bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of dietary cardiac glycosides on blood pressure regulation in rats
Authors: Tamura Masaaki , Utsunomiya Hirotoshi , Nakamura Misa , Landon Erwin J
Published: April 2011

To investigate the possible physiological significance of dietary cardiac glycosides in blood pressure regulation, the blood pressure of normal Sprague Dawley rats raised on a regular diet, which naturally contains large amounts of Na+-pump inhibitors, was compared with that of rats on a purified synthetic diet, which contains no Na+-pump specific inhibitors, and with that of rats on a synthetic diet supplemented with 10 µg·mL-1ouabain or 10 µg·mL-1convallatoxin in the drinking water. After 6 weeks on the synthetic diet, the systolic blood pressure in the synthetic diet group was significantly elevated (145 ± 5 vs. 128 ± 4 mmHg, P < 0.05). At 10 weeks it reached a plateau (154 ± 3 vs. 122 ± 3 mmHg, P < 0.05). Plasma renin activity and Na+level were significantly higher in animals fed synthetic diets than in the regular diet group (P < 0.01). Administration of either losartan or lisinopril or a switch to a low salt synthetic diet (0.03% sodium) normalized the synthetic diet-induced high blood pressure. Supplementation of the synthetic diet with the cardiac glycosides delayed the onset of the increase in blood pressure for 4 weeks. Plasma aldosterone levels were approximately doubled in the cardiac glycoside-treated groups. Higher plasma Na+levels and hematocrit values present in the synthetic diet group were normalized by the glycoside supplements. These results suggest that supplemental dietary cardiac glycosides exert bidirectional effects on blood pressure regulation through actions that modulate extracellular fluid and electrolyte balance.Key words: cardiac glycosides, convallatoxin, ouabain, ouabain-like substance, purified synthetic diet, high blood pressure, renin-angiotensin system.
Modeling the large-scale geometry of human coronary arteries
Authors: Changizi Mark A , Cherniak Christopher
Published: April 2011

Two principles suffice to model the large-scale geometry of normal human coronary arterial networks. The first principle states that artery diameters are set to minimize the power required to distribute blood through the network. The second principle states that arterial tree geometries are set to globally minimize the lumen volume. Given only the coordinates of an arterial tree's source and "leaves", the model predicts the nature of the network connecting the source to the leaves. Measurements were made of the actual geometries of arterial trees from postmortem healthy human coronary arteriograms. The tree geometries predicted by the model look qualitatively similar to the actual tree geometries and have volumes that are within a few percent of those of the actual tree geometries. Human coronary arteries are therefore within a few percent of perfect global volume optimality. A possible mechanism for this near-perfect global volume optimality is suggested. Also, the model performs best under the assumption that the flow is not entirely steady and laminar.Key words: arteries, optimization, volume, power, geometry.
Plasma homocysteine is decreased in the hypothyroid rat
Authors: Jacobs René L , Stead Lori M , Brosnan Margaret E , Brosnan John T
Published: April 2011

Recent clinical studies have indicated that plasma homocysteine was significantly increased in hypothyroid patients. Since hyperhomocysteinemia is an independent risk factor for cardiovascular disease we investigated homocysteine metabolism in hypothyroid rats. Hypothyroidism was induced in one study by addition of propylthiouracil (PTU) to the drinking water for 2 weeks. In a second study, thyroidectomized and sham-operated rats were used with thyroid hormone replacement via mini-osmotic pumps. Unlike the human hypothyroid patients, both groups of hypothyroid rats exhibited decreased total plasma homocysteine (30% in PTU rats, 50% in thyroidectomized rats) versus their respective controls. Thyroid replacement normalised homocysteine levels in the thyroidectomized rat. Increased activities of the hepatic trans-sulfuration enzymes were found in both models of hypothyroidism. These results provide a possible explanation for the decreased plasma homocysteine concentrations. The hypothyroid rat cannot be used as a model to study homocysteine metabolism in hypothyroid patients.Key words: homocysteine, cystathionine beta-synthase, cystathionine gamma-lyase, thyroid hormone.
The suppression of potassium cyanide-induced mortality by the increase of extracellular acetylcholine level in the brain
Authors: Senda Toshihiko , Matsuno Kiyoshi , Mita Shiro
Published: April 2011

We examined whether potassium cyanide (KCN)-induced mortality in mice was regulated by acetylcholine transmission in the brain. Our novel compound, (±)-1-(1,2-diphenyl)ethyl-4-[2-(3,4-dimethoxyphenyl)ethyl]piperazine dihydrochloride (SA3251), suppressed KCN-induced mortality in mice. In parallel, SA3251 increased the cortical and hippocampal extracellular acetylcholine level in conscious, freely-moving rats. Interestingly, the time course patterns of these two events induced by SA3251 correlated. These results suggest that the central cholinergic system plays an important role in the suppression of KCN-induced mortality.Key words: KCN-induced mortality, brain acetylcholine level, (±)-1-(1,2-diphenyl)ethyl-4-[2-(3,4-dimethoxyphenyl)ethyl] piperazine dihydrochloride (SA3251).
Effects of (+) and (-) enantiomers of calcium channel agonist, Bay K 8644, on mechanical and electrical responses of frog skeletal muscle
Authors: Oz Murat , Tchugunova Yuliya , Dinç Meral
Published: April 2011

The effects of (+) and (-) enantiomers of Bay K 8644, a Ca2+ channel agonist, on the mechanical and electrical properties of frog skeletal muscle fibers were investigated. In the concentration range of 10-6 to 10-5 M, both (+) and (-) enantiomers of Bay K 8644 significantly increased the maximum amplitudes of twitch responses. Both (+) and (-) enantiomers of Bay K 8644, at higher concentrations such as 10-4 M, greatly depressed the amplitudes of twitches. Potentiating and depressing effects of (-) enantiomer of Bay K 8644 on twitch responses were significantly greater than those of the (+) enantiomer. At all concentrations used, both (+) and (-) enantiomers of Bay K 8644 significantly decreased the area under the tetanic force × time curve. In intracellular recordings, it was found that the depressing effects of both (+) and (-)-Bay K 8644 on tetanic contractions and twitch responses were due to the inhibition of action potentials. The inhibitory effect of (-) enantiomer of Bay K 8644 on action potentials also was significantly greater than that of the (+) enantiomer. In conclusion, present results suggest that, in contrast with cardiac muscle fibers, (+) and (-) enantiomers of Bay K 8644 have similar inhibitory effects on the electrical and mechanical properties of frog skeletal muscle fibers.Key words: Bay K 8644, calcium channels, sodium channels, skeletal muscle.
Aminoglycosides inhibit hormone-stimulated Mg2+uptake in mouse distal convoluted tubule cells
Authors: Kang Hyung Sub , Kerstan Dirk , Dai Long-jun , Ritchie Gordon , Quamme Gary A
Published: April 2011

The clinical use of aminoglycosides often leads to renal magnesium wasting and hypomagnesemia. Of the nephron segments, both the thick ascending limb of Henle's loop and the distal tubule play significant roles in renal magnesium conservation but the distal convoluted tubule exerts the final control of urinary excretion. An immortalized mouse distal convoluted tubule (MDCT) cell line has been extensively used to study the cellular mechanisms of magnesium transport in this nephron segment. Peptide hormones, such as parathyroid hormone (PTH), glucagon, calcitonin, and arginine vasopressin (AVP) stimulate Mg2+uptake in MDCT cells that is modulated by extracellular polyvalent cations, Ca2+and Mg2+. The present studies determined the effect of aminoglycosides on parathyroid hormone (PTH)-mediated cAMP formation and Mg2+uptake in MDCT cells. Gentamicin, a prototypic aminoglycoside, illicited transient increases in intracellular Ca2+from basal levels of 102 ± 13 nM to 713 ± 125 nM, suggesting a receptor-mediated response. In order to determine Mg2+transport, MDCT cells were Mg2+-depleted by culturing in Mg2+-free media for 16 h and Mg2+uptake was measured by microfluorescence after placing the depleted cells in 1.0 mM MgCl2. The mean rate of Mg2+uptake, d([Mg2+]i)/dt, was 138 ± 24 nM/s in control MDCT cells. Gentamicin (50 µM) did not affect basal Mg2+uptake (105 ± 29 nM/s), but inhibited PTH stimulated Mg2+entry, decreasing it from 257 ± 36 nM/s to 108 ± 42 nM/s. This was associated with diminished PTH-stimulated cAMP formation, from 80 ± 2.5 to 23 ± 1 pmol/mg protein·5 min. Other aminoglycosides such as tobramycin, streptomycin, and neomycin also inhibited PTH-stimulated Mg2+entry and cAMP formation. As these antibiotics are positively charged, the data suggest that aminoglycosides act through an extracellular polyvalent cation-sensing receptor present in distal convoluted tubule cells. We infer from these studies that aminoglycosides inhibit hormone-stimulated Mg2+absorption in the distal convoluted tubule that may contribute to the renal magnesium wasting frequently observed with the clinical use of these antibiotics.Key words: intracellular Mg2+, Mg2+uptake, aminoglycosides, gentamicin, tobramycin, streptomycin, neomycin, parathyroid hormone, microfluorescence, cAMP measurements.
Pancreatic secretory response to feeding in the calf: CCK-A receptors, but not CCK-B/gastrin receptors are involved
Authors: Dréan Gwenola Le , Huërou-Luron Isabelle Le , Gestin Martine , Romé Véronique , Bernard Christine , Chayvialle Jean-Alain , Fourmy Daniel , Guilloteau Paul
Published: April 2011

In bovine species, as in human, the pancreas predominantly expresses cholecystokinin-B (CCK-B)/gastrin receptors. However, the role of this receptor in the regulation of meal-stimulated pancreatic enzyme release has not been determined. In milk-fed calves, we previously described prandial patterns of exocrine pancreatic secretion and a long prefeeding phase was observed. The present study was aimed at determining both the role of external stimuli in the outset of the prefeeding phase and the implication of pancreatic CCK-A and CCK-B/gastrin receptors in the mediation of pancreatic response to feeding. The first objective was studied by suppressing external stimuli associated with food intake (unexpected meal) and the second by infusing highly specific and potent antagonists of CCK-A (SR 27897) and CCK-B/gastrin (PD 135158) receptors during the prandial period. When calves were given an unexpected meal, the long prefeeding increase in pancreatic secretion was absent. SR 27897 (but not PD 135158) inhibited the preprandial phase and greatly reduced postprandial pancreatic juice and enzyme outflows. The expectancy of a meal seemed to elicit an increased pancreatic response right before a meal and CCK-A receptors may mediate this information via neural pathways. The implication of CCK and CCK-A receptors in mediating the postfeeding pancreatic response was also demonstrated. The participation of CCK-B/gastrin receptors in this regulation was not demonstrated.Key words: CCK-A and CCK-B/gastrin receptors, cholecystokinin, exocrine pancreatic secretion, feeding, milk-fed calf.
Gamma radiation effects on α-lactalbumin: structural modifications
Authors: Chapelier A , Desmadril M , Houée-Levin C
Published: April 2011

α-Lactalbumin was irradiated in the lyophilized state in air at ambient temperature. The irradiated protein was examined by size exclusion chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis, circular dichroism, and microcalorimetry. Irradiation induced the loss of aromatic amino acids and of helicity so that fragmentation and aggregation products were obtained. The thermodynamic properties of the protein were also modified. The irradiated protein had lower stability, however, the temperature at which denaturation occurred process remained constant.Key words: ionizing radiation, radiation-induced conformational changes, protein structural modifications, protein thermodynamic properties.
Enhanced strand break induction of DNA by resonant metal-innershell photoabsorption
Authors: Sech C Le , Takakura K , Saint-Marc C , Frohlich H , Charlier M , Usami N , Kobayashi K
Published: April 2011

We determined The number of single and double strand breaks (ssb and dsb) in a DNA-chloroterpyridine platinum complex induced by resonant photoabsorption in the LIII innershell of a platinum atom. The number of ssb and dsb were measured in supercoiled plasmids (AG30) versus the chloroterpyridine platinum concentration, i.e., the ratio of intercalated molecules to the number of phosphate sites in DNA. A significant increase in the number of ssb and dsb was observed when the DNA contained intercalated molecules. This technique is an efficient way to induce ssb and dsb triggered by the atomic Auger effect.Key words: DNA breaks, Auger effect, resonant photoabsorption, intercalated molecules.
Détection des radicaux OH et O2 issus de la radiolyse de l'eau par chimiluminescence résolue en temps
Authors: Wasselin-Trupin V , Baldacchino G , Hickel B
Published: April 2011

A new method for the detection of low concentrations of hydroxyl and superoxide radicals, formed by water radiolysis, is described in this article. The method used is the time resolved chemiluminescence. It has been performed with an electron beam delivered by a Febetron 707 accelerator. This method allows to measure hydroxyl and superoxide radical concentrations in a large range of concentrations, between 105 and 108 M.Key words: chemiluminescence, pulse radiolysis, hydroxyl radical, superoxyde radical.[Traduit par la Rédaction]
Time-related effect of GnRH on histone H1 kinase activity in the goldfish follicle-enclosed oocyte
Authors: Pati D , Lohka M J , Habibi H R
Published: April 2011

The level of cyclin B-associated cdc2 kinase, a component of maturation promoting factor (MPF), is known to be high during metaphase of the meiotic maturation of oocytes. The time-related action of gonadotropin-realising hormones (GnRH) on histone H1 kinase activity (known to reflect cdc2 kinase activity) was investigated in vitro in follicle-enclosed goldfish oocytes. Germinal vesicle breakdown (GVBD) and testosterone production were also investigated in the same follicle-enclosed goldfish oocytes to determine the temporal relationship between GnRH-induced histone H1 kinase activity and the reinitiation of meiosis and steroidogenesis. Treatments with gonadotropin (GTH) or GnRH stimulated the histone H1 kinase activity to the same maximum level. However, sGnRH- and cGnRH-II-induced histone H1 kinase activity were significantly higher compared with controls after 2 hours of treatment, whereas the GTH-induced increase became significantly higher after 6-8 hours of incubation. Overall, the results demonstrate a close temporal relationship between GVBD response and histone H1 kinase activity induced by GTH and sGnRH-cGnRH-II.Key words: GnRH, oocyte meiosis, testosterone, H1 kinase, goldfish.
Auditory-vocal cholinergic pathway in the songbird brain
Authors: Li Rui , Taniguchi Ikuo , Sakaguchi Hironobu
Published: April 2011

Male zebra finches learn to imitate a tutor's song through auditory and motor learning. The two main song control nuclei in the zebra finch forebrain, the higher vocal center (HVC) and the robust nucleus of the archistriatum (RA), receive cholinergic innervation from the ventral paleostriatum (VP) of the basal forebrain which may play a key role in song learning. By injecting neuroanatomical tracers, we found a topographically segregated pathway from nucleus ovoidalis (Ov) to VP that in turn projects in a topographic fashion to HVC and RA. Ov is a major relay in the main ascending auditory pathway. The results suggest that the cholinergic neurons in the VP responsible for song learning are regulated by auditory information from the Ov.Key words: auditory pathway, cholinergic pathway, song control nucleus, zebra finch.
Muscarinic activation of transient inward current and contraction in canine colon circular smooth muscle cells
Authors: Molleman A , Liu L WC , Huizinga J D
Published: April 2011

Muscarinic receptor mediated membrane currents and contractions were studied in isolated canine colon circular smooth muscle cells. Carbachol (105M) evoked a slow transient inward current that was superimposed by a transient outward current at holding potentials greater than 50 mV. Carbachol contracted the cells by 70 ± 2%. The effects of carbachol were blocked by atropine (106M), tetraethyl ammonium (20 mM), and BAPTA-AM (25 mM applied for 20 min). The inward current and contraction were not sensitive to diltiazem (105M), nitrendipine (3 × 107M), niflumic acid (105M), or N-phenylanthranilic acid (104M), but were gradually inhibited after repetitive stimulations in Ca2+free solution. Ni2+(2 mM) inhibited the inward current by 67 ± 4%. The inward current reversed at +15 mV. The outward component could be selectively inhibited by iberiotoxin (20 nM) or by intracellular Cs+. Repeated stimulation in the presence of cyclopiazonic acid (CPA, 3 µM) inhibited the carbachol-induced outward current and partially inhibited contraction. CPA did not inhibit the inward current. In conclusion, muscarinic receptor stimulation evoked a CPA-sensitive calcium release that caused contraction and a CPA-insensitive transient inward current was activated that is primarily carried by Ca2+ions and is sensitive to Ni2+.Key words: calcium, carbachol, smooth muscle, cyclopiazonic acid, sarcoplasmic reticulum.
Evidence for the binding of β-adrenoceptor blockers to microsomal Na+/K+-ATPase in guinea pig heart preparations
Authors: Almotrefi Abdulrahman A , Basco Chona , Moorji Azadali , Dzimiri Nduna
Published: April 2011

We reported in a previous study that β-adrenoceptor blockers inhibit the Mg2+-dependent ATP-hydrolytic function of Na+/K+-ATPase. To determine if this action is a result of binding of β-blockers to the receptor sites that bind the digitalis glycosides, we performed displacement binding assays of eight β-blockers with [3H]-ouabain (OUA) in guinea pig myocardial microsomal preparations. In the first series of experiments, 10-200 µM of the β-blockers were displaced with 250 nM OUA. In the second set of experiments, 10-500 nM of OUA was displaced using 200 µM of the β-blockers. The drugs showed concentration-dependent receptor occupancy at the different OUA levels. Propranolol (PPN), metoprolol (MTP), and sotalol (STL) showed the strongest binding; nadolol (NDL), indenolol (IDN), and atenolol (ATN) had intermediate binding; carazolol (CRZ) and celiprolol (CLP) had the weakest binding properties. The results suggest that β-blockers may compete for the same binding sites with ouabain in their inhibition of the Na+/K+-ATPase. These actions may contribute to the mechanism for some of their cardiac effects, especially their proarrhythmic and arrhythmogenic actions.Key words: β-adrenoceptor blockers, antiarrhythmic agents, arrhythmogenic effects, Na+/K+-ATPase, ouabain binding.
Effect of autonomic neurotransmitters on excitable gap composition in canine atrial flutter
Authors: Rahme Marc M , Jalil Elise , Laflamme Martin , Kus Teresa
Published: April 2011

Atrial arrhythmias are believed to be influenced by autonomic nervous system tone. We evaluated the effects of sympathetic and parasympathetic activation on atrial flutter (AFl) by determining the effects of norepinephrine (NE) and acetylcholine (ACh) on the composition of the excitable gap. A model of reentry around the tricuspid valve was produced in 17 chloralose anesthetized dogs using a Y-shaped lesion in the intercaval area that extended to the right atrial appendage. Excitable gap characteristics were determined during AFl by scanning diastole with a single premature extrastimulus at progressively shorter coupling intervals to define the reset-response curve. Measurements were made during a constant infusion of NE (15 µg/min) into the right coronary artery and repeated during ACh infusion (2 µg/min) following a 15 min recovery period. The excitable gap (27 ± 1 ms) was significantly (P < 0.001) increased by NE (34 ± 1 ms) and ACh (50 ± 2 ms). The fully excitable portion (7 ± 1 ms) was also significantly (P < 0.001) increased by NE (17 ± 1 ms) and ACh (43 ± 2 ms). We conclude that both neurotransmitters increase the safety margin of full excitability ahead of the wavefront, demonstrating that parasympathetic and sympathetic activation can facilitate the persistence of this refractory atrial arrhythmia.Key words: atrial flutter, acetylcholine, norepinephrine, excitable gap.
Spread of Ca2+in the sarcomere during fast and slow activation of mammalian cardiac myocytes
Authors: Konishi Masato , Kusakari Yoichiro , Hongo Kenichi , Kurihara Satoshi
Published: April 2011

A multi-compartment model was used to estimate Ca2+gradients in a sarcomere of a cardiac myocyte. The mathematical model assumed Ca2+release from the sarcoplasmic reticulum as a driving function, and calculated Ca2+binding to myoplasmic buffers, Ca2+uptake by the sarcoplasmic reticulum, and diffusion of Ca2+(and the buffers). During the fast Ca2+transient similar to those observed during a twitch, the model predicted a large Ca2+gradient in the sarcomere. A trajectory of the instantaneous relation between spatially averaged concentrations of Ca2+and the Ca2+-troponin complex showed a counterclockwise loop, indicating non-equilibrium Ca2+binding to troponin. During slow changes in [Ca2+] with time to peaks of ~500 ms or longer, the gradient of [Ca2+] was largely dissipated and the apparent equilibrium of the Ca2+-troponin binding reaction was suggested with little hysteresis of the trajectory. We conclude that a steady-state relation between [Ca2+] and mechanical activity can be achieved uniformly in the sarcomere by slowing the rate of Ca2+release from the sarcoplasmic reticulum.Key words: calcium, troponin, cardiac myocytes, mathematical model.
YC-1 enhances the responsiveness of tolerant vascular smooth muscle to glyceryl trinitrate
Authors: O'Reilly Deirdre A , McLaughlin Brian E , Marks Gerald S , Brien James F , Nakatsu Kanji
Published: April 2011

A major limitation of the use of organic nitrates in cardiovascular medicine is the development of tolerance, which has been attributed, in part, to a decrease in their metabolic activation in the vascular smooth muscle cell. Recently, 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) was shown to potentiate vascular smooth muscle responsiveness to glyceryl trinitrate (GTN), sodium nitroprusside, and the nitric oxide donor NOC 18, in organic nitrate-naïve vascular smooth muscle. We used GTN-tolerant rabbit aortic rings (RARs) to test the hypothesis that a non-vasorelaxant concentration of YC-1 enhances the ability of the prototypical organic nitrate GTN to relax vascular smooth muscle and elevate intravascular cGMP under conditions of GTN tolerance. Treatment with YC-1 (3 µM) produced a left shift of the GTN concentration-response curve and decreased the EC50 value for GTN-induced relaxation in both GTN-tolerant and non-tolerant RARs (P < 0.05). Intravascular cGMP elevation induced by GTN was enhanced in the presence of YC-1 in GTN-tolerant and non-tolerant RARs (P < 0.05). These observations indicate that YC-1, or similarly acting drugs, may be useful in overcoming the tolerance that develops during sustained GTN therapy, and that its mechanism may involve enhanced cGMP formation.Key words: glyceryl trinitrate, 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), organic nitrate tolerance, cGMP, vasorelaxation.
Therapeutic implications of hypothermic and hyperthermic temperature conditions in stroke patients
Authors: Thornhill Jim , Corbett Dale
Published: April 2011

Brain temperature is an important variable in determining the outcome of cerebral ischemia; increases in core temperature escalate neural damage whereas decreases in core temperature reduce damage. Fever induction often occurs in patients prior to or as a direct or indirect result of the ischemic insult, with a worsened stroke outcome, compared with non-febrile ischemic patients. Most importantly, post-ischemic hypothermia reduces long term neural damage and associated behavioral deficits in animals studied for up to a year after the ischemic insult. This review discusses the importance of monitoring the brain temperature of stroke patients and implemention of therapeutic thermoregulatory strategies to reduce the temperature of ischemic patients.Key words: hypothermia, neuroprotection, fever, neural and behavioral outcomes.
Effect oftrans-resveratrol on 7-benzyloxy-4-trifluoromethylcoumarinO-dealkylation catalyzed by human recombinant CYP3A4 and CYP3A5
Authors: Chang Thomas KH , Yeung Rosita KY
Published: April 2011

Red wine concentrate has been reported to inhibit the catalytic activity of human recombinant cytochrome P450 (CYP) 3A4. Wine contains many polyphenolic compounds, including trans-resveratrol, which is also available commercially as a nutraceutical product. In the present study, we examined the in vitro effect of trans-resveratrol on human CYP3A catalytic activity by employing recombinant CYP3A4 and CYP3A5 as model enzymes and 7-benzyloxy-4-trifluoromethylcoumarin (BFC) as a CYP3A substrate. Trans-resveratrol inhibited BFC O-dealkylation catalyzed by CYP3A4 and CYP3A5 in a concentration-dependent manner. In each case, the inhibition was noncompetitive, as determined by Lineweaver-Burk and Dixon plots of the enzyme kinetic data. The apparent Kivalues (mean ± SEM) for the inhibition by trans-resveratrol of BFC O-dealkylation catalyzed by CYP3A4 and CYP3A5 were 10.2 ± 1.1 µM and 14.7 ± 0.3 µM, respectively. Preincubation of trans-resveratrol with NADPH and CYP3A4 or CYP3A5 for 10 or 15 min prior to initiation of substrate oxidation did not enhance the inhibitory effect, suggesting that this compound was not a mechanism-based inactivator of CYP3A4 or CYP3A5 when BFC was used as the substrate. Overall, our study provides the first demonstration that trans-resveratrol inhibits, in vitro, a substrate oxidation reaction catalyzed by human recombinant CYP3A4 and CYP3A5.Key words: 7-benzyloxy-4-trifluoromethylcoumarin, cytochrome P450, CYP3A4, CYP3A5, 7-hydroxy-4-trifluoromethylcoumarin, nutraceutical, trans-resveratrol.
Modulation of AMPA receptors by a novel organic nitrate
Authors: Toong Samuel , Xiong Zhi-Gang , Zavorin Sergei I , Bai Donglin , Orser B A , Thatcher Gregory RJ , Reynolds James N , MacDonald John F
Published: April 2011

Positive modulators of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) channels reduce desensitization and alter their gating kinetics. We have discovered a novel compound nitric oxide-mimetic that similarly modulates the AMPA receptor by reducing desensitization. This, designated GT-005, belongs to the organic nitrate family that includes the nitrovasodilator nitroglycerine. In acutely isolated hippocampal neurons, GT-005 enhanced kainate (100 µM)-evoked currents with an EC50 of 1.7 ± 0.2 mM and a 176 ± 10% maximal increase in the steady-state current response. Similar results were found in cultured hippocampal neurons (EC50 of 1.3 ± 0.2 mM and a maximal 83 ± 14% increase in the steady-state current response). GT-005 reduced the desensitization of glutamate-evoked currents and slowed the onset of desensitization. This compound also increased the rate of recovery from the desensitized state. With respect to alteration of the excitatory synaptic transmission, GT-005 delayed the decay and increased the frequency of spontaneous miniature excitatory postsynaptic currents (mepsc) recorded in cultured hippocampal neurons.Key words: AMPA receptors, desensitization, organic nitrates.
Comparative molecular biology of natriuretic peptide receptors
Authors: Hirose Shigehisa , Hagiwara Hiromi , Takei Yoshio
Published: April 2011

Analysis of the mammalian natriuretic peptide system has established the presence of three types of receptors with distinct structural and functional features and tissue distributions. To clarify the physiological role of each subtype, we studied the natriuretic peptide system in animals with specialized anatomical and physiological features. In this review, following a brief description of the comparative and evolutionary aspects of the ligands, we will analyze the structure and distribution of natriuretic peptide receptors in lower vertebrates, as well as those of rats with essential and salt-sensitive hypertension, and discuss the evolutionary aspects of the natriuretic peptide systems in mammals and fishes. Emphasis is placed on our series of studies with eel receptors that revealed (i) interesting variations in the pattern of intra- and inter-molecular disulfide bonding; (ii) dense chondrocyte localization of NPR-C, which opened a new field of study for natriuretic peptides and bone metabolism; and (iii) the presence of a new receptor subtype, NPR-D, which is abundant in the brain and a member of the receptor subfamily with a short cytoplasmic C-terminal tail.Key words: chloride cell, evolution, natriuretic peptide, osmoregulation, receptor.
Metabolism of angiotensin I by guinea pig aqueous humor
Authors: Igic Rajko , Wania-Galicia Lana , Jackman Herbert L
Published: April 2011

We investigated the degradation of angiotensin I (Ang I) by guinea pig aqueous humor at physiological pH (pH 7.4) and assessed the activity of responsible enzymes using various enzyme inhibitors. The aqueous humor was incubated with Ang I in the presence or absence of an enzyme inhibitor at 37°C for the appropriate time period. The resulting peptides were analyzed by a Beckman HPLC system with a Waters µBondapak C18analytical column using a 30-min increasing linear gradient of 10 to 40% acetonitrile containing 0.05% trifluoroacetic acid (TFA) and H2O containing 0.05% TFA at a flow rate of 1 mL/min. Detection was done by absorbance at 214 nm. Angiotensin II (Ang II) was a major product (39.3 ± 4.10 nmol·h1·mL1, n = 5) of Ang I hydrolysis. Traces of angiotensin 19, angiotensin IV, and angiotensin 17 were also produced. Chymostatin (0.05 mmol/L), EDTA (1 mmol/L), enalaprilat (0.1 mmol/L), and ebelacton B (0.01 mmol/L) inhibited generation of Ang II from Ang I by guinea pig aqueous humor by 89 ± 4.6, 56 ± 7.6, 33 ± 5.1, 20 ± 6.5 %, respectively. Our findings indicate that guinea pig aqueous humor contains several enzymes that can form Ang II. The chymostatin-sensitive type of enzyme was the most active one found in guinea pig aqueous humor. Angiotensin I converting enzyme, carboxypeptidase A, and deamidase may also contribute to angiotensin II formation in guinea pig ocular fluid.Key words: aqueous humor, angiotensin I, angiotensin II, chymase-like activity, ACE, guinea pig.
Short-term carnitine deficiency does not alter aerobic rat heart function but depresses reperfusion recovery after ischemia
Authors: Broderick Tom L , Cifuentes Jenny , Green Denise , Paulson Dennis J
Published: April 2011

Clinical and experimental studies have shown that long-term carnitine deficiency is often associated with cardiomyopathy and ischemic failure. The present study was designed to determine whether cardiac dysfunction is seen in an experimental model of short-term carnitine deficiency. Carnitine deficiency was induced in Sprague-Dawley rats by supplementing the drinking water with sodium pivalate for a period of 2 weeks. This resulted in a 25% depletion of total myocardial carnitine content. When isolated working hearts from these animals were paced and subjected to increments in left atrial filling pressure, there were no differences in mechanical function compared with control hearts. Following no-flow ischemia, however, recovery of cardiac output and relaxation parameters was depressed in hearts from pivalate-treated animals. Under these conditions, L-carnitine prevented the depressions of function from occurring. Our results show that short-term carnitine deficiency is not associated with cardiac dysfunction under normoxic conditions. However, hearts from pivalate-treated animals are more susceptible to ischemic injury and thus may prove to be useful for the study of metabolic and functional aspects of carnitine deficiency.Key words: pivalate, carnitine deficiency, cardiac, ischemia, reperfusion.
Discovery of a natriuretic peptide family and their clinical application
Authors: Matsuo Hisayuki
Published: April 2011

The identification of atrial natriuretic peptide (ANP) induced an explosive series of studies on the new peptide involved in control of the circulation, both in the basic and clinical fields. During the first decade of ANP research surprising progress has been made, revealing that the heart is an endocrine organ regulating the circulation system. ANP has been developed as a diagnostic tool and as a therapeutic drug for cardiac failure. In the second decade, brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) were identified, unveiling new profiles of this peptide family. Although BNP is also a circulating hormone that shares a common receptor with ANP, it is different from ANP in its' synthesis and secretion. Plasma concentration of BNP reflects the severity of heart failure in patients in a dramatic fashion, much moreso than ANP. Thus, BNP has been developed as a powerful diagnostic tool for cardiovascular diseases. The third congener, CNP, having a receptor of its own, was initially thought to function only in the brain. CNP was subsequently found to be produced from vascular endothelial cells and macrophages, indicating that CNP is a local regulator and also an antiproliferative factor in the vascular cell system, rather than a circulating hormone. Trials for the clinical application of CNP have also been discussed.Key words: natriuretic hormone, ANP, BNP, CNP, hypotensive peptides.
Respiratory and metabolic effects of decreased osmolality in conscious rats
Authors: O'Connor Michael D , Jennings Donald B
Published: April 2011

We investigated the respiratory and metabolic effects of decreased osmolality, and the potential roles of angiotensin II (ANG II) and the subfornical organ (SFO) in mediating these effects, in conscious Sprague-Dawley (SD) rats. Gastric water loading was induced either by oral gavage or an externalized indwelling stomach tube (20 mL·kg-1 distilled water at body temperature). Repeated measurements after oral gavage were obtained with and without water loading and with and without ANG II receptor block (saralasin, 1.3 µg·kg-1·min-1 iv). At 15 min after water loading by oral gavage, ventilation ([Formula: see text], 1.14 ± 0.08 L·kg-1·min-1) and tidal volume (10.7 ± 0.6 mL·kg-1) were transiently higher (P < 0.05), at a time when plasma osmolality was decreased (-8 ± 1 mOsm), compared with gavage tube alone (0.95 ± 0.08 L·kg-1·min-1 and 9.1 ± 0.7 mL·kg-1, respectively). However, water loading via stomach tube did not stimulate [Formula: see text]; only during the 60-s period of water infusion did [Formula: see text] increase briefly, but this was due to increased respiratory frequency. Dye indicators demonstrated that oral gavage exposes upper airway and esophageal afferents to water, presumably accounting for respiratory stimulation. Lesions of the SFO did not affect respiration or metabolism. A decrease in osmolality, associated with both water loading techniques, caused a sustained increase in oxygen consumption ([Formula: see text]) and a decrease in the [Formula: see text] ratio. ANG II receptor block reduced the * response and prevented the decrease in [Formula: see text] following water loading by oral gavage, but did not affect the transient stimulation of [Formula: see text]. Unlike larger mammals, decreased osmolality does not stimulate respiration in the SD rat.Key words: alphastat theory of respiratory control, circumventricular organs, gastric distension, osmoreceptors, [Formula: see text] ratio.
Effects of morphine withdrawal on catecholaminergic neurons on heart right ventricle; implication of dopamine receptors
Authors: Milanés M V , Marín M T , Laorden M L
Published: April 2011

The purpose of our study was to examine the effects of D1-and D2-dopamine receptors blockade on the changes in the ventricular content of catecholamines in rats withdrawn from morphine. Rats were given morphine by subcutaneous (sc) implantation of morphine pellets for 5 days. On the eighth day, morphine withdrawal was induced by sc administration of naloxone (1 mg/kg), and rats were killed 30 min later. Pretreatment with SCH 23390 (dopamine D1, D5 receptor antagonist) 15 min prior to naloxone administration suppressed some the behavioural signs of morphine withdrawal, whereas eticlopride (dopamine D2, D3, D4 receptor antagonist) did not. In addition, biochemical analysis indicate that SCH 23390 completely abolished the withdrawal-induced increase in noradrenaline and dopamine turnover in the right ventricle. By contrast, eticlopride did not block the hyperactivity of catecholaminergic neurons in the heart during morphine withdrawal. These data suggest that the hyperactivity of catecholaminergic neurons in the heart during morphine withdrawal is dependent upon D1 dopamine receptor activation. In addition, our results exclude the involvement of D2 dopamine receptors.Key words: morphine withdrawal, right ventricle, catecholaminergic activity.
Increased nitric oxide production in platelets from severe chronic renal failure patients
Authors: Alves de Sá Siqueira Mariana , Brunini Tatiana M.C. , Rodrigues Pereira Natália , Martins Marcela Anjos , Bandeira Moss Monique , Santos Sérgio F. , Lugon Jocemir R. , Mendes-Ribeiro Antônio C.
Published: April 2011

Nitric oxide (NO) production occurs through oxidation of the amino acid l-arginine by NO synthase (NOS). NO inhibits platelet activation by increasing the levels of cyclic guanosine monophosphate (cGMP), thus maintaining vascular homeostasis. Our group previously demonstrated ( da Silva et al. 2005 ) an enhancement of the l-arginine–NO–cGMP pathway in platelets taken from chronic renal failure (CRF) patients on haemodialysis associated with reduced platelet aggregation. We investigate the platelet l-arginine–NO–cGMP pathway, platelet function, and inflammation from patients in CRF on conservative treatment. A total of 42 CRF patients and 42 controls (creatinine clearance = 27 ± 3 vs. 93 ± 1 mL per min per 1.73 m2, respectively) participated in this study. NOS activity and expression and cGMP concentration were measured in platelets. Platelet aggregation induced by collagen or ADP was evaluated and plasma levels of fibrinogen were determined by the Clauss method. A marked increase in basal NOS activity was seen in undialysed CRF patients compared with controls, accompanied by an elevation of fibrinogen plasma levels. There were no differences in expression of NOS and in cGMP levels. In this context, platelet aggregation was not affected. We provide the first evidence of increased intraplatelet NO biosynthesis in undialysed CRF patients, which can be an early marker of future haemostatic abnormalities during dialysis treatment.
PERFUSION PRESSURE IN RELATION TO THE PRODUCTION AND CESSATION OF EXPERIMENTAL CARDIAC ARRHYTHMIAS
Authors: Panisset J.-C. , Carle R. , Beaulnes A.
Published: April 2011

The influence of perfusion pressure on ventricular fibrillation was studied in the isolated rabbit heart. Sudden drops in perfusion pressure inhibit ventricular fibrillation in a few minutes, whereas a slow decrease of the pressure does not stop the fibrillation, but nevertheless reduces the ventricular firing rate. High perfusion pressures facilitate the induction of fibrillation; low pressures delay the production of arrhythmias and shorten their duration. It is postulated that this effect of pressure is primarily mechanical and not strictly dependent upon changes in the coronary flow or in the myocardial temperature.
THE EFFECTS OF PHENELZINE ON SEROTONIN, NORADRENALINE, AND MONOAMINE OXIDASE IN THE RAT
Authors: McNeill John H. , Riedel Bernard E.
Published: April 2011

The serotonin, noradrenaline, and monoamine oxidase (MAO) levels in the brain, liver, lung, and kidney of rats treated with phenelzine (β-phenylethylhydrazine) were compared with the levels in the same tissues in untreated rats. The administration of the drug was found to markedly reduce the MAO activity in all tissues in 3 hours. Recovery to a supranormal level occurred in the liver in 72 hours. Kidney MAO activity returned to normal in 36 hours, while brain and lung MAO had not recovered in 72 hours. The serotonin level in the brain, liver, and kidney increased as the enzyme level decreased. No change occurred in the serotonin concentration in the lung. The noradrenaline level in the brain was not altered by the drug, whereas a decrease was noted in the lung and both kidney and liver showed an increase at 3 and 36 hours. It is postulated that the central action of MAO-inhibiting agents is mediated through serotonin. The increase in liver noradrenaline suggests that MAO must play some role in the metabolism of the amine. Since the concentration of serotonin in the lung was not changed when the enzyme was inhibited, it is conceivable that lung tissue may serve as a storage site for serotonin.
FATTY ACID SYNTHESIS IN NORMAL AND COLD-ACCLIMATED RATS
Authors: Patkin Judith K. , Masoro E. J.
Published: April 2011

Rats acclimated to either 0–2 °C or 25 °C were given glucose-C14via stomach tube and then sacrificed at [Formula: see text], 1, 6, or 24 hours. The cold-acclimated rats incorporated no more and possibly less C14into fatty acids than did the rats acclimated to 25 °C. Evidence is presented which indicates that the white adipose tissue probably did not play a quantitatively important role in the conversion of the glucose-C14to fatty acid. Also, the data indicate that lipogenesis was not a major pathway of the glucose-C14metabolism.
EFFECT OF CHRONIC CORTISONE TREATMENT AND COLD EXPOSURE ON THE ZINC CONTENT AND THE SUCCINIC DEHYDROGENASE ACTIVITY OF THE ADRENAL GLAND
Authors: Dunnigan Jacques
Published: April 2011

Chronic treatment, with cortisone (5 mg/day) results in a dramatic increase in the zinc concentration in the adrenals. The treatment produces an atrophy of the gland without affecting its total zinc content. This fact accounts for the increase in the zinc concentration.Zinc determinations on fat-free adrenals confirm that, as a result of atrophy, zinc is retained; and show that the site of retention is the proteic part of the gland. Exposure to cold produces hypertrophy of the gland, but no change in the total zinc content, resulting in a decrease in the zinc concentration.Adrenal succinic dehydrogenase (S.D.) activity is decreased with cortisone treatment. Cold exposure produces a transient increase in the S.D. activity.Thus, there is no relationship between S.D. activity and zinc content in the adrenals.
EFFECTS OF SINGLE AND REPEATED EXPOSURES TO OXYGEN AT HIGH PRESSURE ON NORMAL RATS
Authors: Patel Yezdi J. , Gowdey C. W.
Published: April 2011

Unanesthetized rats were exposed to oxygen at high pressure (OHP)—60 lb/sq. inch gauge pressure (60 p.s.i.g.)—and kept at this pressure until three convulsions had occurred (average time 3.3 minutes). Electroencephalographic (EEG) frequency decreased and amplitude increased just before and after a convulsion; heart rate decreased and respiratory rate increased. After stage-decompression the EEG pattern became similar to that observed during the precompression stage in about 11 minutes; heart rate returned within 32 minutes, but the respiratory rate fell below precompression levels and did not recover for some 79 minutes. With exposure to 2% carbon dioxide in oxygen (CO2–OHP) at 60 p.s.i.g. the convulsion time was significantly shorter than with pure oxygen. Convulsions did not occur with exposure to air or oxygen at atmospheric pressure nor to air at 60 p.s.i.g. On prolonged exposure to OHP the rats survived an average of 48.4 convulsions, the survival time being 104.45 minutes; rats exposed to CO2–OHP experienced an average of 20.7 convulsions and survived only 38.50 minutes. In both groups the respiration was the first to fail, followed by the heart. Postmortem examination revealed severe pulmonary congestion in these rats.Repeated exposures to OHP at weekly intervals led to a decrease in the time to the first convulsion in one series of experiments but these rats were found to have elevated respiratory rates, marked pulmonary damage, and increased Hb and erythrocytes. In a second series no change in convulsion time was noted over six weekly exposures; these animals had minimal lung pathology and showed no change in the blood picture. An increase in time to the first convulsion was noted in the group exposed repeatedly to CO2–OHP.
LUNG INFLAMMATION IN MICE EXPOSED TO AEROSOLIZED ENDOTOXIN AND ITS REVERSAL BY ANTIPHLOGISTIC AGENTS
Authors: O'Driscoll Robert G. , Beach Vivian L. , Steinetz Bernard G.
Published: April 2011

A uniform lung inflammation was produced in mice by two exposures, 18 hours apart, to an aerosol of Salmonella abortus equi endotoxin. The inflammation reached a peak in 4 days and could be reversed by the subcutaneous or oral administration of steroidal or non-steroidal antiphlogistic agents on the second and third days. The anti-inflammatory potencies of the test compounds were determined by dose-proportional reductions in lung weights. The potencies of various anti-inflammatory steroids, relative to cortisone acetate, following subcutaneous administration were: dexamethasone, 539%; triamcinolone, 158%; methyl prednisolone, 100%; hydrocortisone acetate, 47%; cortisone, 33%; and hydrocortisone, 28%. Neither an antihistamine, an antiserotonin, nor sex steroids reversed the effects of endotoxin on the lungs. This new method offers several distinct advantages over established tests: the activities obtained reflect therapeutic, rather than preventive effectiveness since a state of inflammation exists at the time treatment is started; reversal of inflammation is easily verified by histological methods; and the test is rapid enough (4 days) for large-scale screening, yet sufficiently precise for quantitative assay.
SPONTANEOUS ACTIVITY AND CATECHOL AMINE EXCRETION
Authors: Smith Lorraine C. , Dugal L.-P.
Published: April 2011

No proportional correlation was found between average spontaneous running activity per week and excretion of adrenaline in white rats which were temporarily removed from the activity cages for 24-hour periods for the collection of urine. There was only a slight tendency for the more active rats to excrete more noradrenaline. The catechol amine excretion of rats in the cold did not vary with spontaneous activity.
RADIOIODIDE METABOLISM IN AMPHIUMA AFTER ITS INTRAPERITONEAL ADMINISTRATION
Authors: Moule John W. , Nace Paul Foley
Published: April 2011

Using a new adaptation of the clinical "neck–thigh" method, the thyroid uptake of radioiodide (I131) after intraperitoneal administration was measured in the urodele Amphiuma means. The technique permitted extended serial determinations in vivo in the same animal and showed that the thyroid uptake did not reach a maximum until 8–9 days. When the thyroid mechanisms were blocked by an excess of iodide, the renal excretion of radioiodide was found to be almost an exact replica of the normal thyroid uptake. The significance of this finding to the use of the intraperitoneal route in urodeles is discussed.