bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacology of L-660,711 (MK-571): a novel potent and selective leukotriene D4 receptor antagonist
Authors: Jones T. R. , Zamboni R. , Belley M. , Champion E. , Charette L. , Ford-Hutchinson A. W. , Frenette R. , Gauthier J-Y. , Leger S. , Masson P. , McFarlane C. S. , Piechuta H. , Rokach J. , Williams H. , Young R. N. , DeHaven R. N. , Pong S. S.
Published: April 2011

L-660,711 (3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl) ((3-dimethyl amino-3-oxo propyl)thio)methyl)thio)propanoic acid is a potent and selective competitive inhibitor of [3H]leukotriene D4 binding in guinea pig (Ki value, 0.22 nM) and human (Ki value, 2.1 nM) lung membranes but is essentially inactive versus [3H]leukotriene C4 binding (IC50 value in guinea pig lung, 23 μM). Functionally it competitively antagonized contractions of guinea pig trachea and ileum induced by leukotriene (LT) D4 (respective pA2 values, 9.4 and 10.5) and LTE4 (respective pA2 values, 9.1 and 10.4) and contractions of human trachea induced by LTD4 (pA2 value, 8.5). L-660,711 (5.8 × 10−8 M) antagonized contractions of guinea pig trachea induced by LTC4 in the absence (dose ratio = 28) but not in the presence of 45 mM L-serine borate (dose ratio <2). L-660,711 (1.9 × 10−5 M) did not block contractions of guinea pig trachea induced by histamine, acetylcholine, 5-hydroxytryptamine, PGF2α, U-44069, or PGD2. In the presence of atropine, mepyramine, and indomethacin, L-660,711 (1.9 × 10−5 M) inhibited a small component of the response to antigen on guinea pig trachea but completely blocked anti-IgE-induced contractions of human trachea. L-660,711 (i.v.) antagonized bronchoconstriction induced in anesthetized guinea pigs by i.v. LTC4, LTD4, and LTE4 but did not block bronchoconstriction to arachidonic acid, U-44069, 5-hydroxytryptamine, histamine, or acetylcholine. Intraduodenal L-660,711 antagonized LTD4 (0.2–12.8 μg/kg) -induced bronchoconstriction in guinea pigs, and p. o. L-660,711 blocked LTD4- and Ascaris-induced bronchoconstriction in conscious squirrel monkeys and ovalbumin-induced bronchoconstriction in conscious sensitized rats treated with methysergide (3 μg/kg). The pharmacological profile of L-660,711 indicates that it is a potent, selective, orally active leukotriene receptor antagonist which is well suited to determine the role played by LTD4 and LTE4 in asthma and other pathophysiologic conditions.
Domoic acid, the alleged "mussel toxin," might produce its neurotoxic effect through kainate receptor activation: an electrophysiological study in the rat dorsal hippocampus
Authors: Debonnel Guy , Beauchesne Luc , Montigny Claude de
Published: April 2011

Domoic acid, an excitatory amino acid structurally related to kainate, was recently identified as being presumably responsible for the recent severe intoxication presented by more than 100 people having eaten mussels grown in Prince Edward Island (Canada). The amino acid kainate has been shown to be highly neurotoxic to the hippocampus, which is the most sensitive structure in the central nervous system. The present in vivo electrophysiological studies were undertaken to determine if domoic acid exerts its neurotoxic effect via kainate receptor activation. Unitary extracellular recordings were obtained from pyramidal neurons of the CA1 and the CA3 regions of the rat dorsal hippocampus. The excitatory effect of domoic acid applied by microiontophoresis was compared with that of agonists of the three subtypes of glutamatergic receptors: kainate, quisqualate, and N-methyl-D-aspartate. In CA1, the activation induced by domoic acid was about threefold greater than that induced by kainate; identical concentrations and similar currents were used. In CA3, domoic acid was also three times more potent than kainate. However, the most striking finding was that domoic acid, similar to kainate, was more than 20-fold more potent in the CA3 than in the CA1 region, whereas no such regional difference could be detected with quisqualate and N-methyl-D-aspartate. As the differential regional response of CA1 and CA3 pyramidal neurons to kainate is attributable to the extremely high density of kainate receptors in the CA3 region, these results provide the first electrophysiological evidence that domoic acid may produce its neurotoxic effects through kainate receptor activation.Key words: domoate, kainate, excitotoxin, hippocampus, N-methyl-D-aspartate.
Effect of catecholamine-induced cardiac hypertrophy on the force–interval relationship
Authors: Taylor Paul B. , Helbing Reinhard K. , Rourke Sean , Churchill Dennis
Published: April 2011

Cardiac hypertrophy was induced in adult female Wistar rats following 12 days of daily subcutaneous injections of isoproterenol (ISO). The left atria responded with a 13–14% increase in tissue growth, while the ventricles achieved a 34–39% increased tissue mass. Maximum force generation and twitch characteristics in 1.0 mM external Ca2+ for the left atria or the right papillary muscle were unchanged in the ISO-treated animals. The force–interval relation was determined at 26 °C between 0.5 and 120 s. The development of maximum force clearly passed through two phases identified as alpha and beta. To characterize these two processes the data were fitted to a two-term linear combination of exponentials (two-compartment model). The time constant and capacity of each process to contribute to the whole force–interval curve was determined by a four-parameter least square fit method. In control atrial muscle the time constants for the alpha and beta processes were 0.47 and 11.23 s, respectively. The contribution of each process to the total force curve in control atrial muscle was approximately 50% alpha and 50% beta. Following ISO-induced growth the time constants were 0.38 and 13.33 s with a shift of contributions towards 60% alpha and 40% beta. Control papillary muscle from the right ventricle had a similar alpha time constant of 0.49 s compared with atrial muscle but possessed a considerably slower beta time constant of 26.17 s. The contribution of each process to interval-dependent force development was 44.5 and 55.5%, respectively. Treatment with ISO to induce ventricular growth resulted in a 20% reduced alpha time constant, with a 45% increased contribution by the alpha process. These results suggest that during the development of catecholamine-induced hypertrophy, there is a significant change in the fundamental alpha process which appears to be mediated by a reduced time constant and an enhanced capacity to contribute to force development.Key words: excitation–contraction, interval-dependent force recovery, post-rest contractions, cardiac muscle, sarcoplasmic reticulum.
Uncoupling protein and its mRNA in brown adipose tissue of newborn rabbits
Authors: Rozon D. K. , Harris W. H. , Gibbins A. M. Verrinder
Published: April 2011

Guanosine diphosphate binding to the uncoupling protein of isolated mitochondria of brown adipose tissue in newborn rabbits was measured as an index of thermogenic activity. The binding was 0.281 ± 0.022 nmol GDP/mg mitochondrial protein at 1 day of age, 0.214 ± 0.017 at 3 days, 0.428 ± 0.038 at 5 days, and 0.208 ± 0.016 at 7 days. The increase in binding between 3 and 7 days of age suggests that the brown fat has an increased thermogenic capacity at that age. In addition, the potential for synthesis of the uncoupling protein was investigated in 1- to 5-day-old newborn rabbits by probing the total cellular ribonucleic acid for the messenger that codes for uncoupling protein. The amount of uncoupling protein messenger was highest at 1 day of age and declined at least until 5 days of age. Because the amount of uncoupling protein messenger decreased as the GDP binding increased, the results suggest that either the initially translated uncoupling protein was unmasked at about 5 days of age or there was a delay in the incorporation of uncoupling protein into the mitochondrial inner membrane, or both.Key words: brown fat, neonatal rabbit, thermogenin, messenger RNA, age-related changes.
A superfusion bioassay for platelet-activating factor
Authors: Cirino Giuseppe , Wallace John L.
Published: April 2011

A superfusion bioassay for platelet-activating factor is described using various types of tissues. By washing the tissue with 0.1–0.5% bovine serum albumin for 2–3 min after each addition of platelet-activating factor, desensitization did not develop in most tissues studied. Because of the ability to apply a sample directly onto an assay tissue with negligible dilution, this bioassay can detect smaller amounts of platelet-activating factor than those previously reported in which an organ bath was utilized. The ascending colon of the rat and dog appeared to be the most sensitive of the tissues tested, with a limit of detectability in the range of 100–500 fg. Repeated additions of platelet-activating factor could be made for up to 4 h without desensitization. Release of platelet-activating factor from samples of rat stomach was measured using the superfusion bioassay and a platelet aggregation bioassay. There was a significant correlation (r = 0.96; p < 0.01) between the values obtained using the two assay systems. Thus, the sensitivity, the reproducibility, and the inexpensive nature of this bioassay make it an attractive alternative to existing bioassays for platelet-activating factor.Key words: platelet-activating factor – acether, bioassay, colon, superfusion.
Changes in the regional brain histamine and histidine levels in postmortem brains of Alzheimer patients
Authors: Mazurkiewicz-Kwilecki I. M. , Nsonwah S.
Published: April 2011

In postmortem brains of Alzheimer patients, statistically significant decreases in histamine levels were observed in the frontal (45%), temporal (20%), and occipital cortices (38%) and in the caudate nucleus (25%). Histidine levels were decreased in the frontal (15%), temporal (21%), and occipital cortices (30%) and in the caudate nucleus (25%); the decrease was statistically significant in the last two brain regions. Histamine was determined by the double isotope technique, and histidine was determined fluorometrically by a fluorescamine method. The data indicate that brain histamine regulation is altered in Alzheimer's disease.Key words: histamine, histidine, brain, Alzheimer's disease.
Synthetic nitrovasodilators are effective, in vitro, in relaxing penile tissue from impotent men: the findings and their implications
Authors: Heaton Jeremy P. W.
Published: April 2011

Normal penile erectile function is dependent on arterial adequacy, appropriate venous occlusion, neurohumoral factors, and finally the relaxation of penile cavernous trabecular smooth muscle. The present experiments were designed to test whether compounds related to endothelium-derived relaxing factor have a role in penile smooth muscle relaxation and whether this role is preserved in clinically impotent tissue. Isometric tension experiments were conducted using strips of human tissue (appropriately obtained) from patients found to be impotent by clinical criteria. Glyceryl trinitrate and isosorbide dinitrate produced maximal relaxations of 66 and 63%, respectively, in tissues contracted with norepinephrine: 50% relaxation was observed at 6 × 10−7 and 8 × 10−5 M, respectively. The finding of a relaxant response to synthetic nitrovasodilators in "impotent" tissue implies that (i) complete end organ (smooth muscle) failure is not always, if ever, seen, (ii) endothelium-derived factors probably play a role in erectile tissue parallel with their role in other vascular tissues, (iii) more proximal factors may be responsible for clinical impotence, and (iv) synthetic nitrovasodilators may have a role in the therapy of clinical impotence.Key words: penis, erection, nitrovasodilators, endothelium-derived relaxing factor, human.
Attenuated response to cold of brown adipose tissue of mice made obese with gold thioglucose
Authors: Eley Judy , Himms-Hagen Jean
Published: April 2011

In a first study, mice made obese with gold thioglucose became hypothermic when exposed to 4 °C. In a second study, lean mice and mice made obese with gold thioglucose (dynamic phase) were acclimated to 14 °C for up to 2 weeks and their brown adipose tissue was studied. The cold-induced increase in thyroxine 5′-deiodinase activity was initially slightly smaller in obese mice, but by 24 h and 2 weeks in the cold the activity of thyroxine 5′-deiodinase was the same in lean and obese mice. Unexpectedly, the elevated activity of 5′-deiodinase returned to the low level seen in warm-acclimated mice in both lean and obese mice after 2 weeks of cold acclimation. In gold thioglucose obese mice, a progressive cold-induced increase in the binding of guanosine diphosphate to isolated mitochondria, an index of both acute thermogenic activation and a long-term increase in uncoupling protein concentration, paralleled that seen in normal lean mice and remained at a high level after 2 weeks in the cold, although still remaining slightly lower than normal. It is not clear how a high level of mitochondrial GDP binding is maintained in cold-acclimated mice at the same time as a low level of thyroxine 5′-deiodinase activity when both are believed to be controlled by the sympathetic nervous system. We conclude that the gold thioglucose obese mouse can activate its brown adipose tissue fairly normally when it is exposed to cold, but that some attenuation of this process may contribute to the impaired survival of this mouse at low temperatures.Key words: hypothalamus, thyroxine 5′-deiodinase, guanosine diphosphate binding, sympathetic nervous system, thermoregulation.
Characterization of the effects of AHN 086, an irreversible ligand of "peripheral" benzodiazepine receptors, on contraction in guinea-pig atria and ileal longitudinal smooth muscle
Authors: Bolger G. T. , Newman A. H. , Rice K. C. , Lueddens H. W. M. , Basile A. S. , Skolnick Phil
Published: April 2011

The effects of AHN 086 and its reversibly acting structural analogue Ro 5-4864 were studied in the spontaneously beating guinea-pig atria and field-stimulated guinea-pig ileal longitudinal smooth muscle in the presence and absence of dihydropyridine calcium channel modulators. The treatment of guinea-pig atria with AHN 086 followed by extensive washing did not alter contraction. However, AHN 086 (0.5 μM) potentiated (88%) the positive inotropic responses by BAY K 8644, an effect that was not reversed by extensive washing of the tissue. Higher concentrations of AHN 086 (> 2 μM) irreversibly inhibited the intropic, but not the chronotropic responses to BAY K 8644, nifedipine, and isoproterenol. Ro 5-4864 (10 μM) produced a reversible enhancement of the inotropic responses and block of the chronotropic responses to BAY K 8644. In guinea-pig ileal longitudinal smooth muscle, both AHN 086 and Ro 5-4864 reversibly inhibited field-stimulated contractions. Neither Ro 5-4864 nor AHN 086 affected the ability of nifedipine to inhibit field-stimulated contractions of ileal longitudinal smooth muscle. Treatment of intact atria with 5 μM AHN 086 followed by extensive washing resulted in a significant inhibition (30–50%) of [3H]Ro 5-4864 binding to peripheral benzodiazepine receptors and of [3H]nitrendipine binding to voltage-operated calcium channels, but did not affect [3H]dihydroalprenolol binding to β-adrenergic receptors on atrial membranes. The same treatment applied to intact ileal longitudinal smooth muscle affected neither [3H] (−)-quinuclidinyl benzilate binding to muscarine receptors nor [3H]nitrendipine binding, but did result in a significant inhibition (30–50%) of [3H]Ro 5-4864 binding to ileal longitudinal smooth muscle membranes. The pharmacology of AHN 086 suggests that there is a different relationship between peripheral benzodiazepine receptors and voltage-operated calcium channels in guinea-pig atria and ileal longitudinal smooth muscle.Key words: calcium channels, peripheral benzodiazepine receptors, dihydropyridines, benzodiazepines, dihydropyridine binding sites.
Prostacyclin release induced by neurokinins in cultured human endothelial cells
Authors: Marceau François , Tremblay Brigitte , Couture Réjean , Regoli Domenico
Published: April 2011

The effects of neurokinins (NK) and related peptides on the secretion of 6-keto-prostaglandin F1α, a stable metabolite of prostacyclin, were measured. These peptides enhanced three- to five-fold the basal secretion rate with the following rank order of potency (based on threshold concentrations for a significant output): substance P (SP) ≥ NKA > SP 4–11 ≥ [pGlu6]SP 6–11 = SP7–11. NKB and SP 1–9 were inactive. Ac[Arg6, Sar9, Met(O2)11]SP, a NK1 receptor selective agonist, was more potent than other selective agonists for the NK2 and NK3 receptor subtypes. These results suggest that the NK receptors, which mediate the release of prostacyclin from human endothelial cells, belong to the NK1 subtype.Key words: neurokinins, substance P fragments, selective agonists, prostacyclin release, human endothelial cells.
Intravenous morphine infusion (IMF) to drug-naive, conscious rats evokes bradycardic, hypotensive effects, but pressor actions are elicited after IMF to rats previously given morphine
Authors: Thornhill J. A. , Townsend C. , Gregor L.
Published: April 2011

Hemodynamic (blood pressure and heart rate) responses of conscious drug-naive rats were studied following intravenous (i. v.) infusion of sterile saline, morphine sulphate, and then naloxone hydrochloride, as well as of other groups previously injected with morphine sulphate. Those groups chronically given morphine sulphate received twice daily injections of morphine sulphate (5 mg/kg, s.c. per injection) for 3 or 6 days before testing with the i. v. infusion of morphine sulphate. Drugs were infused (135 μL/min) through an indwelling femoral venous catheter via a Harvard infusion pump, and blood pressure was recorded from the abdominal aorta via a femoral arterial catheter. Other pretreatment studies were done to determine the receptor mechanisms mediating the blood pressure responses of drug-naive and chronic morphine-treated rats, whereby equimolar doses (0.32 μmol) of specific receptor antagonists were given as a bolus i.v. injection 5 min after saline but before subsequent infusion with morphine sulphate. Intravenous infusion of morphine sulphate (7.5 mg/kg total over 15 min) to drug-naive rats caused a transient but precipitous fall in mean arterial pressure and mean heart rate with an associated rise in mean pulse pressure; these effects were blocked in other groups pretreated with atropine. Interestingly, however, rats chronically injected with morphine sulphate for 3 days previously evoked a transient pressor response when subsequently infused i.v. with morphine sulphate, actions that were blocked in other groups when pretreated i.v. with 0.32 μmol of phentolamine, yohimbine, prazosin, or guanethidine. A greater and persistent pressor response occurred following morphine infusion to groups of rats previously injected over 6 days with morphine sulphate, which was associated with tachycardia during the later stages of the 15-min morphine sulphate infusion period. The prolonged pressor and tachycardic responses of this 6-day chronically injected group were completely blocked in another group pretreated i.v. with both phentolamine and propranolol (0.32 μmol). The results suggest that morphine sulphate infusion to conscious, drug-naive rats evokes classical hypotensive effects due to decreases in mean heart rate caused by activation of parasympathetic vagal activity. With 3 or 6 days of chronic morphine sulphate administration beforehand, subsequent i.v. infusion of morphine sulphate evoked pressor actions felt to be caused by a progressive activation of the sympathetic nervous system. These events cause vasoconstriction of peripheral vasculature and, with time, increased cardiac frequency, actions that can be blocked by pretreatment with specific α- and β-adrenergic receptor blockers.Key words: drug-naive rats, morphine-pretreated rats, acute hypotension, bradycardia, chronic pressor responses, opiate and non-opiate receptor blockade.
Relationship between oxidative phosphorylation and adenine nucleotide translocase activity of two populations of cardiac mitochondria and mechanical recovery of ischemic hearts following reperfusion
Authors: Duan Jianmin , Karmazyn Morris
Published: April 2011

The possible relationship of the atractyloside-sensitive adenine nucleotide translocase activity, oxidative phosphorylation, and the recovery of ventricular contractility following reperfusion of the ischemic isolated rat heart was studied. Five minutes of total global ischemia without reperfusion produced a significant depression in adenine nucleotide translocase in subsarcolemmal mitochondria (SLM), whereas a minimum of 10 min ischemia was required to observe a significant depression in interfibrillar mitochondria (IFM). Increasing durations of ischemia resulted in a progressively larger depression in translocase activity, with a maximum depression of approximately 75% seen in both populations following 20 min ischemia. In contrast, oxidative phosphorylation was totally unaffected in either mitochondrial population following up to 20 min of ischemia. We assessed whether translocase activity or oxidative phosphorylation were related to contractile recovery in hearts reperfused following various durations of ischemia. In SLM, translocase activity was further depressed following reperfusion compared with pre-reperfusion ischemic values, whereas with IFM only reperfusion following 5 min ischemia produced a further depression in translocase values. Oxidative phosphorylation rates of SLM and IFM were significantly depressed following reperfusion of ischemic hearts, although SLM exhibited a generally higher sensitivity in this regard. In reperfused hearts, an overall significant relationship was found between oxidative phosphorylation rate and adenine translocase activity as well as between translocase activity and post-reperfusion contractile recovery. These data show that ischemia can produce a significant depression in translocase activity in the absence of any change in oxidative phosphorylation. The results also suggest that the depression in mitochondrial ADP/ATP translocase and subsequent inhibition of oxidative phosphorylation in the reperfused heart may represent one of the important contributory mechanisms involved in cardiac failure and injury during acute ischemia and reperfusion.Key words: myocardial ischemia, myocardial reperfusion, mitochondria, oxidative phosphorylation, adenine nucleotide translocase.
Effects of hepatic blood flow on hepatic ethanel kinetics measured in cats and predicted from the parallel tube model
Authors: Greenway C. V.
Published: April 2011

In cats anesthetized with pentobarbital, a long-circuit technique was used to measure hepatic blood flow while portal flow was varied from 0 to 300% of normal in random steps. Arterial, portal, and hepatic venous blood samples were analyzed for ethanol concentrations during continuous infusion of ethanol (20 μmol/(min∙kg body weight)) into the reservoir. Measured values for logarithmic mean sinusoidal ethanol concentration, hepatic venous ethanol concentration, hepatic ethanol uptake, and ethanol extraction were compared with the values predicted by the parallel tube model for hepatic uptake of substrates using Vmax and Km determined in each cat at the start of the experiment. Measured and predicted values were very similar at all blood flows above 65% control, but statistical regression analysis indicated a small but highly significant deviation of the measured values from the predicted values. At low flows, measured values of logarithmic mean sinusoidal and hepatic venous concentrations markedly exceeded the predicted values in most cats. The results indicate that the parallel tube model, which assumes all sinusoids are identical and equally perfused, provides a useful approximation for the effects of hepatic blood flow on hepatic ethanol kinetics except at low flows. However, there appears to be a significant degree of sinusoidal heterogeneity that results in a better fit to the distributed model. Our previously reported data for hepatic galactose uptake followed a similar pattern when reanalyzed in this more rigorous way.Key words: liver circulation, ethanol metabolism, sinusoidal heterogeneity, distributed model for hepatic uptake.
Arrhythmic effects of norepinephrine in a model of cardiac ischemia and reperfusion
Authors: Lukas Anton , Ferrier Gregory R.
Published: April 2011

The aim of this study was to assess the direct effects of norepinephrine on mechanisms of arrhythmia induced by conditions of ischemia followed by reperfusion. Isolated canine Purkinje fiber–papillary muscle preparations were studied using standard microelectrode techniques. Tissues were superfused for 40 min with a solution simulating "ischemia" (i.e., hypoxic, acidotic, elevated lactate, and zero substrate) and then "reperfused" for 60 min. Ischemia produced a moderate loss of membrane potential in both tissues. Reperfusion resulted in rapid polarization of the tissues, which was accompanied by oscillatory afterpotentials and aftercontractions in 6 of 12 and 4 of 12 Purkinje fibers, respectively. This was followed by a progressive loss of membrane potential and inexcitability in Purkinje fibers. Recovery was associated with activity resembling depolarization-induced automaticity in 4 of 12 fibers. Addition of norepinephrine (0.5 μM) to the ischemic and reperfusion solutions altered primarily the reperfusion responses. Oscillatory afterpotentials and aftercontractions were larger and occurred in 8 of 8 and 6 of 8 Purkinje fibers, respectively. Norepinephrine also prevented or blunted the progressive depolarization to inexcitability in Purkinje tissues and increased automaticity occurring at low (depolarization-induced automaticity) and more polarized membrane potentials (enhanced normal pacemaker activity). This study demonstrates that norepinephrine exacerbates several potential mechanisms of arrhythmia elicited by reperfusion in canine Purkinje tissues.Key words: reperfusion, arrhythmias, catecholamines, canine Purkinje tissue, oscillatory afterpotentials, automaticity.
Carotid sinus pressure, blood volume, and vasopressin in the anaesthetized rabbit
Authors: Courneya C. A. , Wilson N. , Ledsome J. R.
Published: April 2011

Experiments were carried out on anaesthetized rabbits to determine the influence of carotid sinus pressure (CSP) on the changes in the plasma concentration of arginine vasopressin (AVP) that occurred in response to changing blood volume. The aortic depressor nerves were sectioned in all experiments and the vagus nerves remained intact. Both carotid sinuses were perfused at constant controlled pressure. Blood volume was increased (n = 10) or decreased (n = 10) by 10 and 20% of the estimated blood volume. Plasma immunoreactive arginine vasopressin concentration (IR-AVP) was significantly higher at a CSP of 60 mmHg (1 mmHg = 133.322 Pa) than it was at a CSP of 120 mmHg in both groups of animals. Increasing blood volume did not cause any significant change in IR-AVP at either carotid sinus pressure. Haemorrhage of 10% of the blood volume did not change IR-AVP. Haemorrhage of 20% of the blood volume significantly increased IR-AVP at both CSPs; the magnitude of the increase in IR-AVP was not altered by changing the CSP. No interaction was demonstrated between the effects of CSP and blood volume on plasma IR-AVP.Key words: carotid sinus pressure, arterial baroreceptors, vasopressin, blood volume.
The 1989 James A. F. Stevenson Memorial Lecture. The knee jerk: still an enigma?
Authors: Matthews Peter B. C.
Published: April 2011

This is a wide-ranging review of muscle proprioceptors, intended primarily for the nonspecialist. It emphasizes how much more they are concerned with, than just the production of the knee jerk; it concentrates on principle rather than documenting detail and cites selectively. The main topics covered are the effect of deafferentation, position sense, the proprioceptors themselves, the control of the muscle spindle by the CNS, and spinal and long-latency "stretch" reflexes. The emphasis is on human work. The knee jerk itself is seen as a "physiological artefact," resulting from a mode of stimulation that does not occur in life, with the normal function of its underlying circuitry still under debate.Key words: tendon reflex, stretch reflex, muscle afferents.
Corelease of neuropeptide Y like immunoreactivity with catecholamines from the adrenal gland during splanchnic nerve stimulation in anesthetized dogs
Authors: Briand Richard , Yamaguchi Nobuharu , Gagne Jacques , Kimura Tomohiko , Farley Lisa , Foucart Sylvain , Nadeau Reginald , Champlain Jacques de
Published: April 2011

The release of neuropeptide Y like immunoreactivity (NPY-li) from the adrenal gland was studied in relation to the secretion of catecholamines (CA:NE, norepinephrine; E, epinephrine) during the left splanchnic nerve stimulation in thiopental–chloralose anesthetized dogs (n = 16). Plasma concentrations of NE, E, and NPY-li were determined in the left adrenal venous and aortic blood. Adrenal outputs of NPY-li, NE, and E were 2.4 ± 0.4, 1.4 ± 0.2, and 7.3 ± 1.7 ng/min, under basal conditions, respectively. These values increased significantly (p < 0.05; n = 8) in response to a continuous stepwise stimulation at frequencies of 1, 3, and 10 Hz given at 3-min intervals during 9 min, reaching a maximum output of 4.6 ± 0.9 (NPY-li), 240.2 ± 50.2 (NE), and 1412.5 ± 309.7 ng/min (E) at a frequency of 10 Hz. Burst electrical stimulation at 40 Hz for 1 s at 10-s intervals for a period of 10 min produced similar increases (p < 0.05) in the release of NPY-li (4.8 ± 1.0 ng/min, n = 8), NE (283.5 ± 144.3 ng/min, n = 8), and E (1133.5 ± 430.6 ng/min, n = 8). Adrenal NPY-li output was significantly correlated with adrenal NE output (r = 0.606; n = 24; p < 0.05) and adrenal E output (r = 0.640; n = 24; p < 0.05) in dogs receiving the burst stimulation. The present findings demonstrate that NPY-li is coreleased with NE and E from the adrenal gland in response to direct splanchnic nerve stepwise or burst stimulation at high frequencies in anesthetized dogs. It is thus possible that the adrenal medullary NPY-li contributes to the modulation of circulating NPY-li levels under various physiopathological conditions.Key words: adrenal medulla, burst stimulation, catecholamines, corelease, neuropeptide Y, splanchnic nerves.
Enhanced in vivo sensitivity of vanadyl-treated diabetic rats to insulin
Authors: Ramanadham S. , Cros G. H. , Mongold J. J. , Serrano J. J. , McNeill J. H.
Published: April 2011

Vanadium has been reported to have insulin-like properties and has recently been demonstrated to be beneficial in the treatment of diabetic animals. In the present study, concentration dependence of the therapeutic effects of vanadium and the nature of interaction under in vivo conditions between vanadium and insulin were examined in streptozotocin-diabetic rats. During a 2-week period, blood glucose levels in all treated animals were decreased. At higher concentrations of vanadyl this decrease was greater and more rapid, and remained consistently lower for the entire treatment period. Daily intake of vanadyl, however, reached a similar steady state in all groups. Acute administration of submaximal doses of insulin, which had minimal effects in untreated diabetic rats, lowered blood glucose concentrations in vanadyl-treated and vanadyl-withdrawn animals to control levels. Chronic treatment of streptozotocin-diabetic rats with submaximal levels of vanadyl and insulin, ineffective alone, also produced significant decreases in blood glucose levels when used in combination. Finally, the insulin dosage required to maintain a nonglycosuric state in spontaneously diabetic (BB) rats was reduced in the presence of vanadyl. These studies indicate that chronic oral vanadyl treatment (a) produces a concentration-related lowering of blood glucose in diabetic rats, (b) potentiates the in vivo glucose lowering effects of acute and chronic administrations of insulin in streptozotocin-diabetic rats, and (c) substitutes for, or potentiates, the effects of chronic insulin therapy in spontaneously diabetic BB rats.Key words: vanadium, diabetes, insulin, blood glucose.
Fluid production by in vitro lungs from fetal guinea pigs
Authors: Perks A. M. , Dore J. J. , Dyer R. , Thom J. , Marshall J. K. , Ruiz T. , Woods B. A. , Vanderhorst E. , Ziabakhsh S.
Published: April 2011

Lungs from fetal guinea pigs (54–67 days of gestation) were supported in vitro, and lung liquid secretion rates were measured by a dye-dilution technique. The average secretion rate in the first hour was 2.14 ± 0.08 (SE) mL∙kg−1 body weight∙h−1 (0.21 ± 0.01 mL/h) (n = 450); this was comparable to intact preparations. In an independent study of 30 lungs, secretion continued unchanged for 3 h, with no significant change in fluid composition. Between 54 days and term, production appeared to fall in terms of millilitres per kilogram per hour. The following agents were placed in the supporting saline during the middle hour of incubation. (i) Sodium iodoacetate: at 10−4 M this produced a fall in secretion (fall, succeeding hours; 55.4 ± 23.0 and 64.9 ± 17.5%; n = 6); at 10−3 M it stopped secretion (fall, succeeding hours; 87.2 ± 10.3 and 100%, n = 6). (ii) Ouabain: at 10−5 M there was no change in production (n = 6); at 10−4 M, four preparations were unaffected, two reduced production. (iii) Epinephrine (10−7 M) produced a significant fall in production in all cases (n = 6); in four preparations secretion reduced (average fall, 64.4 ± 10.8%); in two preparations there was reabsorption (average rate, −1.03 mL∙kg−1∙h−1). This extends the effect of epinephrine to the guinea pig, and suggests that the in vitro preparation is a useful model for studies of the fetal lung.Key words: fetus, lung fluid, secretion, iodoacetate, epinephrine.
Intestinal microsomes: polyunsaturated fatty acid metabolism and regulation of enterocyte transport properties
Authors: Garg M. L. , Keelan M. , Thomson A. B. R. , Clandinin M. T.
Published: April 2011

Recent evidence has suggested that transport of nutrients from the lumen to the interior of the gastrointestinal epithelium and exit of nutrients from the enterocyte to the circulation is governed by physicochemical properties of brush border and basolateral membranes, respectively. The main determinants of membrane properties are phospholipid, cholesterol, and fatty acyl chain composition (chain length and degree of unsaturation). Lipid synthesis occurs in enterocyte microsomes and the fine tuning of lipid composition is done at other subcellular sites by deacylation–reacylation or by changing the polar head group (e.g., by phosphatidylethanolamine methyltransferase). The present paper will focus on the mechanisms by which enterocyte membranes adapt functional properties in response to external stimuli. It is proposed that under the influence of internal or external stress, the enzymes of lipid metabolism in microsomes are modulated. These changes in lipid synthesis are reflected in other subcellular membranes, changing their physicochemical status and thus transport phenomena. One of the initial events appears to be alteration in desaturase enzyme activity. Our results suggest that desaturase activity and the fatty acyl profiles of the intestinal mucosal phospholipid rapidly respond to physiological conditions such as fasting and dietary fat treatment.Key words: polyunsaturated fatty acids, desaturases, enterocyte, intestinal microsomes, adaptation.
Diabetes affects retrograde but not anterograde transport of sciatic nerve phosphofructokinase in Sprague–Dawley rats
Authors: Kilgour R. D. , Gardiner K. , Gardiner P. F.
Published: April 2011

Phosphofructokinase activity was measured in the sciatic nerve of streptozotocin-induced diabetic and nondiabetic rats. Average steady-state phosphofructokinase activity was obtained from three consecutive segments of the mid-femoral region in the left sciatic nerve in both diabetic (4 and 24 weeks) and nondiabetic, age-matched animals. Over time, phosphofructokinase activity significantly decreased (p < 0.05) with diabetes, with no effect demonstrated within similar age-groups. The accumulation of phosphofructokinase activity was accomplished by ligating the mid-femoral region of the right sciatic nerve for 24 h. Anterograde and retrograde axonal transport of phosphofructokinase was measured in the 3-mm segment proximal and distal to the ligature, respectively. There was a trend (p = 0.0627) towards a decline in net proximal accumulation (mean proximal minus mean background) with age. Net distal (mean distal minus mean background) activity declined by 80% (p < 0.05) in the control group between 4 and 24 weeks of the diabetic state. However, diabetic animals did not experience the same age-related decline in retrograde transport. The findings suggest that diabetes affects the age-associated evolution of retrograde transport, presumably a reflection of the neuropathy occurring in the distal axon branches, without altering anterograde transport to any appreciable extent.Key words: phosphofructokinase, slow axonal transport, sciatic nerve, diabetes, streptozotocin.
Tricyclic antidepressants inhibit voltage-dependent calcium channels and Na+–Ca2+ exchange in rat brain cortex synaptosomes
Authors: Lavoie P.-A. , Beauchamp G. , Elie R.
Published: April 2011

We have used a resting (5 mM K+) or depolarizing (60 mM K+) choline-based medium, and a nondepolarizing sodium-based or choline-based medium, to characterize the inhibitory potential of tricyclic antidepressants against the voltage-dependent calcium channels or the Na+–Ca2+ exchange process, respectively, in synaptosomes from rat brain cortex. Imipramine, desipramine, amitriptyline, and clomipramine inhibited net K+-induced 45Ca uptake with similar IC50 values (26–31 μM), and this uptake was also inhibited by diltiazem with an IC50 of 36 μM; these results indicate an inhibition of voltage-dependent calcium channels by tricyclic antidepressants. The net uptake of 45Ca induced by Na+–Ca2+ exchange was also inhibited by the four tricyclic antidepressants tested, but not by diltiazem; imipramine (IC50 = 94 μM) was a more potent inhibitor of this process than desipramine (IC50 = 151 μM), and the IC50 values of amitriptyline (107 μM) and clomipramine (97 μM) were similar to that of imipramine. Some degree (~25%) of brain calcium channel blockade could be present at the steady-state concentrations of tricyclic antidepressants expected to occur during therapeutic use of these compounds to treat depression or panic disorder.Key words: voltage-dependent calcium channels, Na+–Ca2+ exchange, synaptosomes, tricyclic antidepressants, diltiazem.
Structural characterization of interstitial cells of Cajal in myenteric plexus and muscle layers of canine colon
Authors: Berezin I. , Huizinga J. D. , Daniel E. E.
Published: April 2011

We have carried out a detailed ultrastructural study of the interstitial cells near the myenteric plexus of the canine colon and defined the structural characteristics which distinguish them from other resident non-neural cells. We have also examined the interconnections of these interstitial cells with nerves, the longitudinal muscle, and the circular muscle. In addition, we sought connections between interstitial cells of the myenteric plexus and those described earlier at the inner border of the circular muscle in proximal and distal colon. The interstitial cells of the myenteric plexus were structurally distinctive, and made gap junctions with one another and occasionally with smooth muscle. There seemed to be two subsets of these interstitial cells, one associated with the longitudinal muscle and the other with the circular muscle. Cells of both subsets were often close (≤20 nm) to nerve profiles. The interstitial cells near the longitudinal muscle layer penetrated slightly into the muscle layer, but those near the circular muscle did not and neither set contacted the other. Moveover, interstitial cells of Cajal located near the myenteric plexus were never observed to contact those at the inner border of circular muscle. The interstitial cells of Cajal at the canine colon myenteric plexus are structurally organized to provide independent pacemaking activities for the longitudinal and adjacent circular muscle. Their dense innervation suggests that they mediate neural modulation of intestinal pacemaker activities. Moreover, they lack direct contacts with the interstitial cell network at the inner border of circular muscle, which is essential for the primary pacemaking activity of circular muscle. The structural organization of interstitial cells in canine colon is consistent with their proposed role in pacemaking activity of the two muscle layers.Key words: pacemakers, neuromodulation, interstitial cells of Cajal.
Myosin heavy chain isoform distribution in normal and hypertrophied rat aortic smooth muscle
Authors: Stephens N. L. , Halayko A. J. , Swynghedauw B.
Published: April 2011

Causes of hypertension have been well scrutinized, whereas the secondary, disabling effects of high blood pressure are less well investigated. We have used a rat model of hypertension and developed a technique to study the secondary vascular smooth muscle component of the disorder. Banding patterns of myosin heavy chain isoforms from rat aortae were examined using denaturing electrophoresis, Western blotting, immunochemical identification, and degradation studies. Myofibrillar ATPase activities were also measured. Left ventricular hypertrophy and hypertension were induced in rats by aortic banding just proximal to the renal artery. Aortic banding increased the heart weight/body weight (mg/g) ratio from 2.8 to 3.8 and mean aortic weight by 53%. Two distinct myosin heavy chain isoforms, molecular masses of 204 and 200 kDa, were identified by 4% sodium dodecyl sulphate – polyacrylamide electrophoresis of crude aortic extracts from normal rats in a relative molar ratio of 1.54:1. The development of significant thickening of the aorta was marked by substantial increases in aortic wall smooth muscle content but was not associated with any changes in distribution of the isoforms. The band patterns obtained on gel electrophoresis were not the result of contamination by other proteins, as Western blotting studies with specific antibodies demonstrated that the isoforms were smooth muscle in origin and were not derived from nonmuscle myosin sources. Myofibrillar ATPase activity of aortic smooth muscle from hypertensive rats was increased. It is suggested that this increase may be the result of post-transcriptional alterations of one or more sarcomeric proteins involved in the regulation of smooth muscle contraction.Key words: myosin, isoforms, aorta, hypertension.
The effect of L-glutamate and related agents on adenylate cyclase in the cestode Hymenolepis diminuta
Authors: Eklove Harley , Webb Rodney A.
Published: April 2011

The effect of the putative amino acid transmitter, L-glutamate, on adenylate cyclase in crude membrane preparations of the rat tapeworm Hymenolepis diminuta was investigated to determine if glutamate effects the generation of the second messenger cAMP. Addition of glutamate at 10−3 and 5.5 × 10−9 M resulted in significant elevations in basal activity of adenylate cyclase, while concentrations in the 10−5–10−7 M range caused significant depressions below basal activity. Assays with glutamate agonists and other acidic compounds showed glutamate to be the only amino acid, dicarboxylic acid, or acidic compound capable of this pattern of stimulation and inhibition. While the response of adenylate cyclase to glutamate agonists suggested that an N-methyl-D-aspartic acid (NMDA) type receptor may be present, glutamate agents acting as NMDA antagonists in vertebrate systems were agonists. Metabolic end products of glycolysis stimulated adenylate cyclase, suggesting that these, along with metabolic glutamate may regulate glycolytic enzymes. Only 10−3 M L-glutamate significantly stimulated adenylate cyclase activity in tissue slices, and this response was restricted to those slices rich in nervous tissues. L-Glutamate eliminated the 5-hydroxytryptamine (5-HT) stimulated adenylate cyclase response suggesting that glutamate can modulate the 5-HT stimulated elevations in adenylate cyclase activity. The data support the hypothesis that L-glutamate is a neurotransmitter–modulator in the cestode.Key words: L-glutamate, cAMP, cestode, modulator.
Estimation of the amount of dietary starch available to different populations
Authors: Bright-See Elizabeth , Jazmaji Vartouhi
Published: April 2011

The daily per capita availability of dietary starch was estimated for 38 selected countries using food disappearance data from the FAO provisional food balance sheets (1972–1974 average); starch availability was also estimated for Canada from 1960 to 1987 using Agriculture Canada disappearance data. Total starch availability varies fourfold among the different countries; the availability of different sources of starch vary up to 80-fold. Wheat and roots–tubers were the major sources of starch in countries with low total starch availability. Either corn and pulses, rice and pulses, or wheat and potatoes were the major sources of starch in those countries with high total starch availability. Starch availability in Canada, both total and by source, has been relatively constant over the 27 years examined. Slight increases in total starch and starch from cereals and pulses in 1987 will need to be followed to determine whether these represent the beginning of a real change in per capita starch availability.Key words: starch, availability.
Small intestinal effects of starchy foods
Authors: Wolever Thomas M. S.
Published: April 2011

Recent dietary guidelines advocate increased starch intake, but it is not clear as to how the increased intake of starch should be achieved. Recent data suggest that the quality of starch as well as its quantity is important in determining the biological effects of high carbohydrate diets. The quality of starchy foods can be assessed by their rates of digestion, which in turn are related to their glycaemic responses. Many factors affect the rate of digestion of foods and these are probably related to alterations in the chemical structure or nature of the starch. The incorporation of slowly digested, low glycaemic index foods into the diets of healthy subjects and individuals with diabetes and hyperlipidaemia is associated with the predicted reductions in postprandial glycaemic responses and with reductions in insulin secretion and blood lipids. In the past, the aim of starch processing has been to increase digestibility and improve absorption. However, it is now suggested that the use of more slowly digested starchy foods may have positive health benefits.Key words: carbohydrate, blood glucose responses, diet, small intestine, colonic fermentation.