bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduced vulnerability of the hypertrophied rat heart to oxygen-radical injury
Authors: Gupta Madhu , Gameiro Annabel , Singal Pawan K.
Published: April 2011

Effects of xanthine – xanthine oxidase produced oxygen radicals were studied in hypertrophied rat hearts in a Langendorff preparation. Heart hypertrophy was produced by banding of the abdominal aorta for 6 weeks. This resulted in a 22% increase in ventricle/body weight ratio compared with that of sham-operated controls. Perfusion with xanthine – xanthine oxidase caused contractile failure and a significant rise in the resting tension. Complete contractile failure in hypertrophied hearts was seen at 25.5 ± 3.2 min, whereas in control hearts it happened at 14.4 ± 5.6 min. Contractile failure due to oxygen radicals in both groups was associated with a decline in high energy phosphates, increased lipid peroxidation, and extensive structural damage. Sarcolemma in both groups became permeable to the extracellular tracer lanthanum. As compared with control, in hypertrophied hearts the malondialdehyde content, indicative of lipid peroxidation, was less by 40%; whereas superoxide dismutase, a free radical scavenger, was higher by a similar amount. These data show a greater capacity of the 6-week hypertrophied heart to withstand a free radical induced contractile failure. This delay in oxygen radical effect can be partially explained by the reduced lipid peroxide content and increased superoxide dismutase activity in the hypertrophied hearts.
Effects of hypoxia on lung mechanics in the newborn cat
Authors: Fisher John T. , Waldron Mark A. , Armstrong Craig J.
Published: April 2011

The present study was designed to investigate the effects of hypoxia on lung mechanics in the newborn cat and to determine if vagal efferent innervation to the airways is involved in the response. We studied 11 animals, aged 2–7 days, anesthetized with a mixture of chloralose–urethane administered intraperitoneally. A tracheal cannula was inserted just below the larynx and following paralysis (pancuronium bromide), mechanical ventilation was initiated. A pneumothorax was created by a midline thoracotomy and an end-expiratory load was applied to maintain functional residual capacity. Animals were placed in a flow plethysmograph from which measurements of transpulmonary pressure, flow, and volume, mean inspiratory resistance, and dynamic compliance of the lung were calculated. The experimental protocol consisted of a series of 8-min trials, each preceded by a controlled volume history. The hypoxia challenge was composed of 1 min of ventilation with 40% O2, followed by 5 min exposure to 10% O2 and 2 min of recovery. In the majority of animals (7 out of 11), hypoxia had no effect on lung mechanics compared with control trials. Four animals responded to hypoxia with an increase in resistance and a decrease in compliance. Resistance remained elevated throughout the hypoxia with an average maximal increase of 47.2 ± 22.2% (SD). Dynamic compliance was significantly decreased at the 2nd, 3rd, and 4th min only of hypoxia. Bilateral vagotomy abolished the response in the four animals and hypoxia had no effect on mechanics postvagotomy. Our data suggest that in most cases changes in lung mechanics do not play a causal role in the biphasic ventilatory response to hypoxia seen in the newborn.
The development of a febrile response to pyrogen in the thyroid-deficient rabbit
Authors: Macari M. , Pelá I. R. , Silva C. A. A.
Published: April 2011

The development of the febrile response to E. coli lipopolysaccharide (1.5 μg/kg, i.v.) in thyroid-deficient rabbits has been studied. Twenty-eight New Zealand White rabbits weighing 2.1 – 2.3 kg were used. Hypothyroidism was induced by treatment with propylthiouracil (100 or 200 mg/kg body wt./15 days). Thyroid-deficient animals showed a reduction in the febrile response to lipopolysaccharide, but the effect was significantly different (p < 0.01) from the control only for rabbits treated with 200 mg/kg of propylthiouracil. Propranolol (2 mg/kg, i.p.) given 30 min before lipopolysaccharide also reduced (p < 0.01) the fever response in control rabbits. The results of this experiment are consistent with the hypothesis that the reduction in the febrile response of thyroid-deficient rabbits is due to the reduced number of β-adrenergic receptors, or to a change in the availability of neurotransmitter in thermogenically active tissues, such as brown fat.
Thermoregulation and diurnal rhythms in 1-week-old rat pups
Authors: Schmidt Ingrid , Kaul Randy , Heldmaier Gerhard
Published: April 2011

This paper reviews the ontogeny of thermoregulation and diurnal rhythmicity in rats. Additionally, original data are presented that indicate the emergence of an endogenous circadian core temperature rhythm during the first postnatal week. Despite neurological immaturity, newborn rats display autonomic and behavioral thermoregulatory responses within 24 h of birth. Their "biological clock" is already running before birth. The thermal environment of pups changes cyclically owing to diurnal variations in maternal behavior, but the core temperatures of 1-week-old pups huddling in the absence of the dam also show marked diurnal fluctuations. Five- to 8-day-old lean Zucker rat pups artificially reared in the absence of 24-h cycles of ambient temperature and food intake show diurnal changes in core temperature similar to those in huddling mother-reared pups. Diurnal core temperature changes, evident only when regulatory effectors are not overwhelmed, are one of the first self-maintained diurnal rhythms to appear. Because thermoregulation and circadian rhythmicity both appear before maturation of the neural networks believed to be critical for their control in adult animals, studying the immature rat might increase our understanding of the control of these processes in the more complex mature central nervous system.
Effects of endogenous pyrogen and prostaglandin E2 on hypothalamic neurons in rat brain slices
Authors: Watanabe Tatsuo , Morimoto Akio , Murakami Naotoshi
Published: April 2011

We investigated the effects of endogenous pyrogen and prostaglandin E2 (PGE2) on the preoptic and anterior hypothalamic (POAH) neurons using brain slice preparations from the rat. Partially purified endogenous pyrogen did not change the activities of most of the neurons in the POAH region when applied locally through a micropipette attached to the recording electrode in proximity to the neurons. This indicates that partially purified endogenous pyrogen does not act directly on the neuronal activity in the POAH region. The partially purified endogenous pyrogen, applied into a culture chamber containing a brain slice, facilitated the activities in 24% of the total neurons tested, regardless of the thermal specificity of the neurons. Moreover, PGE2 added to the culture chamber facilitated 48% of the warm-responsive, 33% of the cold-responsive, and 29% of the thermally insensitive neurons. The direction of change in neuronal activity induced by partially purified endogenous pyrogen appears to be almost the same as that induced by PGE2 when these substances were applied by perfusion to the same neuron in the culture chamber. These results suggest that partially purified pyrogen applied to the perfusate of the culture chamber stimulates some constituents of brain tissue to synthesize and release prostaglandin, which in turn affects the neuronal activity of the POAH region.
An endogenous digitalis-like compound extracted from human urine: biochemical and chemical studies
Authors: Cloix Jean-François , Crabos Maryse , Grichois Marie-Laure , Meyer Philippe
Published: April 2011

Plasma and urine levels of an endogenous digitalis-like compound (EDLC) are increased in low renin Na+-dependent experimental hypertension, in some normotensive offspring of hypertensive patients and in some essential hypertensive patients. Urine-drived EDLC was purified from 550 L of urine from essential hypertensive patients (n = 8) and from normotensive subjects with a family history of hypertension (n = 27), using flash chromatography on C18 reversed-phase, anion exchange chromatography and various reversed-phase high performance liquid chromatographies. The mechanism of Na+–K+ ATPase inhibition and the related effects of semipurified urine-derived EDLC were studied and compared with those of ouabain. Its action was similar to that of ouabain in 8 out of 10 of the tests applied. The main effects of such a compound were the depression of Na+–K+ pump activity of human erythrocytes, the inhibition of 5-hydroxytryptamine reuptake by human platelets, and the induction of natriuresis in urethanized rats. Therefore, EDLC may be considered as one of the natriuretic hormones whose mechanism of action closely resembles that of ouabain.
Vasomotor control by subretrofacial neurones in the rostral ventrolateral medulla
Authors: Dampney R. A. L. , Goodchild A. K. , McAllen R. M.
Published: April 2011

In this paper we review our recent work in the rabbit and cat on the role of the rostral ventrolateral medulla in cardiovascular regulation. Microinjection of neuroexcitatory amino acids into a highly circumscribed region, located just ventral to the retrofacial nucleus at the level of the rostral part of the inferior olive, leads to an increase in blood pressure, owing to sympathetic vasoconstriction. Bilateral destruction of this region, which we have termed the subretrofacial nucleus, leads to a profound fall in blood pressure. Anatomical studies show that the subretrofacial nucleus contains a compact group of bulbospinal neurones that project to sympathetic preganglionic nuclei in the thoracolumbar spinal cord. Single-unit recording studies have shown that these bulbospinal neurons are spontaneously active and are powerfully inhibited by baroreceptor inputs. These observations indicate that the subretrofacial bulbospinal cells are sympathoexcitatory and play a major role in the tonic and phasic control of the cardiovascular system. Some important unresolved questions regarding the subretrofacial neurones will be discussed. (i) Are they functionally homogeneous, or are they viscerotopically organized with respect to particular end organs? (ii) What are their afferent inputs? (iii) What are their histochemical properties? Specifically, are they part of the group of adrenaline-synthesizing cells, or alternatively, substance P cells?
Endorphinergic mechanism in the central cardiovascular and analgesic effects of clonidine
Authors: Kunos G. , Mosqueda-Garcia R. , Mastrianni J. A. , Abbott F. V.
Published: April 2011

In urethane-anesthetized male rats, injection of 5 nmol clonidine into the nucleus of the solitary tract (NTS) causes hypotension and bradycardia. These effects are greater in spontaneously hypertensive rats (SHR) and normotensive Sprague–Dawley (SD) rats than in normotensive Wistar–Kyoto (WKY) rats. The effects of clonidine are stereoselectively inhibited by 100 ng intra-NTS naloxone in SHR and SD but not in WKY rats. In SHR, the effects of clonidine are also inhibited by intra-NTS administration of ICI 174864 (a δ-receptor antagonist) but not by β-funaltrexamine (a μ-receptor antagonist), while in SD rats only the μ- and not the δ-antagonist was effective. Neonatal treatment of SHR with monosodium glutamate (MSG) reduced the β-endorphin content of the arcuate nucleus and the NTS, reduced the cardiovascular effects of clonidine, and abolished their naloxone sensitivity. MSG treatment of newborn WKY reduced the β-endorphin content of the arcuate nucleus but not the NTS and did not affect the responses to clonidine. Measurement of pain sensitivity by the formalin test indicated that clonidine was more potent as an analgesic in SHR and SD than in WKY rats, and its effect was inhibited by naloxone (2 mg/kg i.p.) in the former two strains but not in WKY. It is proposed that a naloxone-sensitive component of the cardiovascular effects of clonidine is due to release of a β-endorphin-like opioid from the NTS, and that this mechanism is present in SHR and SD but not in WKY rats. The opiate receptors mediating the effects of the opioid appear to be of the μ-subtype in SD rats and of the δ-subtype in SHR. The results also support a close relationship between central cardiovascular and pain regulatory mechanisms.
The actions of atrial natriuretic factor on the vascular wall
Authors: Vlasuk George P. , Babilon Robert W. , Nutt Ruth F. , Ciccarone Terry M. , Winquist Raymond J.
Published: April 2011

The actions of atrial natriuretic factor (ANF) on the vascular wall are diverse and show a profound regional heterogeneity. ANF is a potent relaxant of aortic smooth muscle, a response which is associated with activation of particulate guanylate cyclase and elevation in tissue levels of cyclic GMP. However, many large and small muscular arteries and most veins are unresponsive to the peptide. The regional vascular heterogeneity may be due to an altered distribution of high affinity receptors and (or) alterations in the coupling of receptor activation to elevations in cyclic 3′,5′-guanosine monophosphate (cGMP). Species differences exist in the structural requirements for receptor activation as well as the effects of infused ANF on peripheral resistance. Although the relaxation to ANF in vitro does not require an intact endothelium, endothelial cells contain multiple receptor subtypes for ANF. Differences amongst tissues and (or) species in the receptor profile for ANF may, in part, explain some of heterogeneity in responsiveness to ANF.
The cardiovascular amplifiers in human primary hypertension and their role in a strategy for detecting the underlying causes
Authors: Korner P. I. , Jennings G. L. , Esler M. D. , Anderson W. P. , Bobik A. , Adams M. , Angus J. A.
Published: April 2011

The present review considers evidence that in chronic hypertension, hypertrophy of the muscles of the resistance vessels and left ventricle (LV) accounts for their intrinsic properties as haemodynamic amplifiers. In spontaneously hypertensive rats (SHR) there is early hypertrophy of both vessels and LV, suggesting that they may initiate hypertension; slow development of α-adrenoceptors may contribute to the early preponderance of the LV amplifier. In human hypertension LV hypertrophy occurs in most patients, including a high proportion of mild hypertensives. In Goldblatt one-kidney hypertension the stenosis resistance, which is the initiating cause, accounts for 25% of the rise in blood pressure throughout, with 75% initially due to systemic constrictor action of angiotensin II and later due to the amplifier properties of the hypertrophied heart and vessels. The cardiovascular amplifiers must be important in all chronic hypertension, so that if hypertrophy can be reversed, detection of the initiating mechanism should be easier. Studies in patients indicate that drug therapy can reverse hypertrophy and that subsequent redevelopment of hypertension is markedly slowed. We postulate an intrinsic disturbance of muscle performance in all primary hypertension, which may be triggered through the sympathetic nervous system in some patients and through altered cation transport in others.
The effect of 3-methylindole on the rates of phospholipid and neutral lipid synthesis in cultured fibroblasts
Authors: Kirkland James B. , Bray Tammy M. , Bettger William J.
Published: April 2011

The present study was designed to test the hypothesis that a pneumotoxin, 3-methylindole, alters the basic metabolic pathways involved in phospholipid and neutral lipid synthesis in cultured fibroblasts. Rat skin fibroblasts were obtained from day-old pups. Confluent monolayers were preincubated for up to 24 h with a range of concentrations (0–0.76 mM) of 3-methylindole. Following these treatments, the cell lipids were labelled by incubation for 6 h with [14C]glycerol. The lipids were extracted, separated by thin layer chromatography, and the radioactivity in each fraction was determined. 3-Methylindole had no effect on the total incorporation of [14C]glycerol into lipids, but significantly altered the the distribution among lipid fractions. Incubation with 3-methylindole caused a decrease in the incorporation of [14C]glycerol into phosphatidylcholine, while radioactivity accumulated in the neutral lipid fraction. The other lipid fractions responded variably. Similarity, Flow 2000 human diploid lung fibroblasts were incubated for 24 h with 3-methylindole followed by treatment with [14C]glycerol, resulting in a 74% decrease in the incorporation of [14C]glycerol into phosphatidylcholine and a 50% increase in its accumulation in neutral lipid. The results indicate that 3-methylindole inhibits the synthesis of phosphatidylcholine from diacylglycerol precursors on the endoplasmic reticulum in cultured fibroblasts. This is an important observation as it shows that 3-methylindole affects the synthesis of phospholipids required for membrane turnover in cells that are not specialized for the production of phospholipids for surfactant.
From arthritis to Alzheimer's disease: current concepts on the pathogenesis of amyloidosis
Authors: Kisilevsky R.
Published: April 2011

Amyloid is a generic term referring to a group of diverse but specific extracellular protein deposits which all have common morphologic properties, staining characteristics, and x-ray diffraction and infrared spectra. This review considers the new classification of amyloids, based on the underlying peptides forming the protein fibril, and their diversity. The pathogenesis of inflammation-associated amyloid and its relationship to high density lipoprotein metabolism is examined in detail. The lessons learned from models of inflammation-associated amyloid are extended to the other amyloids (e.g., Alzheimer's disease), and potential reasons for the common structural properties of all amyloids are explored.
Calcium channels and excitation–contraction coupling in cardiac cells. II. A pharmacological study of the biphasic contraction in guinea-pig papillary muscle
Authors: Honoré E. , Adamantidis M. M. , Dupuis B. A. , Challice C. E. , Guilbault P.
Published: April 2011

Biphasic contractions were obtained in guinea-pig papillary muscle by inducing partial depolarization in K+-rich solution (17 mM) in the presence of 0.3 μM isoproterenol. Mn2+ ions inhibited the two components of contraction in a similar way. Nifedipine and particularly Cd2+ ions specifically inhibited the second component of contraction. Isoproterenol and BAY K 8644 markedly increased the amplitude of the second component (P2) of contraction. Nevertheless, a moderate positive inotropic effect of isoproterenol was found on the first component (P1) of contraction when excitability was restored by 0.2 mM Ba instead of isoproterenol. Acetylcholine and hypoxia decreased the amplitude of the second component of contraction to a greater extent. In the presence of digoxin or Na+-free solution, P1was strongly increased. When sarcoplasmic reticular function was hindered by 1 mM caffeine or in the presence of Ca2+-free Sr2+ solution, digoxin always induced a negative inotropic effect on P2. Inversely in these conditions the transient positive inotropic effect of Na+-free solution was strongly reduced. These results are consistent with the hypothesis that the late component of contraction is triggered by the slow inward Ca2+ current and that the early component is due to Ca2+ release from the sarcoplasmic reticulum.
Responsiveness of isolated tracheal smooth muscle from normal and sensitized guinea pigs
Authors: Mansour S. , Daniel E. E.
Published: April 2011

Studies of the responsiveness of strips of tracheal smooth muscle and the changes after sensitization of ovalbumin were carried out. The hypothesis that there might be a generalized or a selective change of airway smooth muscle responsiveness to sensitization was examined in vitro. Agonists acting on muscarinic receptors, α1-, α2-, and β-adrenoceptors, purine receptors, histamine and serotonin receptors, and leukotriene and prostaglandin receptors were tested, as well as mediators released from local nerves by field stimulation and procedures such as elevation of potassium or addition of Ca2+ ionophores which do not involve specific receptors. Sensitivity to serotonin increased significantly in sensitized animals. Total magnitude of the contraction and subsequent relaxation responses to field stimulation also increased significantly. Neither of these changes was large in magnitude. Although there were a few minor changes in sensitivity (pD2) or in maximum responses, the hypothesis of important changes in responses of any sort in tracheal muscle after sensitization was rejected. The question was raised whether this general absence of changed responsiveness in vitro reflected (i) the failure of sensitization to induce generalized smooth muscle hyperresponsiveness, (ii) the loss of the mechanisms of such responsiveness in vitro, or (iii) the inadequacy of in vitro techniques to assess responsiveness present in vivo.
On the shoulders of giants: the discovery of atrial natriuretic factor
Authors: Bold Adolfo J. de
Published: April 2011

Investigations culminating at the beginning of this century clearly established that the cardiac muscle cell (cardiocytes) is differentiated for excitation, conduction, and contraction. All of the physiology and pathophysiology of the heart was developed subsequently based on this concept. However, morphological investigations in the mid 1950s suggested a secretory function for mammalian atrial cardiocytes. These cells contain storage granules, the specific atrial granules, which resemble granules found in polypeptide hormone-producing cells. The development of techniques for the study of these granules using a combined biochemical–morphological approach during the 1970s defined their general chemical nature and their behaviour under different experimental conditions. Because the number of atrial granules change dramatically following upsets of water and electrolyte balance, atrial muscle extracts were tested for effects on kidney function. In 1981, it was reported that atrial extracts contain a natriuretic factor (ANF) capable of inducing massive diuresis, increases in hematocrit, and lowering of blood pressure. It was demonstrated soon thereafter that ANF is stored within specific atrial granules. More recent work has defined ANF as a polypeptide hormone that appears to modulate or antagonize the renin – angiotensin – aldosterone system. Current work attempts to define the physiological and pathophysiological role for ANF as well as possible therapeutic uses.
Ca2+ channel ligand activities in uterine smooth muscle: influence of hormonal status
Authors: Ruzycky A. L. , Crankshaw D. J. , Triggle D. J.
Published: April 2011

The effects of estrogen and progesterone domination, achieved by administering estrogen (E) and estrogen plus progesterone (E+P), on rat uterine reactivity to Ca2+ and to Ca2+ channel ligands (antagonist and activator) were compared. The inhibitory activities of nifedipine, diltiazem, and D 600 against K+ depolarization-induced responses were not significantly different between E- and E+P-dominated states in longitudinal or circular muscle preparations. Tonic responses were significantly more sensitive than phasic responses, but the rank orders of activity for a series of 14 antagonists were identical, suggesting the existence of a common structure–activity relationship which paralleled that seen previously in other smooth muscles. E+P-dominated uteri were slightly more sensitive to Ca2+ responses in K+ depolarizing media, but pA2 values for nifedipine, diltiazem, and D 600 inhibition were not significantly different in tissues from animals in either hormone-dominated state. Binding of [3H]nitrendipine did not differ between hormonal states. Responses to Bay K 8644 were larger in E+P-dominated uteri but the binding density was twofold greater in the E-dominated uterus. This study suggests that pathways of Ca2+ mobilization through potential-dependent Ca2+ channels in rat uterus are not significantly altered between E- and E+P-dominated environments.
Persistence of the electrophysiologic effects of mexiletine in canine Purkinje fibers alters the response to subsequent hypoxia
Authors: Berman Neil D. , Ogilvie Richard I. , Loukides James E.
Published: April 2011

The persistence of cellular electropharmacologic effects of mexiletine on canine Purkinje fibers was studied utilizing standard microelectrode techniques and two different protocols. In the first, the tissue was exposed to hypoxic perfusion before and 30 min after perfusion with one of the following: mexiletine hydrochloride 6.25 μM solution, mexiletine hydrochloride 12.5 μM solution, or drug-free Tyrode's solution. With the higher concentration of mexiletine, depression of the maximal upstroke velocity [Formula: see text] persisted 30 min after drug washout and subsequent exposure to hypoxia did not result in the anticipated shortening of action potential duration but did prevent the restoration of normal [Formula: see text]. After perfusion with the lower concentration of mexiletine, [Formula: see text] was not depressed and hypoxic action potential duration shortening was not prevented. In the second protocol, Purkinje fibers were perfused with 12.5 μM mexiletine hydrochloride solution and then exposed to hypoxia after 15, 30,45, or 60 min of perfusion with drug-free solution. Depression of maximal upstroke velocity and shortening of action potential duration persisted during washout, returning to control values by 45 min, although mexiletine was not detectable in the tissue bath after 10 min of washout. Hypoxia initiated at 15 or 30 min of washout failed to produce the anticipated shortening of action potential duration. At 45 and 60 min, action potential duration was shortened by hypoxia. We concluded that mexiletine depression of [Formula: see text] and shortening of action potential duration may persist in the absence of drug. Further shortening of action potential duration in response to hypoxia is prevented during this period. The persistence of [Formula: see text] depression is prolonged by hypoxia.
Precursor utilization of 5-hydroxytryptophan for 5-hydroxytryptamine biosynthesis in isolated and perfused rabbit and rat lungs
Authors: Rao Kodavanti S. Prasada , Mehendale Harihara M.
Published: April 2011

The present study was designed to investigate whether lungs can utilize 5-hydroxytryptophan (5-HTP), formed elsewhere and transported, for the synthesis of 5-hydroxytryptamine (5-HT). [14C]5-HTP uptake was 7.7 ± 1.1 and 3.9 ± 0.2% by rabbit and rat lungs, respectively, after 1 h of perfusion with 10 μM [14C]5-HTP. There was an increase in the lung uptake of [14C]5-HTP when the lungs were preperfused with 0.5 mM chlorphentermine (CP) and the uptake was low when the lungs were preperfused with 0.1 mM hydroxybenzylhydrazine dihydrochloride (HBH). The perfusate concentration of 5-hydroxyindole acetic acid (5-HIAA) increased significantly (3–4 μg/100 mL) during rabbit lung perfusion with 10 μM [14C]5-HTP and this did not change significantly when the lungs were preperfused with 0.5 mM CP. However, 5-HT increased with time in the perfusate, 5-HT, but not 5-HIAA, was detected in the perfusate and increased with time of perfusion when the rat lungs were perfused either with 10 μM 5-HTP or with 0.5 mM CP and 10 μM 5-HTP. However, no metabolites were detected in either the rabbit lung or rat lung perfusates when they were preperfused with 0.1 mM HBH. Lung contents of 5-HT and 5-HIAA were significantly higher in the rat lungs and only 5-HIAA increased in rabbit lungs after 1 h of perfusion with 10 μM 5-HTP. Preperfusion with 0.5 mM CP resulted in a greater increase in the 5-HT content of both rabbit and rat lungs. When the lungs were preperfused with 0.1 mM HBH, [14C]5-HT formation from [14C]5-HTP was obtunded. Homogenates of rabbit and rat lungs incubated with [14C]5-HTP (10 μM) resulted in the formation of substantial amounts of [14C]5-HT and [14C]5-HIAA. Incubations with CP (0.5 or 1 mM) resulted in significant increases of 5-HT levels and a corresponding significant reduction in 5-HIAA levels. On the other hand, incubations with HBH (0.1 mM) resulted in significant inhibition of 5-HT and 5-HIAA formation. 5-HT formation from 5-HTP by rat and rabbit lungs in in vitro incubations is in consonance with the perfusion experiments. These results provide evidence that lung can synthesize 5-HT from the circulating 5-HTP, and pulmonary contribution of 5-HT to the circulating levels is possible.
Generation of spiking activity in circular muscle cells of the canine colon
Authors: Huizinga Jan D. , Barajas-Lopez Carlos , Chow Edwin
Published: April 2011

Spontaneous and current-induced electrical activity was recorded intracellularly to resolve the controversy whether or not the circular muscle layer of the colon generates spiking activity. Particularly in the first hour after mounting the tissue in the organ bath, spikes were recorded at both the submucosal and the myenteric plexus side of the muscle layer. Spikes were seen as part of the slow wave upstroke in the submucosal surface cells, and spikes occurred both at the upstroke potential and superimposed on the plateau potential in myenteric plexus surface cells. Spikes increased the force of contraction. The study supports earlier claims using extracellular recording techniques that circular muscle cells generate spiking activity, particularly in the presence of depolarizing stimuli, and that spikes contribute to contractile activity.
Pressor inhibition of angiotensin-induced ACTH secretion
Authors: Kucharczyk John , Cowan John , Layberry Ross
Published: April 2011

We investigated whether the pressor effects of systemically administered angiotensin II (AII) influence ACTH secretion. Adrenalectomized barbiturate-anesthetized mongrel dogs with constant low resting cortisol concentrations due to slow constant cortisol infusion received either bolus injections (2.5 μg kg−1) or 15-min i.v. infusions of a low dose (12.5 ng kg−1 min−1) of AII during which blood samples were taken for ACTH and cortisol determinations. In sequential continuous experiments in each dog, blood pressure was allowed to increase in response to AII administration or was controlled by means of concurrent i.v. injections or infusions of the hypotensive drug papaverine, or by blood withdrawal from the vena cava. When the arterial pressure rise induced by AII was substantially attenuated or prevented by papaverine administration or blood withdrawal, mean ACTH secretion rates increased 400–800% and mean ACTH concentrations increased by 280–500%. On the other hand, AII administration alone caused large increases in mean arterial blood pressure but did not increase ACTH secretion significantly above control levels. These data suggest that when endogenous AII levels are elevated without a concurrent increase in blood pressure, as occurs during hypovolemia or sodium depletion, AII may have a significant influence on ACTH secretion.
The 1986 Borden Award Lecture. The role of the kidney in amino acid metabolism and nutrition
Authors: Brosnan John T.
Published: April 2011

Measurement of the arteriovenous differences for free amino acids across rat kidney reveals that glycine and citrulline are removed and serine and arginine are added to the circulation. In addition, glutamine is taken up in large quantities by kidneys of animals that need to excrete large quantities of acid (e.g., diabetic animals, NH4Cl-fed animals, and animals fed a high protein diet). Glutamine is the major precursor of urinary ammonia and thus renal glutamine metabolism plays a key role in acid–base homeostasis. This process occurs primarily in the cells of the convoluted proximal tubule. Glutamine carbon is converted to glucose in acidotic rats and is totally oxidized in dogs. Regulation of glutamine metabolism occurs at two levels: acute regulation and chronic regulation. Acute regulation is, in part, mediated through a fall in intracellular [H+]. This activates α-ketoglutarate dehydrogenase and, ultimately, glutaminase. Chronic regulation involves induction of key enzymes, including, in the rat, glutaminase, glutamate dehydrogenase, and phosphoenolpyruvate carboxykinase. During the acidosis of prolonged starvation, the kidneys' requirement for glutamine must be met from muscle proteolysis and thus becomes a drain on lean body mass. Serine synthesis occurs by two separate pathways: from glycine by the combined actions of the glycine cleavage enzyme and serine hydroxymethyltransferase and from gluconeogenic precursors using the phosphorylated-intermediate pathway. Both pathways are located in the cells of the proximal tubule. Conversion of glycine to serine is ammoniagenic and the activity of the glycine cleavage enzyme is increased in acidosis. The function of serine synthesis by the phosphorylated-intermediate pathway is not apparent. Renal serine synthesis is quantitatively important; in man it is comparable to the serine obtained in the diet. Nevertheless, renal serine synthesis was not sensitive to serine status in rats as neither removal of dietary serine nor supplementation of the diet with serine affected renal serine synthesis. Arginine synthesis occurs from citrulline removed from the circulation. The citrulline is produced in the intestine. The kidney is the major endogenous source of arginine.
Opposing actions of the enantiomers of BAY-K-8644 on calcium currents and ACTH secretion in clonal pituitary corticotrophs
Authors: MacDonald J. F. , Miljkovic Z. , Heisler S.
Published: April 2011

BAY-K-8644 in low concentrations is known to stimulate, and in higher concentrations, to depress calcium-dependent ACTH secretion from mouse clonal (tumor) pituitary corticotrophs, AtT-20/D16-16 (AtT-20). In the present study, voltage-dependent inward calcium currents in these cells were potentiated by low concentrations of this compound and depressed by higher concentrations consistent with its actions on ACTH secretion. A similar relationship was demonstrated for a different but related compound, CGP 28 392. Each of BAY-K-8644's enantiomers, BAY-R(−)5417 and BAY-R(+)4407, had opposing effects upon these inward calcium currents and ACTH secretion. The (+)isomer antagonized both inward calcium currents and ACTH secretion. In contrast, the (−)enantiomer was responsible for the stimulatory effects of BAY-K-8644. Nevertheless, some antagonistic properties were noted with high concentrations of this latter enantiomer. The stimulation of ACTH secretion in AtT-20 cells by low concentrations of BAY-K-8644 can be attributed to a potentiation of voltage-activated calcium currents by one of its enantiomers, BAY-R-(−)5417. In contrast, the depression of secretion that occurs at higher concentrations is likely to be the result of the reduction of these currents by the other enantiomer (BAY-R(+)4407).
Sodium-dependent [3H]imipramine binding in rat hippocampus and its relationship to serotonin uptake
Authors: Hrdina Pavel D.
Published: April 2011

The relationship of [3H]imipramine recognition sites and serotonergic function was investigated by simultaneously determining the desipramine-defined and sodium-dependent components of [3H]imipramine binding and the serotonin levels and uptake in hippocampus of rats without and with selective lesion of serotonergic neurons with 5,7-dihydroxytryptamine. In control rats, the desipramine-defined [3H]imipramine binding to hippocampal membranes showed a high affinity (Kd = 2 nM) and low affinity (Kd = 31 nM) component. In contrast, the Scatchard analysis of sodium-dependent binding revealed a single class of sites of high affinity (Kd = 1.5 nM). Displacement of sodium-dependent [3H]imipramine binding by cold imipramine resulted in a steep curve best fitted to a one-site model. Sodium-dependent binding of [3H]imipramine at 4 nM concentration represented only about 38% of desipramine-defined binding. 5,7-Dihydroxytryptamine treatment resulted in marked reduction of hippocampal serotonin concentration and uptake without any changes in norepinephrine levels. Virtually only the low affinity component of desipramine-defined [3H]imipramine binding was detected by Scatchard analysis in 5,7-dihydroxytryptamine lesioned rats. The desipramine-defined "specific" [3H]imipramine binding in hippocampi of lesioned rats was decreased by 46%, whereas the sodium-dependent binding was only 18% of that seen in controls. Desipramine-defined specific binding in absence of sodium was not altered by lesion to serotonergic neurons. The results suggest that desipramine-defined specific [3H]imipramine binding may not be appropriate for studying the role of imipramine sites in relation to serotonin neuronal uptake and that determination of sodium-dependent binding components of both [3H]imipramine binding and serotonin uptake should be used in future studies.
Morphometric analysis of the distributing vessels of the kidney
Authors: Zamir M. , Phipps S.
Published: April 2011

Branching angles and branch diameters of the distributing vessels in the renal networks of rats were measured and the results are compared with data reported previously from the coronary network of the same species. Comparison is also made with what is known to be optimum on theoretical grounds to determine to what extent the branching characteristics of the renal network are governed by considerations of optimality, and to what extent they are affected by other considerations, relating particularly to the role that the network plays in the blood processing function of the kidney.
Decreased in vitro responses to vasoconstrictors during gestation in normotensive and spontaneously hypertensive rats
Authors: Massicotte G. , St-Louis J. , Parent A. , Schiffrin E. L.
Published: April 2011

We have investigated the in vitro vascular responses to vasoconstrictor agents in pregnant normotensive (Sprague–Dawley (SDR) and Wistar–Kyoto (WKR)) and spontaneously hypertensive rats (SHR) to measure the sensitivity and contractility of blood vessels of pregnant rats. In the perfused mesenteric vascular bed from rats on the 21st day of gestation, the concentration–response curves for the increase in perfusion pressure by arginine8-vasopressin and norepinephrine were displaced to the right by comparison to nonpregnant female rats when all strains of rats were considered together. The increase in EC50 to both agents in pregnant rats was from 1.3- to 2.7-fold in the mesenteric bed; SDR showed the highest increase in EC50, followed by SHR and WKR. No consistent effect was observed on the maximum response. Similar results were obtained in isolated portal veins for angiotensin II and norepinephrine, except that the increase in EC50 in pregnant rats was smaller in magnitude (from 1.0 to 1.7) and followed the same interstrain pattern. These data show that the decreased responsiveness to vasoconstrictor agents in pregnant rats observed in vitro is similar in normotensive and hypertensive rats and suggest that the factor(s) responsible for this effect is a phenomenon affecting vascular smooth muscle in both arteries and veins.
Ethanol vapours above lacrimal fluid in the rabbit
Authors: Giles H. G. , Sandrin S. , Kapur B. M. , Thiessen J. J.
Published: April 2011

Ethanol was administered intravenously to rabbits. The concentration of ethanol, determined by gas chromatographic analysis, in lacrimal fluid was shown to reflect the concentration in plasma. The vapour above lacrimal fluid was analyzed in situ by the use of a small resistivity sensor that measures ethanol vapours. After a dose of approximately 750 mg/kg, the metabolic rates of ethanol determined by gas chromatographic analysis of plasma (226 ± 13 mg∙kg−1∙h−1) and by eye ethanol vapour analysis (210 ± 8 mg∙kg−1∙h−1) were virtually identical. The data suggest that ethanol eye vapour analysis may be an attractive, noninvasive method for the determination of ethanol in animals.
Role of inositol phospholipid hydrolysis in the initiation of agonist-induced contractions of rat uterus: effects of domination by 17β-estradiol and progesterone
Authors: Ruzycky A. L. , Crankshaw D. J.
Published: April 2011

The role of inositol phospholipid (IP) hydrolysis in agonist-mediated contractility was examined in rat uterine smooth muscle by comparing carbachol-, oxytocin-, and PGF2αmediated [3H]IP accumulation and tension generation. In both estrogen- and progesterone-dominated uteri, all three agonists exhibited dose-dependent contractile responses. Agonist potencies (EC50 values) for eliciting [3H]IP accumulation or contractile responses were found to be very similar and did not change significantly between hormonal states. Maximal responses of agonist-mediated [3H]IP accumulation and tension generation were significantly affected by the endocrine state of the uterus and were dependent on the agonist examined. Maximal carbachol- and PGF2α-induced [3H]IP accumulation were found to be elevated in estrogen-dominated relative to progesterone-dominated uteri, whereas maximal forces generated by these two agonists were smaller in progesterone-dominated relative to estrogen-dominated tissues. Oxytocin-induced responses did not differ between hormonal states. To determine whether these differences between [3H]IP accumulation and contractility responses could be attributed to changes in receptor-mediated signal transduction mechanisms, receptor expression and coupling to phospholipase C were studied. Myometrial muscarinic and oxytocin receptors assessed by radioligand binding were found to have three- to four-fold greater capacities in estrogen-dominated than in progesterone-dominated uteri without significant changes in agonist affinities. Agonist-mediated [3H]IP accumulation was potently inhibited by both pertussis and cholera toxins in both hormonal states. These experiments show that estrogen- and progesterone-dominated environments regulate both uterine excitability and contractility and that the mechanisms of this regulation are complex and dependent on the agonist system stimulated.
Simultaneous and independent release of vasopressin and oxytocin in the rat
Authors: Kasting Norman W.
Published: April 2011

The relative dependence or independence of the secretion of the neurohypophysial hormones, arginine vasopressin and oxytocin, was investigated using a wide variety of stimuli reported to cause the secretion of one or the other hormone. Differences in species, animal preparations, sampling techniques, assays, and other factors make comparison of many previous studies difficult. The aim of this study was to overcome these problems by using the same methodology, animal species, and assays to compare vasopressin and oxytocin release. To further strengthen the analysis, determinations of vasopressin and oxytocin were done in the same blood samples. The results demonstrated that during simultaneous release of both hormones, vasopressin is released in greater proportion following restraint stress, hemorrhage, isotonic hypovolemia, and nicotine, whereas oxytocin is released in greater proportion following endotoxin or hypertonic saline. Vasopressin was released without oxytocin following diethylstilbestrol. Oxytocin was released without concomitant vasopressin release following exercise, hypothermia, hyperthermia, labour, and lactation. Neither oxytocin nor vasopressin release was observed following thyroid-releasing hormone or insulin-induced hypoglycemia. These data illustrate the marked flexibility of the hypothalamo-neurohypophysial system that regulates secretion of vasopressin and oxytocin.
Opioidergic control of luteinizing hormone secretion in the female rabbit: influence of age on the response to naloxone
Authors: YoungLai E. V. , Wilkinson M. , Thompson N. , Byrne A.
Published: April 2011

To examine the role of opioid neurons on luteinizing hormone (LH) secretion in the female rabbit, we determined LH release at timed intervals after naloxone administration to rabbits aged 25–150 days. The LH response to naloxone (10 mg/kg) was not significantly elevated until day 43 when LH rose 76–113% above basal levels at 40–80 min. In 56-day-old females the corresponding increase was 160% at 15 min and in 65- to 67-day-olds it was 154%. From 70 to 80 days of age the LH response was blunted and no significant elevations could be elicited. By contrast, naloxone-induced LH increases were again evident when rabbits were older than 100 days. At all ages no significant change in FSH concentrations was observed. In the adult females, naloxone at 2.5, 5, and 10 mg/kg caused increases in LH secretion which occasionally were high enough to induce ovulation as exemplified by elevated serum progesterone 4 days later. These data suggest that opioid peptides may be involved in the prepubertal rise in LH and in the normal inhibition of adult secretion in the female rabbit.
The mobility and reactivity of maleimide-binding proteins in the rat erythrocyte membrane. Effects of dietary zinc deficiency and incubation with zinc in vitro
Authors: Kubow Stan J. , Bettger William J.
Published: April 2011

Erythrocyte ghosts, prepared from rats fed zinc-deficient diets, were analyzed for the mobility of membrane proteins by electron spin resonance spectroscopy of the sulfhydryl-binding spin probe, 4-maleimido-2,2,6,6-tetramethylpiperidine-N-oxyl. Compared with erythrocyte membranes from rats fed zinc-adequate diets ad libitum or pair-fed, erythrocyte membranes from zinc-deficient rats had a significantly increased ratio of weakly immobilized to strongly immobilized probe-binding proteins. This suggests that dietary zinc deficiency causes a conformational change in erythrocyte membrane proteins. Dietary zinc deficiency did not significantly affect N-ethylmaleimide (NEM)-induced thermal sensitivity or NEM-induced mechanical fragility in rat erythrocytes; however, the addition of zinc in vitro to red cells significantly inhibits NEM-induced mechanical fragility.
Increased pulmonary vascular capacitance with β-adrenergic receptor stimulation: an experimental study of the effect of isoproterenol on the pulmonary vascular volume–pressure relationship
Authors: Smiseth O. A. , Scott-Douglas N. W. , Manyari D. , Kingma I. , Smith E. R. , Tyberg J. V.
Published: April 2011

The present study is an investigation of the effect of β-adrenergic receptor stimulation by isoproterenol on pulmonary vascular capacitance. The experiments were done in six intact-chest, anaesthetized dogs in which pulmonary and cardiac blood volumes were assessed by blood pool scintigraphy. Isoproterenol (0.150 μg∙kg−1∙min−1) significantly (p < 0.005) lowered pulmonary capillary wedge pressure (PPCW) and pulmonary artery pressure (PPA) but did not significantly change pulmonary blood volume (PBV). Left ventricular end-diastolic pressure and total cardiac volume both significantly (p < 0.005) decreased. Pulmonary vascular volume – pressure (V–P) relationships before and during isoproterenol were described by means of blood transfusions and hemorrhage. In individual dogs the PBV–PPCW and the PBV–(PPCW + PPA)/2 relationships were significantly shifted upward by isoproterenol (p < 0.05 or less); slope changes were variable. Pooled data from all dogs also showed a significant (p < 0.001) upward shift in the pulmonary vascular V–P relationship regardless of which measure of distending pressure was used. These results suggest that β-receptor stimulation by isoproterenol increases pulmonary vascular capacitance by increasing the unstressed volume.