bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of calcium and Ca antagonists upon excitation–contraction coupling
Authors: Lüttgau H. C. , Gottschalk G. , Berwe Dorothea
Published: April 2011

The effect of a Ca2+ -free tetraethylammonium sulfate solution on force development in short skeletal muscle fibres of the frog was investigated under voltage clamp control. Maximum force could still be reached under this condition. The removal of external Ca2+, however, caused an acceleration of force inactivation leading to a shift of the steady-state potential dependence of force inactivation to more negative potentials. With reference to the "modulated-receptor hypothesis" this result was explained by assuming a potential-dependent binding of Ca2+ to a force-controlling system in the T-tubular membrane, with a low affinity in the depolarized-inactivated state. A dissociation of Ca2+ is assumed to turn the system into a secondary inactivated state (paralysis) from which it only slowly recovers after repolarization. Ca antagonists like D600 and diltiazem accelerated the shift into paralysis, probably by an allosteric displacement of Ca2+ from its binding site. The application of 1–2 μM of the Ca antagonist nifedipine blocked the inward Ca2+ current and caused a prolongation of the transient force development following a depolarization. A similar retardation of force inactivation and a threshold shift to more negative potentials occurred when the Ca2+ chelator ethyleneglycol-bis (β-aminoethyl ether)-N,N′-tetraacetic acid (EGTA) was injected into the fibre and when in Ca2+-free solutions sodium ions entered the cell through Ca2+ channels.
Effects of intravenous infusions of vasopressin and angiotensin II on central and peripheral noradrenergic function in conscious rabbits
Authors: Patel K. P. , Whiteis C. A. , Lund D. D. , Schmid P. G.
Published: April 2011

Vasopressin (AVP) and angiotensin II (AII) are proposed to exert part of their cardiovascular effects via different actions within the central nervous system. These peptides are also known to alter central noradrenergic function. In the present study we determined the effects of these peptides administered intravenously on norepinephrine (NE) turnover in discrete brain regions thought to be involved in the regulation of circulation, and simultaneously, in various peripheral tissues. An index of NE turnover was determined by measuring the decline in tissue NE concentration 75 min after administration of α-methyl tyrosine (240 mg∙kg−1∙min−1, i.p.). During NE synthesis blockade, five separate groups of rabbits were infused intravenously (1 h) with either saline, AVP (4 and 16 mU∙kg−1∙min−1), AII (0.1 μg∙kg−1∙min−1), or phenylephrine (PE) (5 μg∙kg−1∙min−1). The low dose of AVP produced an increased index of NE turnover in the median preoptic area and the paraventricular nucleus, and concomitantly, a decreased index of NE turnover in kidney and skeletal muscle. In contrast, AII produced an increased index of NE turnover in the locus ceruleus and the intestine. Neither the infusion of vehicle nor the infusion of phenylephrine, which increased arterial pressure comparable to AVP and AII, produced detectable changes in indices of central and peripheral norepinephrine turnover. A higher dose of AVP produced a different pattern of changes in NE turnover than the low dose. These results demonstrate that intravenous infusion of the low dose of AVP produced changes in noradrenergic function in specific central areas known to be involved in autonomic outflow. Concomitant with the central changes, there were selective changes in peripheral noradrenergic function. AII produced changes in both central and peripheral noradrenergic function that differed from the effects of AVP. These desperate actions might account for the previously observed differences in effects of AVP and AII on baroreflex control of the circulation.
The sensitivity of the longitudinal and circular muscle layers of the rat's myometrium to oxytocin in vitro during pregnancy
Authors: Crankshaw D. J.
Published: April 2011

To test the hypothesis that binding site regulation is the primary process controlling the responsiveness of the rat's myometrium to oxytocin during pregnancy, I have studied the effects of oxytocin on longitudinal and circular strips of myometrium in vitro throughout pregnancy. Longitudinal muscle was as sensitive on day 10 of pregnancy (EC50 = 1.6 nM) as it was at term (EC50 = 1.3 nM) and there was no significant change in the mean maximal force developed in response to the hormone (2.1 ± 0.9 vs. 1.5 ± 0.3 N cm−2). Circular muscle on the other hand was essentially refractory to the hormone until day 21 of pregnancy at which time its sensitivity and the maximum response were similar to those of longitudinal muscle. These results indicated that regulation of oxytocin sensitivity in the two muscle layers was temporally different, and they suggested different mechanisms. The effect of oxytocin on longitudinal muscle was not compatible with the hypothesis that changes in binding site number regulate the responsiveness of the tissue, whereas the effect on circular muscle was.
Tip size of ion-exchanger based K+-selective microelectrodes. I. Effects on selectivity
Authors: Carlini Walter G. , Ransom Bruce R.
Published: April 2011

Double-barreled ion-exchanger based K+ -selective microelectrodes (K+ ISMs) of a variety of tip diameters were used to study the dependency of ion selectivity upon tip size. The selectivity of K+ ISMs depended on tip size and barrel configuration. Within the range of tip diameters tested (~ 0.5–6 μm) all K+ ISMs constructed of two barrels glued side by side ("figure-eight glass") exhibited sensitivity to K+ and NH4+. Figure-eight K+ ISMs with tip diameters < 1.5 μm were not sensitive to tetramethylammonium, tetraethylammonium, or choline, whereas K+ ISMs with tip diameters ≥ 1.5 μm sensed all of the quaternary amines. Tip size dependent selectivity was not present in K+ ISMs made from thick septum theta glass. The explanation for tip size dependent changes in ion selectivity is unknown but a discussion of theoretical possibilities is given.
Intracellular calcium recordings from isolated cells of the mammalian central nervous system
Authors: Morris M. E. , MacDonald J. F. , Friedlich J. J. , Szekelyhidi I.
Published: April 2011

Measurements made with two different techniques of intracellular calcium levels from small isolated cells of the mammalian central nervous system are described and compared. Recordings in cultured mouse embryo spinal cord and dorsal root ganglion neurons, made with double-barrelled borosilicate Ca2+-selective microelectrodes yielded a mean Ca2+ level of 2.3 (SE ± 0.54) μM for the lowest values recorded in 24 out of 46 cells. Intracellular Ca2+ dependence on membrane potential was apparent with levels of calcium ≥4 μM (r = 0.371, n = 29). Both cyclic fluctuations induced by tetraethylammonium and an apparent increase in Ca2+ evoked by the depolarizing excitatory amino acid, L-aspartate, were observed. In contrast, estimates of intracellular Ca2+ obtained by spectrofluorimetry of suspensions of mouse embryo brain cells, loaded with the intracellular Ca-binding fluorescent probe, quin2 provided a [Formula: see text]-fold lower value, 152 (SE ± 7) nM. This more closely resembles levels reported for large neurons where large-tip microelectrodes with greater sensitivity were used, and in spite of the heterogeneity of the cells this value is presumed to be a more accurate estimate of intraneuronal Ca2+ concentration. In these fluorescence studies KCl readily evoked increases in intracellular Ca2+ which could be blocked by verapamil and Cd2+ and were not induced in the absence of Ca2+. Increases were also produced by N-methyl-D-aspartate, but not by the kainate-like Lathyrus neurotoxin, L-3-oxalylamino-2-aminopropionic acid. These results provide preliminary evidence for both voltage-sensitive and receptor-activated Ca channels in embryonic brain cells. Although the recording of intraneuronal Ca2+ with conventional ion-selective microelectrodes in small cells has problems with respect to accuracy, stability, and time constant, recent advances in the design of Ca2+ sensors and electrodes are promising. These, as well as developments in techniques of single cell fluorescence analysis, now offer methods with improved and powerful capacity for accurate and simultaneous measurements of intracellular Ca2+ and membrane electrophysiological parameters.
Surface pH and the control of intracellular pH in cardiac and skeletal muscle
Authors: Hemptinne A. de , Marrannes R. , Vanheel B.
Published: April 2011

Both surface pH (pHs) and intracellular pH (pHi) were measured using single- and double-barreled pH-sensitive microelectrodes in isolated sheep cardiac Purkinje strands, rabbit and cat papillary muscle, and mouse and rat soleus muscle. Superfusion of the preparations with a relatively low buffered solution (containing 5 mM HEPES buffered to control pH) causes surface acidosis that correlates with efflux of metabolically produced acids in the unstirred layer of fluid surrounding the tissue. Acidification of the surface layer induces a slower acid change of pHi and depresses the rate of proton extrusion following an imposed intracellular acid load. In cardiac preparations, the lowering of pHi correlates with depression of twitch tension. Transient changes of pHs and pHi are seen when a weak acid or base is suddenly added to, or removed from the superfusion solution. Indirect evidence of the presence of carbonic anhydrase in the extracellular surface layer is obtained from analysis of transient pHs changes in presence and absence of acetazolamide.
Measurement of potassium turnover in rod photoreceptors in toad isolated retina using ion-selective microelectrodes
Authors: Oakley II Burks
Published: April 2011

Ion-selective microelectrodes (ISMs) were used to measure the turnover of intracellular K+[Formula: see text] in rods in the isolated retina of the toad, Bufo marinus. The light-evoked hyperpolarization of rods decreases their passive K+ efflux, which in combination with active K+ uptake, decreases extracellular K+ concentration, [Formula: see text]. Rb+ substitutes for K+ in these processes. The turnover of [Formula: see text] was measured as Rb+ and K+ were exchanged, using ISMs that were approximately five times more sensitive to Rb+ than to K+. When [Formula: see text]was replaced by [Formula: see text], the light-evoked decrease in K+ efflux produced only a small change in ISM voltage, ΔVISM, owing to the background of [Formula: see text]. As [Formula: see text] replaced [Formula: see text], the efflux shifted from K+ to Rb+ and ΔVISM grew in amplitude. After loading the rods with [Formula: see text], [Formula: see text] was replaced by [Formula: see text]. The light-evoked decrease in Rb+ efflux lead transiently to a large ΔVISM, since the change in [Formula: see text], was superimposed upon a background of [Formula: see text]. As [Formula: see text] replaced [Formula: see text], the amplitude of ΔVISM declined. When measured using this technique, the turnover of [Formula: see text] was 95% complete in approximately 15 min. In low Ca2+ solutions, transmembrane fluxes of K+ (Rb+) increased and turnover of [Formula: see text] occurred more rapidly. During background illumination, transmembrane fluxes of K+ (Rb+) decreased and turnover of [Formula: see text] was slowed. These experiments have provided independent corroboration of earlier observations concerning rod K+ fluxes. This ISM-based technique also may be useful in measuring K+ turnover in other cell types.
Modulation of spinal cord transmission by changes in extracellular K+ activity and extracellular volume
Authors: Syková Eva
Published: April 2011

The neuronal activity in spinal cord in response to electrical or adequate stimulation of afferent fibres increases extracellular K+ activity. The increase during a stimulation can reach 9–10 mM (so-called ceiling level) and persists for some time even when a stimulation is discontinued. The activation of a neuronal Na–K pump is a limiting factor in stimulation-evoked increase in extracellular K+ activity and in the time course of its recovery to the resting level. Drugs that affect either the neuronal activity (picrotoxin, strychnine, GABA, 5-HT) or activity of Na–K ATPase (oubain, naloxone, morphine, enkephalins) substantially change the K+ transience. Repetitive electrical stimulation of low threshold cutaneous afferents at frequency 1–100 Hz induced transient shrinkage of extracellular space in spinal dorsal horns by 5–75%. The increase in extracellular K+ activity depolarizes the membranes of neurones, glial cells, and primary afferent fibres and may eventually lead to either facilitation or inhibition of synaptic transmission. It is also suggested that the transient poststimulation changes in extracellular volume may alter synaptic potency in spinal cord.
Ionic changes induced by excitatory amino acids in the rat cerebral cortex
Authors: Pumain R. , Kurcewicz I. , Louvel J.
Published: April 2011

The ionic mechanisms underlying the action of excitatory amino acids were investigated in the rat motor cortex. Ion-selective microelectrodes were attached to micropipettes such that their tips were very close and local changes in extracellular concentration of sodium, calcium, and potassium ions elicited through ionophoretic applications of glutamate (Glu) and of its agonists N-methyl-D-aspartate (NMDA), quisqualate (Quis), and kainate (Ka) were measured. These agents produced moderate increases in [K+]o (up to 13 mM) but, in contrast, substantial tetrodotoxin-insensitive decreases in [Na+]o (maximally of 60 mM). NMDA-induced sodium responses could be blocked by manganese, while the Quis- and Ka-induced responses were not. Quis and Ka produced increases in [Ca2+]o or biphasic responses while NMDA, even with small doses, induced each time drastic decreases in [Ca2+]o (maximally of 1.15 mM), which could be attenuated or blocked by manganese but not by organic calcium channel blockers. NMDA responses could be abolished by reduced doses of 2-amino-phosphonovaierate. The largest Glu- and NMDA-induced calcium responses were observed in the superficial cortical layers, but such maxima disappeared after selective degeneration of pyramidal tract neurons. All amino acids produced sizeable reductions in the extracellular space volume. The following can be concluded. (i) All the excitatory amino acids tested induce an increased permeability to sodium and potassium ions. (ii) In addition, the NMDA-operated channels have specifically a large permeability for calcium, although calcium ions contribute only by less than 10% to the NMDA-induced inward currents, (iii) Glu-induced calcium responses are due to the activation by Glu of NMDA receptors. (iv) In the motor cortex, the largest density of NMDA receptors is found on apical dendrites of pyramidal tract neurons.
The 1986 Upjohn Award Lecture. Interaction of chemicals with hemoproteins: implications for the mechanism of action of porphyrinogenic drugs and nitroglycerin
Authors: Marks Gerald S.
Published: April 2011

The ferrochelatase inhibitory activity of a variety of analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) was studied in chick embryo liver cells. The ferrochelatase inhibitory activity of the 4-butyl, 4-pentyl, and 4-hexyl analogues was considered to be due to catalytic activation by cytochrome P-450 leading to heme alkylation and formation of the corresponding N-alkylporphyrins. The relative ferrochelatase inhibitory activity of the DDC analogues has implications for a postulated model of the binding of porphyrins in the ferrochelatase active site. 3-[2-(2,4,6-Trimethylphenyl)thioethyl]-4-methylsydnone (TTMS) was shown to be a potent porphyrinogenic agent and to inhibit ferrochelatase in chick embryo liver cells. A related sydnone, 3-benzyl-4-phenylsydnone did not inhibit ferrochelatase activity. These results supported the idea that the porphyrinogenicity of TTMS was due to catalytic activation by cytochrome P-450 leading to heme alkylation and formation of N-vinylprotoporphyrin which inhibits ferrochelatase. Polychlorinated biphenyls, phenobarbital, nifedipine, and a large number of structurally different chemicals which are porphyrinogenic in chick embryo liver cells inhibit uroporphyrinogen decarboxylase by an unknown mechanism. Thus drug-induced porphyrin biosynthesis in chick embryo liver cell culture appears to be caused by inhibition of either ferrochelatase or uroporphyrinogen decarboxylase. The biotransformation of nitroglycerin by human red blood cells is due to a combination of a sulfhydryl-dependent enzymatic process and an interaction with reduced hemoglobin. Biotransformation of nitroglycerin was shown to occur only with the deoxy form of hemoglobin and to involve a two-electron denization, resulting in the oxidation of two molecules of heme iron (II) per mole of nitroglycerin biotransformed to glyceryl dinitrate and nitrite anion. Since nitroglycerin biotransformation appears to be involved in the mechanism of nitroglycerin-induced vasodilation, we have suggested the following hypothesis: biotransformation of nitroglycerin in vascular smooth muscle might occur by interaction of nitroglycerin with the iron (ferrous) of guanylate cyclase-bound heme. The nitrite ion formed may be converted via nitrous acid to nitric oxide. This in turn would combine with the heme moiety of guanylate cyclase to activate the enzyme and through a series of enzymatic reactions cause vasodilation.
The role of fetal urinary excretion in the transfer of ethanol into amniotic fluid after maternal administration of ethanol to the near-term pregnant ewe
Authors: Clarke David W. , Patrick John , Wlodek Mary E. , Smith Graeme N. , Richardson Bryan , Brien James F.
Published: April 2011

The objective of this study was to determine whether fetal urinary excretion is a major route of ethanol transfer into the amniotic fluid surrounding the fetus following maternal administration of ethanol. Conscious instrumented pregnant ewes between 130 and 137 days' gestation (term, 147 days) with (n = 3) or without (n = 3) a catheter in the fetal bladder were administered 1 g ethanol/kg maternal body weight as a 1-h maternal intravenous infusion. Maternal blood, fetal blood, and amniotic fluid samples were collected at selected times, and fetal urine was collected continuously from the bladder-cannulated fetus during the 14-h study for the determination of ethanol concentrations. Fetal urinary excretion of ethanol occurred, and the total amount of ethanol excreted represented 0.30 ± 0.07 (SD)% of the maternal ethanol dose. The renal clearance of ethanol by the fetus was 0.43 ± 0.06 mL/min. The pharmacokinetics of ethanol in the maternal–fetal unit and the amniotic fluid for the bladder-cannulated fetal preparation were similar to the data for the nonbladder-cannulated preparation. The data indicate that fetal urinary excretion of ethanol is a secondary route of ethanol transfer into the amniotic fluid. It would appear that diffusion of ethanol across membranes from the maternal and fetal circulations is a major route of ethanol transfer into this intrauterine compartment.
Effects of monovalent and divalent cations and of guanine nucleotides on binding of vasopressin to the rat mesenteric vasculature
Authors: Larivière Richard , Schiffrin Ernesto L.
Published: April 2011

The rat mesenteric vasculature contains high affinity binding sites specific for [3H]Arg8-vasopressin which mediate its vasoconstrictor action. We have investigated the in vitro effect of monovalent and divalent cations and guanine nucleotides on the interactions between [3H]Arg8-vasopressin and its receptor in this preparation. Binding was increased by divalent cations from fourfold in the presence of Mg2+ at 5 mM to ninefold in the presence of Mg2+ at 5 mM. The potency order of divalent cations to increase binding was Mn2+ > Co2+ > Ni2+ > Mg2+ > Ca2+ ≈ control without cations. Addition of Na+ or other monovalent cations (K+, Li+, and NH4+) in the presence or absence of divalent cations reduced binding significantly. Analysis of saturation binding curves showed a single high affinity site. In the presence of 5 mM Mn2+, binding capacity (Bmax) increased to 139 ± 23 fmol/mg protein. Receptor affinity was enhanced (KD decreased to 0.33 ± 0.07 nM). In presence of 5 mM Mg2+ or 150 mM Na+, fmax and affinity were reduced. The addition of 100 μM GTP or its nonhydrolyzable analogue, Gpp(NH)p, reduced receptor affinity in the presence of Mn2+ + Na+, Mg2+, and Mg2+ + Na+, but not in the presence of Mn2+ alone. Computer modeling of competition binding curves demonstrated that in contrast with saturation studies, the data were best explained by a two-site model with high affinity, low capacity sites and low affinity, high capacity sites. Mn2+ or Mn2+ + Na+ with or without guanine nucleotides resulted in a predominance of high affinity sites. GTP or Gpp(NH)p in the presence of Mg2+ or Mg2+ + Na+ induced a reduction of affinity of the high affinity binding sites and the number of these sites. In the presence of Mg2+ + Na+ and guanine nucleotides, high affinity sites were maximally decreased. An association kinetic study indicated that the association rate constant (K+1) was increased by divalent cations and reduced by guanine nucleotides, without change in the dissociation rate constant (K−1). The equilibrium dissociation constant (KD) calculated with these rate constants (K−1/K+1) was similar to that obtained in saturation experiments at steady state. Dissociation kinetics were biphasic, indicating the presence of two receptor states, one of high and one of low affinity, associated with a slow and a rapid dissociation rate. Cations and guanine nucleotides interact with one or more sites closely associated with vasopressin receptors, including possibly with a GTP-sensitive regulatory protein, to modulate receptor affinity for vasopressin.
Modulation of gastric acid secretion by adenosine in conscious rats
Authors: Glavin G. B. , Westerberg V. S. , Geiger J. D.
Published: April 2011

Basal (nonstimulated) gastric acid output was determined in conscious rats fitted with indwelling gastric cannulae. The adenosine deaminase resistant analog of adenosine, R-phenylisopropyladenosine, elevated intraluminal pH beyond 7.0 and decreased gastric acid secretion when given at doses of 0.10 or 1.0 mg/kg, while S-phenylisopropyladenosine at similar doses did not affect either gastric acid output or pH. The potent adenosine receptor antagonist, 8-phenyltheophylline, given at doses of 0.1, 1.0, and 2.5 mg/kg augmented gastric acid output and, at doses of 0.01, 0.1,1.0, and 2.5 mg/kg, blocked the acid-reducing effect of R-phenylisopropyladenosine (0.1 mg/kg). These data suggest that adenosine systems may be important regulators of gastric function.
Collecting duct function in cis-platinum nephrotoxicity
Authors: Wilson Douglas R. , Honrath Ursula
Published: April 2011

Microcatheterization was used to study the effect of cis-platinum nephrotoxicity on inner medullary collecting duct function in anaesthetized rats. Osmolality of collecting duct fluid increased from the beginning to the end (papillary tip) of the collecting duct by only 69 ± 11 mosmol/kg in cis-platinum treated rats (at 5–6 days) compared with 306 ± 75 mosmol/kg in sham controls (p < 0.01). Tubular fluid to plasma inulin concentration ratio was reduced at the beginning and end of the collecting duct. Tubular fluid sodium, chloride, and potassium concentrations were lower at the papillary tip in cis-platinum treated rats (p < 0.01). The results indicate that collecting duct water reabsorption is reduced, but electrolyte reabsorption is normal (or even increased) in cis-platinum nephrotoxicity. Papillary tissue sodium chloride concentration was reduced in cis-platinum treated rats. We conclude that the characteristic decrease in urine concentrating ability in cis-platinum nephrotoxicity is not primarily the result of an intrinsic abnormality in collecting duct function but is secondary to decreased papillary hypertonicity resulting from impaired function in more proximal nephron segments, presumably the pars recta of the proximal tubule and the loop of Henle where previous studies have demonstrated abnormal function.
Gastric inhibitory polypeptide, dietary-induced thermogenesis, and obesity
Authors: Bahendeka Silver K. , Moore Roland E. , Tomkin Gerald H. , Buchanan Keith D.
Published: April 2011

Blood glucose, plasma concentrations of gastric inhibitory polypeptide, insulin, glucagon, Cortisol, and thyroid hormones were measured in nonobese and obese human subjects at 30 and 22 °C ambient temperature (Ta). Oxygen consumption [Formula: see text], carbon dioxide output [Formula: see text], and temperatures in the external auditory meatus (Tc) and on the skin surface [Formula: see text] were also measured. After 1 h, near naked at the chosen Ta, an oral dose of sucrose (~1.5 g/kg) was given and the subjects were then monitored for a further 60 or 90 min. Following sucrose ingestion, both in the nonobese and obese, there were significant (p < 0.001) increases in the following: glucose, gastric inhibitory polypeptide, insulin, [Formula: see text], and respiratory quotient. The effect of Ta on these responses in the nonobese was that gastric inhibitory polypeptide rose more at Ta 30 than at Ta 22 (p < 0.05) and [Formula: see text] rose more at Ta 22 than at Ta 30 (p < 0.05). In the obese, glucose rose more at Ta 30 than at Ta 22 (p < 0.02), [Formula: see text] rise was less than in the nonobese at Ta 22 (p < 0.05), and the respiratory quotient was lower than in the nonobese at both Ta 30 and 22 (p < 0.001). Gastric inhibitory polypeptide changes with respect to Ta in the obese were inconsistent. It is concluded that responses to oral sucrose are modified by environmental temperature.
The renal afferent nerves in the pathogenesis of hypertension
Authors: Oparil Suzanne , Sripairojthikoon Wanida , Wyss J. Michael
Published: April 2011

The renal nerves play a role in the pathogenesis of hypertension in a number of experimental models. In the deoxycorticosterone acetate – salt (DOCA–NaCl) hypertensive rat and the spontaneously hypertensive rat (SHR) of the Okamoto strain, total peripheral renal denervation delays the development and blunts the severity of hypertension and causes an increase in urinary sodium excretion, suggesting a renal efferent mechanism. Further, selective lesioning of the renal afferent nerves by dorsal rhizotomy reduces hypothalamic norepinephrine stores without altering the development of hypertension in the SHR, indicating that the renal afferent nerves do not play a major role in the development of hypertension in this genetic model. In contrast, the renal afferent nerves appear to be important in one-kidney, one-clip and two-kidney, one-clip Goldblatt hypertensive rats (1K, 1C and 2K, 1C, respectively) and in dogs with chronic coarctation hypertension. Total peripheral renal denervation attenuates the severity of hypertension in these models, mainly by interrupting renal afferent nerve activity, which by a direct feedback mechanism attenuates systemic sympathetic tone, thereby lowering blood pressure. Peripheral renal denervation has a peripheral sympatholytic effect and alters the level of activation of central noradrenergic pathways but does not alter sodium or water intake or excretion, plasma renin activity or creatinine clearance, suggesting that efferent renal nerve function does not play an important role in the maintenance of this form of hypertension. Selective lesioning of the renal afferent nerves attenuates the development of hypertension, thus giving direct evidence that the renal afferent nerves participate in the pathogenesis of renovascular hypertension.
Do pressor neurons in the ventrolateral medulla release amines and neuropeptides?
Authors: Chalmers John , Kapoor Vimal , Mills Eric , Minson Jane , Morris Margaret , Pilowsky Paul , West Malcolm
Published: April 2011

Activation of neurons arising in the rostral ventrolateral medulla evokes a pressor response in the rat and the rabbit. This region of the medulla gives rise to bulbospinal neurons containing many different neurotransmitters, including amines such as adrenaline, noradrenaline and serotonin, and neuropeptides such as substance P and neuropeptide Y. Colocalization of amines and neuropeptides has been described in some neurons descending from the rostral ventrolateral medulla. In this paper we discuss the evidence that bulbospinal serotonin-containing neurons (B3) and adrenaline-containing neurons (C1) arising from this part of the medulla exert pressor effects by distinct central pathways and conclude that they do. We also consider the possibility that the pressor effects of activating these two groups of neurons are associated with release of neuropeptides and highlight evidence that substance P is released into the spinal cord by activation of descending serotonin-containing neurons, while neuropeptide Y may be released by activation of bulbospinal adrenaline-containing neurons.
Neurotransmitters and neuropeptides in blood pressure regulation in the spontaneously hypertensive rat
Authors: Louis W. J. , Conway E. L. , Howes L. G. , Maccarrone C. , Beart P. M. , Jarrott B.
Published: April 2011

Studies of the roles played by neurotransmitters in the development of hypertension in the spontaneously hypertensive (SHR) rat are complicated by the presence of genetic differences between SHR and normotensive control rats, which are not related to differences in blood pressure. One approach that may be used in an attempt to overcome this difficulty is to study the manner in which neurotransmitter and metabolite levels change with age, and to relate these changes to alterations in blood pressure with ageing. Noradrenaline (NA) levels in the brainstem and spinal cord of SHR and Wistar Kyoto rats fell with age, while 3,4-dihydroxyphenylethyleneglycol (DHPG) levels (a neuronal metabolite of noradrenaline) remained constant. Similar changes were seen when NA and DHPG levels were measured in the discrete brainstem A1, A2, and C2 region, and when adrenaline, NA, and DHPG levels were examined in the C1 region. Differences in age-related changes of neuropeptide Y (NPY) levels were also found in the ventromedial nucleus of the hypothalamus and the locus coeruleus, and of β-endorphin in the anterior hypothalamic nucleus, the paragigantocellular nucleus of the brainstem, and the locus coeruleus. These changes may indicate either a progressive increase in the activity of neurons in the sympathoexcitatory C1 region or a progressive reduction in the activity of vasodepressor A1, A2, and C2 regions with ageing, or both. However, changes in catecholamines and metabolites with age were similar in both strains and therefore cannot readily explain the more rapid rise in blood pressure with ageing in SHR rats.
Catecholamines and atrial natriuretic factor in Dahl and spontaneously hypertensive rats
Authors: Kuchel Otto , Racz Karoly , Debinski Waldemar , Gutkowska Jolanta , Buu Nguyen T. , Cantin Marc , Genest Jacques
Published: April 2011

We have previously demonstrated two different catecholaminergic patterns in genetic and experimental hypertension: a hyperdopaminergic state in spontaneously hypertensive (Okamoto) rats (SHR) and a hypernoradrenergic state in salt-sensitive Dahl rats. Plasma immunoreactive atrial natriuretic factor (IR ANF) concentrations increase in both models as a response to hypertension. To distinguish between the genetic and acquired components of these abnormalities, we measured adrenal dopamine-β-hydroxylase (DβH) activity and coeliac ganglionic atrial natriuretic factor (ANF) like immunoreactivity in the two animal strains. While adrenal DβH activity was increased in Dahl S rats, it was diminished in SHR in the prehypertensive as well as in the hypertensive stages. In the hypertensive stage, the ANF-like immunoreactivity in the coeliac ganglia was lower in the Dahl S group but higher in SHR than in their respective normotensive controls; there were no changes in these animals when they were prehypertensive. Differences in DβH activity, which determines the fine tuning of sympathoadrenomedullary catecholamine synthesis may account for the inheritance of mechanisms resulting in salt-sensitive hypertension (as in SHR) or salt-dependent hypertension (as in Dahl salt-sensitive rats). In contrast, plasma IR ANF concentrations may reflect a defense mechanism against hypertension. However ANF-like immunoreactivity in coeliac ganglia does not follow its plasma concentrations and changes in different directions in the two hypertensive strains; it may reflect a neuromodulatory function of ANF in the ganglionic neurotransmission and different implications of this role of ANF in the two hypertensive models.
Plasma levels of human atrial natriuretic peptide in patients with hypertensive diseases
Authors: Iimura Osamu , Shimamoto Kazuaki , Ando Toshiaki , Ura Nobuyuki , Ishida Hiroyuki , Nakagawa Motoya , Yokoyama Toyoharu , Fukuyama Shuzaburo , Yamaguchi Yasukazu , Yamaji Izumi
Published: April 2011

Three types of antihuman atrial natriuretic peptide antiserum were obtained. From the study of cross-reactivity to human atrial natriuretic peptide fragments, it was suggested that antisera-1, -2, and -3 are mostly specific to 1–28, 5–25, and the ring structure, respectively. The estimated values of this hormone were significantly lower in the order of antisera-1, -2, and -3. Moreover, high performance liquid chromatographic study showed that various types of fragments of atrial natriuretic peptide exist in human plasma. These findings suggested that the highly specific antiserum to 1–28 human atrial natriuretic peptide such as antiserum-1 should be used to estimate the 1–28 human atrial natriuretic peptide levels in human plasma. From the study by using antiserum-1, it was concluded that the plasma human atrial natriuretic peptide increased in essential hypertensives, and in patients with primary aldosteronism, chronic renal failure, and malignant hypertension. Regarding the pathophysiological significance of increased plasma atrial natriuretic peptide, it is unlikely that this plays an important role in the etiology of essential hypertension or other hypertensive diseases, because the plasma level of this hormone is elevated in these patients. The increase of plasma atrial natriuretic peptide level in these patients should be considered to be a secondary or compensatory reaction to high blood pressure.
Central cardiovascular actions of vasopressin in the rat
Authors: Lebrun Christine , Rohmeiss Peter , Demmert Gudrun , Rettig Rainer , Unger Thomas
Published: April 2011

Arginine vasopressin (AVP) containing neurones and pathways have been localized in various cardiovascular control centers of the central nervous system in rats. AVP influences cardiovascular regulation when injected into various areas of the central nervous system. The blood pressure increases in response to central AVP injections were shown to be initiated by stimulation of central V1-AVP receptors and mediated by stimulation of sympathetic outflow to the periphery. On the other hand, AVP has also been shown to attenuate the pressor responses to electrical stimulation of the mesencephalic reticular formation when injected into the brain ventricular system. In addition, AVP can participate in cardiovascular regulation by modulating baroreceptor reflex sensitivity. We have shown that in rats peripheral (hormonal) AVP can sensitize the heart rate component of the baroreceptor reflex by acting on V2-AVP receptors accessible from the blood, while at the same time central (neuronal) AVP can attenuate the baroreceptor reflex through brain V1-AVP receptors that cannot be reached from the blood. Binding and functional studies favour the existence of V1-AVP receptors in the central nervous system, whereas evidence for central V2-AVP receptors is still scarce. The role of AVP in hypertension remains controversial, but recent evidence suggests that a discordance between the various central and peripheral cardiovascular actions of AVP, rather than its hormonal vasopressor effects, may contribute to the pathogenesis of hypertension.
General anesthesia and hepatic circulation
Authors: Gelman Simon
Published: April 2011

This article describes hepatic circulatory disturbances associated with anesthesia and surgical intervention. The material is presented in three parts: part 1 describes the effects of general anesthetics on the hepatic circulation; part 2 deals with different factors related to surgical procedures and anesthesia; and part 3 analyzes the role of hepatic circulatory disturbances and hepatic oxygen deprivation in anesthesia-induced hepatotoxicity. The analysis of available data suggests that general anesthesia affects the splanchnic and hepatic circulation in various directions and to different degrees. The majority of anesthetics decreases portal blood flow in association with a decrease in cardiac output. However, hepatic arterial blood flow can be preserved, decreased, or increased. The increase in hepatic arterial blood flow, when it occurs, is usually not enough to compensate for a decrease in portal blood flow and therefore total hepatic blood flow is usually decreased during anesthesia. This decrease in total hepatic blood flow-has certain pharmacokinetic implications, namely a decrease in clearance of endogenous and exogenous substances with a high hepatic extraction ratio. On the other hand, a reduction in the hepatic oxygen supply might play a certain role in liver dysfunction occurring perioperatively. Surgical procedures–preparations combined with anesthesia have a very complex effect on the splanchnic and hepatic circulation. Within this complex, the surgical procedure–preparation plays the main role in developing circulatory disturbances, while anesthesia plays only a modifying role. Hepatic oxygen deprivation may play an important role in anesthesia-induced hepatotoxicity in different experimental models.
Agonist interactions at the calcium pools in skinned and unskinned canine tracheal smooth muscle
Authors: Kannan M. S. , Davis C. , Ladenius A. R. C. , Kannan L.
Published: April 2011

We studied the functionally discrete calcium sources used by acetylcholine, 5-hydroxytryptamine, histamine and high K+ in the dog tracheal smooth muscle. The extracellular calcium dependence of their responses was assessed by altering the calcium and by pretreatment with the calcium antagonist, nifedipine. The intracellular calcium pool was assessed by studying the interactions between caffeine and the agonists in both skinned and unskinned preparations. The extent of overlap for the different calcium pools between the various agonists was determined by studying the dose–response relationships of these agents before and after pretreatment with another agonist, i.e., the conditioning agonist, in zero calcium conditions. The rank order of sensitivity to calcium removal and to nifedipine was histamine > KCl > 5-hydroxytryptamine > acetylcholine. Caffeine-induced atenuation of the agonist responses was predominantly through physiological antagonism. However, the caffeine responses in unskinned fibres were augmented by pretreatment with the agonists through both nifedipine-sensitive (as with KCl) and -insensitive (as with acetylcholine) mechanisms. The responses to acetylcholine and caffeine were inhibited by theophylline and forskolin. In the skinned muscle fibres, the pCa–tension relationship suggested high calcium sensitivity, a significant caffeine-sensitive calcium pool, and no evidence of calcium release by exogenous inositol trisphosphate. The results are consistent with multiple extracellular and intracellular calcium sources for the agonist responses. We observed considerable overlap of the calcium sources used by these agonists. Of the four agonists studied, histamine appeared to inhibit the release and sequestration of calcium utilized by the other agonists most effectively.
Differential effects of diazepam on rat hindlimb muscles
Authors: Chua Michael , Dulhunty Angela F.
Published: April 2011

The effects of diazepam on internal membrane potential and action potentials and the isometric twitch and tetanus have been examined in rat fast-twitch (extensor digitorum longus) and slow-twitch (soleus) fibres. Low concentrations of the drug encountered during clinical usage (about 10 μM) had no effect on the membrane electrical properties or contractile properties of the fibres. Higher concentrations of diazepam (100–800 μM) induced changes in action potentials and excitation–contraction coupling but not in the resting membrane potential. After exposure to diazepam there was a rapid, concentration-dependent increase in twitch tension, which was attributed to an effect on excitation–contraction coupling, since the action potential and membrane potential were not altered. Soleus fibres were most sensitive to the potentiating action of diazepam. The decay of the tetanus was prolonged in both types of fibre, which indicated that diazepam blocked calcium uptake by the sarcoplasmic reticulum. Unexpectedly, the decay of isometric twitches was sensitive to diazepam only in soleus fibres, suggesting that calcium uptake was rate-limiting for tension relaxation in slow- but not fast-twitch fibres. The amplitude of the twitch and tetanus fell below control levels after prolonged exposure to diazepam, and there was a parallel reduction in action potential overshoot, especially during tetanic stimulation. Fast-twitch fibres were most susceptible to the depressant effect of diazepam.
Analysis of venous flow transients for estimation of vascular resistance, compliance, and blood flow distribution
Authors: Ogilvie Richard I. , Zborowska-Sluis Danuta
Published: April 2011

We analysed venous flow transients using a long venous circuit and right heart bypass in 17 dogs after a rapid decrease in atrial pressure. A biphase curve was obtained which we decomposed into a two-compartmental model, one with a fast time constant for venous return (0.069 min) and 52% of total circulating flow [Formula: see text], and one with a slower time constant (0.456 min) and 48% of [Formula: see text]. Subsequently, separate drainage from splanchnic and peripheral beds (with the renal venous return in the peripheral bed drainage) allowed comparison of time constants and venous outflow in these beds. The sum of the venous outflow volumes over time during separate drainage was indistinguishable from the single biphasic venous outflow volume curve over time observed with a long circuit and single reservoir. The fast time constant of the biphasic curve was not different from that determined by separate drainage from the peripheral circulation. The slow time constant of the single biphasic curve of 0.456 min was hybrid of two time constants, 0.216 min in the splanchnic bed and 0.862 min in the peripheral bed. Separate drainage from peripheral and splanchnic vascular beds demonstrated that the peripheral bed constituted 70% of venous outflow in the fast time constant compartment using Caldini's technique, whereas the splanchnic bed constituted 63% of venous outflow in the slow time constant compartment. It is concluded that, although Caldini's technique demonstrates biphasic venous flow transients, neither the fast nor the slow time constant compartments resolved from this analysis represent a particular anatomical region or vascular bed.
La β-alanylation, une voie de neutralisation de l'histamine dans le système nerveux central de Carcinus maenas
Authors: Arnould J.-M.
Published: April 2011

Histamine neutralization in Carcinus maenas is not ensured by oxidation, methylation, or acetylation. After injecting labelled histamine, radioactive carcinine (β-alanylhistamine), biosynthesized in the central nervous system, rapidly accumulates in the heart. This synthesis is intense and proportional to the amount of histamine injected; on the contrary, it is very low after injecting labelled β-alanine, whatever the amount injected. Ten days after injecting [14C]histamine, the amounts of radioactive carcinine stocked in the heart remain high. When incubated in the presence of labelled carcinine, various Carcinus tissues are unable to metabolize it. Thus it appears that carcinine would be the catabolite of histamine in Carcinus maenas and that β-alanylation would be a novel pathway for histamine neutralization. Since carcinine synthetase activity is very high in the central nervous system, this enzyme might neutralize not only neuronal histamine, but also possibly exogenous histamine; thus it would constitute an element of the blood–brain barrier.
Magnesium reabsorption in the juxtamedullary loop of Henle: effect of magnesium deprivation
Authors: Roy Denis R.
Published: April 2011

To determine the contribution of the juxtamedullary loop of Henle to magnesium reabsorption during magnesium deficiency, we performed two-phase micropuncture studies of end-descending limbs in a group of magnesium-deficient rats (n = 7) and in a pair-fed control group (n = 8) given MgCl2 in their drinking water. In the magnesium-deficient rats, daily excretion of magnesium fell to very low values (1.2 ± 0.2 vs. 52 ± 12 μM∙day−1∙100 g body weight−1, p < 0.05). Plasma magnesium concentration and fractional magnesium excretion during the control phase were nearly 52 and 27%, respectively, of the values observed in pair-fed controls. Fractional magnesium delivery to the end-descending limb did not differ significantly between the two groups. During the acute magnesium repletion phase, fractional magnesium excretion and fractional magnesium delivery to the end-descending limb increased by a similar value in the two groups of rats, despite a lower filtered load of magnesium in the magnesium-deficient group. Absolute magnesium reabsorption upstream to the end-descending limb was lower in the magnesium-deficient rats but was otherwise tightly coupled to the filtered load of magnesium (Y = 0.91 + 0.37 x, r = 0.82, p < 0.05). Similar observations were made with regards to whole kidney magnesium reabsoiption. Our results suggest that, in young magnesium-deficient rats, magnesium reabsorption is tightly coupled to the filtered load of magnesium both in segments upstream to the juxtamedullary end-descending limb and in the whole kidney, and that a reabsorptive defect for magnesium is not evident in this setting.