane potential and cell excitability, as well as some aspects of regulation and kinetics of this channel in canine coronary arterial cells.Key words: coronary arteries, potassium current, single channels.
Nutrition and ontogenetic development of the intestine
Authors: Buddington Randal K.
Published: April 2011

Fetal, suckling, and postweaning vertebrates have distinct dietary inputs that impose different functional demands on the developing intestine. Differences between species and life-history stages in intestinal structure and functions are set by genetic determinants that reflect evolutionary diets. Dietary inputs interacting with genetic determinants influence intestinal functions by triggering the production of new enterocyte populations and (or) by reprogramming existing enterocytes. In addition to nutrients, nonnutritive components of amniotic fluid and milk, such as growth factors and hormones, are important mediators of intestinal development and in humans can exert influences at as early as 10 weeks of gestation, when fetuses begin swallowing amniotic fluid. Changes in diet composition during suckling elicit limited and apparently nonspecific responses in intestinal structure and activities of brush-border hydrolases and transporters. The ability to adaptively modulate intestinal brush-border functions develops at weaning, when diet composition begins to vary unpredictably. Hydrolytic and transport capacities of the developing intestine are matched to age-related increases in dietary inputs, are not in great excess, and may be growth limiting. Although not as extensively studied, postnatal diet also influences development of intestinal endocrine and immune functions and has a complex, poorly understood interaction with the developing microflora.Key words: nutrition, intestine, development, diet, vertebrates.
Nonadrenergic mechanisms of cocaine-induced regional vascular responses in rats
Authors: Knuepfer Mark M. , Branch Carrie A. , Wehner David M. , Gan Qi , Hoang Dung
Published: April 2011

The pressor response to cocaine is a consequence of mesenteric vasoconstriction and hindquarters vasodilation as a result of activation of α1- and β-adrenergic receptors, respectively. In the present study, evidence for additional, nonadrenergic effects of cocaine-induced changes in regional blood flow was obtained using pulsed Doppler flowmetry in conscious rats. Cocaine produced dose-dependent initial peaks (within 1 min) in mean arterial pressure concomitant with an increase in hindquarters and mesenteric vascular resistance. The sustained, modest pressor response was associated with hindquarters vasodilation and bradycardia. The cocaine-induced vasodilation was enhanced by pretreatment with indomethacin (5 mg/kg), prevented by ibuprofen (12.5 mg/kg) or 3-amino-1-[m-(trifluoromethyl)-phenyl]-2-pyrazoline (BW755C, 10.5 mg/kg) pretreatment, and unaffected by meclofenamate administration (2.5 mg/kg). Equipotent local anesthetic doses of procaine produced equivalent hindquarters vasodilator responses and more modest pressor responses. Dial–urethane anesthesia did not affect hindquarters vasodilation in response to cocaine or procaine but did reduce the mesenteric vasoconstrictor and pressor responses. These data demonstrate that the cocaine-induced hindquarters vasodilation is not mediated solely by β-adrenergic receptors but is also dependent upon eicosanoids. Furthermore, the cocaine-induced vasodilation may be due, in part, to a direct local anesthetic effect but is not dependent upon a locomotor or behavioral stress induced increase in blood flow.Key words: anesthesia, eicosanoids, arterial pressure, hindquarters and mesenteric vascular resistances, pulsed Doppler flowmetry.
Characterization of perfused periaortic brown adipose tissue from the rat
Authors: Matthias Anita , Richards Stephen M. , Dora Kim A. , Clark Michael G. , Colquhoun Eric Q.
Published: April 2011

A technique was developed for the perfusion of periaortic brown adipose tissue (BAT) with a view to assessing vascular system involvement in BAT thermogenesis. The procedure involved cannulation of the thoracic aorta and ligation of the intercostal branches and the distal thoracic aorta. Perfusion was conducted in a buffer-filled chamber using constant flow at 37 °C. Lactate dehydrogenase leakage was less than 2%/h, and after 30 min of perfusion the energy charge was 0.72 ± 0.05 (n = 4) and differed little from freshly sampled interscapular BAT (0.71 ± 0.03 (n = 7)). Periaortic BAT was indistinguishable from interscapular BAT in enzyme content, mitochondrial size, mitochondrial cristae, lipid content, and cell size. Basal oxygen consumption [Formula: see text] was 64.3 ± 7.4 μmol∙h−1∙g−1 wet weight, and basal perfusion pressure was 65 ± 3 mmHg (1 mmHg = 133.3 Pa). Norepinephrine and isoproterenol each increased [Formula: see text] of perfused periaortic BAT in a time-dependent and reversible manner. Half-maximal stimulation of [Formula: see text] occurred at 12 nM norepinephrine and 8 nM isoproterenol; maximally stimulated tissue had a [Formula: see text] of approximately 150 μmol∙h−1∙g−1 wet weight. Norepinephrine (50 nM) had no consistent effect on perfusion pressure, but the increase in [Formula: see text] by this agonist was completely blocked by 10 μM DL-propranolol and unaffected by phentolamine (1–20 μM) or nitroprusside (0.01–1 mM). Increasing the perfusion flow rate increased pressure and had no effect on basal [Formula: see text] but increased the [Formula: see text] response due to norepinephrine. Several observations suggest that vascular thermogenesis and (or) vascular control of BAT thermogenesis were minimal in constant flow perfused periaortic BAT. These include (i) the failure of norepinephrine to consistently cause vasoconstriction or vasodilation in association with an increase in [Formula: see text]; (ii) isoproterenol-mediated increase in [Formula: see text]; (iii) the failure of increased flow to increase basal [Formula: see text]; (iv) the failure of nitroprusside or phentolamine to inhibit norepinephrine mediated increase in [Formula: see text]; and (v) the complete inhibition by propranolol of the norepinephrine- or isoproterenol-mediated increase in [Formula: see text]. Finally, the present findings provide no evidence for the presence of an α-adrenergic mechanism to control BAT thermogenesis directly, or indirectly by alterations in flow.Key words: brown adipose tissue, perfusion, thermogenesis, oxygen consumption, norepinephrine, isoproterenol.
Mechanisms underlying the modulation of arrhythmogenic events by components of ischemia in guinea pig cardiac myocytes
Authors: Liu Qi-Ying , Vassalle Mario
Published: April 2011

The effects of some components of ischemia on the oscillatory (Vos) and nonoscillatory (Vex) potentials and respective currents (Ios and Iex), as well as their mechanisms, were studied in guinea pig isolated ventricular myocytes by means of a single-microelectrode, discontinuous voltage clamp method. Repetitive activations induced not only Vos and Ios, but also Vex and Iex. A small decrease in resting potential caused an immediate increase in Vos followed by a gradual increase due to the longer action potential. Immediate and gradual increases in Ios also occurred during voltage clamp steps. A small depolarization increased Vos and Vex, and facilitated the induction of spontaneous discharge by fast drive. At Vh where INa is inactivated, depolarizing steps induced larger Ios and Iex, indicating the importance of the Na-independent Ca loading. High [K]odecreased the resting potential, but also Vos, Vex, Ios, Iex, and ICa. In high [K]o, depolarization still increased Vos and Vex. Norepinephrine (NE) enhanced Vos and Vex, and also Ios and Iex, during voltage clamp steps. High [K]o antagonized NE effects, and NE those of high [K]o. In conclusion, on depolarization, Vos and Ios immediately increase through a voltage-dependent mechanism; and then Vos and Ios gradually increase, apparently through an increased Ca load related to the longer action potentials and the Na–Ca exchange. The depolarization induced by Vex may contribute to increase Vos size. Vos and Vex are similarly influenced by different procedures that modify Ca load. The arrhythmogenic events are enhanced by the simultaneous presence of depolarization, faster rate, or NE. Instead, high [K]o decreases Vos and Vex by decreasing ICa and opposes the effects of NE. The voltage clamp results show that potentiation and antagonism between different components of ischemia are due primarily to changes in Ca loading and not to changes in action potential configuration.Key words: ischemia, arrhythmias, oscillatory and nonoscillatory potentials and currents, norepinephrine, potassium.