bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of a cysteine prodrug, L-2-oxothiazolidine-4-carboxylic acid, on the urinary elimination of mercapturic acids of ethylene oxide, dibromoethane, and acrylonitrile: a dose–effect study
Authors: Goyal R. , Tardif R. , Brodeur J.
Published: April 2011

Metabolic disposition of ethylene oxide, dibromoethane, and acrylonitrile in rats after acute exposure was studied by examining the relationship between dose and urinary metabolites, and by establishing the influence of a glutathione precursor, L-2-oxothiazolidine-4-carboxylic acid (OTCA), on the above relationship. Respective urinary metabolites, hydroxyethylmercapturic acid, cyanoethylmercapturic acid, thiocyanate, and ethylene glycol, were quantified to estimate the extent to which each compound was metabolized. The animals were given either ethylene oxide (0.34, 0.68, or 1.36 mmol/kg), dibromoethane (0.2, 0.4, or 0.6 mmol/kg), or acrylonitrile (0.10, 0.38, or 0.76 mmol/kg). Urine samples were collected at 24 h. The metabolic biotransformation of all three chemicals to their respective mercapturic acids was strongly indicative of saturable metabolism. Administration of OTCA (4–5 mmol/kg) enhanced gluthathione availability and increased excretion of urinary mercapturic acids at the higher doses of the chemicals. This study indicates that OTCA increases the capacity for detoxification via the glutathione pathway thereby partially correcting the nonlinearity between the administered dose of ethylene oxide, dibromoethane, and acrylonitrile and the amount of certain urinary metabolites.Key words: ethylene oxide metabolism, dibromoethane metabolism, acrylonitrile metabolism, mercapturic acids, glutathione, cysteine prodrugs, L-2-oxothiazolidine-4-carboxylic acid.
Neuropharmacological properties of V-9-M, a putative neuropeptide derived from procholecystokinin, in the rat
Authors: Takashima Akira , Itoh Shinji
Published: April 2011

It has been suggested that a nonapeptide called V-9-M (Val-Pro-Val-Glu-Ala-Val-Asp-Pro-Met) is produced by the processing of procholecystokinin. However, its physiological and pharmacological activities are not known. In the present study, synthetic V-9-M amide was injected into the lateral ventricle of the rat and its effects on general activities were observed. V-9-M caused a marked sedation; it suppressed spontaneous activity and hypermotility induced by thyrotropin-releasing hormone, methamphetamine, and apomorphine. Hypomotility induced by small doses of apomorphine was also decreased further. V-9-M caused hypothermia and prolonged the duration of pentobarbital-induced sleep, and it decreased locomotion in an open-field situation. However, V-9-M did not affect appetite in fasted rats.Key words: V-9-M, sedative action, hypothermia, sleep, appetite.
Preservation of guinea pig hearts by hypothermic gas perfusion
Authors: Bailey Leslie E.
Published: April 2011

The lack of a satisfactory method for long-term preservation of hearts during transport limits the source of human hearts for transplant to the geographic vicinity of the transplant center. Experimentally, reduction of myocardial oxygen requirements with hypothermia and cardioplegia prolong storage time to 48 h, but always with some evidence of myocardial damage. In this study, the combination of hypothermia with a procedure known to increase oxygen tension in cardiac muscle, gas perfusion, preserved contractile activity in guinea pig hearts for 24 h and did not cause edema. Cardioplegia or gas perfusion at temperatures below 10 °C or above 20 °C resulted in failure of hearts to contract upon rewarming. Contracture, dehydration, elevation of tissue calcium, reduced perfusate flow, and elevated creatine kinase levels occurred if liquid reperfusion was begun at 15 °C but not 25 °C. The results suggest that under the appropriate conditions, hypothermic gas perfusion is a potentially useful means of extending storage time of hearts for transplant.Key words: myocardial preservation, heart storage, hypothermia, gas perfusion, contractility.
Frequency- and voltage-dependent effects of disopyramide in canine Purkinje fibers
Authors: Flemming Matthew A. , Sasyniuk Betty I.
Published: April 2011

The voltage- and frequency-dependent blocking actions of disopyramide were assessed in canine Purkinje fibers within the framework of concentrations, membrane potentials, and heart rates which have relevance to the therapeutic actions of this drug. [Formula: see text] was used to assess the magnitude of sodium channel block. Disopyramide produced a concentration- and rate-dependent increase in the magnitude and kinetics of [Formula: see text] depression. Effects on activation time (used as an estimate of drug effect on conduction) were exactly analogous to effects on [Formula: see text]. A concentration-dependent increase in tonic block was also observed. Despite significant increases in tonic block at more depolarized potentials, rate-dependent block increased only marginally with membrane potential over the range of potentials in which propagated action potentials occur. Increases in extracellular potassium concentration accentuated drug effect on [Formula: see text] but attenuated drug effect on action potential duration. Recovery from rate-dependent block followed two exponential processes with time constants of 689 ± 535 ms and 15.7 ± 2.7 s. The latter component represents dissociation of drug from its binding site and the former probably represents recovery from slow inactivation. A concentration-dependent increase in the amplitude of the first component suggested that disopyramide may promote slow inactivation. There was less than 5% recovery from block during intervals equivalent to clinical diastole. Thus, depression of beats of all degrees of prematurity was similar to that of basic drive beats. Prolongation of action potential duration by therapeutic concentrations of drug following a long quiescent interval was minimal. However, profound lengthening of action potential duration occurred following washout of drug effect at a time when [Formula: see text] depression had reverted to normal, suggesting that binding of disopyramide to potassium channels may not be readily reversed. Variable effects on action potential duration may thus be attributed to a block of the window current flowing during the action potential being partially or over balanced by block of potassium channels. Purkinje fiber refractoriness was prolonged in a frequency-dependent manner. Disopyramide did not significantly alter the effective refractory period of basic beats but did increase the effective refractory period of sequential tightly coupled extra stimuli. The results can account for the antiarrhythmic actions of disopyramide during a rapid tachycardia and prevention of its initiation by programmed electrical stimulation.Key words: action potential duration, effective refractory period, upstroke velocity, conduction, rate of sodium channel unblocking.
Electrophysiological effects of encainide and its metabolites in normal canine Purkinje fibers and Purkinje fibers surviving infarction
Authors: Kinnaird Anne A. A. , Man Ricky Y. K.
Published: April 2011

In this study, we assessed the effects of O-demethyl encainide (0.5 μM), the most active metabolite of encainide, and the combination with 3-methoxy-O-demethyl encainide (0.5 μM) and encainide (0.1 μM) on cardiac action potential characteristics in normal canine Purkinje fibers and Purkinje fibers surviving 24 h of myocardial ischemia. O-demethyl encainide decreased [Formula: see text] and conduction in normal Purkinje fibers and Purkinje fibers surviving infarction. Further decreases were observed with the combination. Action potential duration at both 50 and 95% repolarization was decreased by O-demethyl encainide. The combination of O-demethyl encainide, 3-methoxy-O-demethyl encainide, and encainide had no further effect. The combination of O-demethyl encainide, 3-methoxy-O-demethyl encainide, and encainide produced a smaller change in effective refractory period than O-demethyl encainide in normal Purkinje fibers and in Purkinje fibers surviving infarction. O-demethyl encainide and the combination shifted the membrane responsiveness curve to more negative potentials in both normal Purkinje fibers and Purkinje fibers surviving infarction. It is apparent from this study that there are differences in the effects of O-demethyl encainide and the combination of O-demethyl encainide, 3-methoxy-O-demethyl encainide, and encainide in normal Purkinje fibers compared with Purkinje fibers surviving infarction. Also, the combination used in this study had different electrophysiological effects than those of O-demethyl encainide alone.Key words: encainide, metabolites, electrophysiological effects, Purkinje fibers, infarction.
The protective effect of vagus nerve stimulation on catecholamine–halothane-induced ventricular fibrillation in dogs
Authors: Waxman Menashe B. , Sharma Arjun D. , Asta John , Cameron Douglas A. , Wald Robert W.
Published: April 2011

Parasympathetic neural activity modulates some ventricular arrhythmias in man. Therefore, a canine model of arrhythmias produced by the interaction of halothane and catecholamines was used to study the effects of vagal stimulation on the induction of ventricular fibrillation. The dose of catecholamine required to induce ventricular fibrillation was determined during a constant heart rate. Vagal stimulation reversibly raised the norepinephrine dose that produced ventricular fibrillation from 16.4 ± 2.4 to 30.0 ± 3.8 μg (p < 0.001, n = 10), and the epinephrine dose from 15.5 ± 2.0 to 22.5 ± 2.6 μg (p < 0.001, n = 5). Following atropine, vagal stimulation failed to raise the threshold dose of norepinephrine (16.8 ± 2.4 vs.18.3 ± 3.3 μg, nonsignificant, n = 6) or epinephrine (15.5 ± 2.0 vs. 16.0 ± 2.3 μg, nonsignificant, n = 5). Ligation of the cervical vagus nerves did not affect the epinephrine threshold dose (16.3 ± 3.3 vs. 17.5 ± 2.7 μg, nonsignificant, n = 5). Following elevation of basal vagal tone by morphine premedication, the norepinephrine threshold dose of 53.0 ± 9.2 μg declined by a nonsignificant amount to 46.5 ± 11.5 μg after vagotomy (nonsignificant, n = 5). Thus resting vagal tone does not prevent catecholamine–halothane-induced ventricular fibrillation, whereas increasing vagal tone by electrical stimulation substantially protects against this arrhythmia. The protection is mediated through a muscarinic cholinergic receptor.Key words: ventricular arrhythmias, vagal tone.
Effects of aging on α1-adrenoceptor mechanisms and the inhibitory effect of diltiazem on noradrenaline maximum response in isolated rat aortic preparation
Authors: Takayanagi I. , Shinkai M. , Yamasawa K.
Published: April 2011

The effects of aging on α1-adrenoceptor mechanisms in aortic preparations isolated from 3-, 6-, 10-, 18-, and 40-week-old rats were studied and compared with serotonin receptor mechanisms in the same preparations. The potency (pD2 value) of noradrenaline increased with age from 3 to 10 weeks, but decreased thereafter with age from 10 to 40 weeks. The affinity (pKA value) of noradrenaline and of prazosin (pA2 value) did not alter with aging. The change in potency or the pD2 value of noradrenaline was proportional to receptor reserve (pD2 − pKA value) for noradrenaline, suggesting that the change of potency of noradrenaline with age was due to a change of receptor reserve, but not to change of drug affinity to α1-adrenoceptors. The potency (pD2 value) and affinity (pKA value) of serotonin, and the affinity (pA2 value) of ketanserin, did not alter with aging, suggesting that serotonin receptor mechanisms in rat aorta did not change with age. The inhibitory effect of diltiazem on noradrenaline maximum response decreased with age from 3 to 10 weeks, but increased with age from 10 to 40 weeks. An inverse relationship between changes of diltiazem inhibition and receptor reserve of noradrenaline was found. Diltiazem's inhibitory effect on serotonin maximum response did not alter with aging.Key words: α1-adrenoceptors, aging, serotonin receptors, diltiazem, rat aortic preparation.
The effect of glucagon on vasoconstriction and vascular escape from nerve- and norepinephrine-induced constriction of the hepatic artery of the cat
Authors: D'Almeida Mark S. , Lautt W. Wayne
Published: April 2011

Glucagon, in the anesthetized cat, was capable of dilating the hepatic artery to the same extent and in a dose-dependent manner when administered directly into the hepatic artery or into the portal vein. Portal venous infusions of glucagon did not inhibit nerve- or norepinephrine-induced vasoconstriction of the hepatic artery in contrast to previous reports in the dog. Rather, at certain doses, glucagon mildly potentiated the vasoconstriction induced by both constrictor stimuli. Vascular escape from nerve- and norepinephrine-induced constrictor responses was found to be inhibited by glucagon in a dose-dependent manner. Glucagon infusion is the first intervention reported to modulate vascular escape in the hepatic artery. Owing to its similar effects on nerve- and exogenous norepinephrine-induced responses, glucagon appears to be acting at a postsynaptic site. Therefore, we suggest that in the cat, glucagon is not an inhibitory modulator of nerve- and norepinephrine-induced vasoconstriction, but rather may potentiate the constrictor response in a postsynaptic manner.Key words: glucagon, hepatic artery, modulation, vascular escape, vasoconstriction.
The effect of sulfonylurea therapy on defective calcium movement associated with diabetic cardiomyopathy
Authors: Mozaffari Mahmood S. , Allo Simon , Schaffer Stephen W.
Published: April 2011

Adult rats exposed to 70 mg/kg streptozocin developed characteristic symptoms of overt diabetes, such as muscle wasting and severely elevated blood glucose levels. Chronic treatment of these rats with the sulfonylurea glyburide for a period of 5 weeks did not affect either the weight of the animal or the degree of hyperglycemia. The drug also failed to influence myocardial glucose metabolism. Nevertheless, the decline in myocardial function associated with the diabetic cardiomyopathy was less in the glyburide-treated rats. At higher preload, myocardial work was significantly reduced in the untreated diabetic but was only moderately depressed in the glyburide-treated heart relative to the nondiabetic heart. The improvement in mechanical function was associated with partial recovery of sarcolemmal calcium pump activity. The drug did not alter the initial rate of Na+–Ca2+ exchange, but decreased the capacity of the transport system. The results indicate that glyburide benefits the diabetic heart by a mechanism independent of carbohydrate metabolism.Key words: diabetes, cardiomyopathy, heart, calcium, sulfonylurea.
Haloperidol reduction can be assayed in human red blood cells
Authors: Inaba T. , Kalow W. , Someya T. , Takahashi S. , Cheung S. W. , Tang S. W.
Published: April 2011

One metabolite of haloperidol present in plasma is "reduced haloperidol." This study demonstrates that human red blood cells are capable of converting haloperidol to reduced haloperidol in vitro. The reductase involved requires NADPH, as does haloperidol (ketone) reductase in human liver cytosol.Key words: haloperidol reductase, human red blood cells, ketone reductase.
Reflex control of vascular capacitance during hypoxia, hypercapnia, or hypoxic hypercapnia
Authors: Rothe Carl F. , Flanagan A. Dean , Maass-Moreno Roberto
Published: April 2011

We tested the hypothesis that the changes in venous tone induced by changes in arterial blood oxygen or carbon dioxide require intact cardiovascular reflexes. Mongrel dogs were anesthetized with sodium pentobarbital and paralyzed with veruronium bromide. Cardiac output and central blood volume were measured by indocyanine green dilution. Mean circulatory filling pressure, an index of venous tone at constant blood volume, was estimated from the central venous pressure during transient electrical fibrillation of the heart. With intact reflexes, hypoxia (arterial Pao2 = 38 mmHg), hypercapnia (Paco2 = 72 mmHg), or hypoxic hypercapnia (Pao2 = 41; Paco2 = 69 mmHg) (1 mmHg = 133.32 Pa) significantly increased the mean circulatory filling pressure and cardiac output. Hypoxia, but not normoxic hypercapnia, increased the mean systemic arterial pressure and maintained the control level of total peripheral resistance. With reflexes blocked with hexamethonium and atropine, systemic arterial pressure supported with a constant infusion of norepinephrine, and the mean circulatory filling pressure restored toward control with 5 mL/kg blood, each experimental gas mixture caused a decrease in total peripheral resistance and arterial pressure, while the mean circulatory filling pressure and cardiac output were unchanged or increased slightly. We conclude that hypoxia, hypercapnia, and hypoxic hypercapnia have little direct influence on vascular capacitance, but with reflexes intact, there is a significant reflex increase in mean circulatory filling pressure.Key words: cardiovascular reflex, vascular capacitance, hypoxia, hypercapnia, mean circulatory filling pressure, venoconstriction.
Attenuated renal responses to atrial natriuretic factor in streptozotocin-induced diabetic rats
Authors: Patel Kaushik P. , Zhang Ping L.
Published: April 2011

To determine whether the renal responses to atrial natriuretic factor (ANF) are altered in the diabetic state, the diuretic and natriuretic responses to ANF (0.25 μg∙kg−1∙min−1, i.v.) were measured in streptozotocin (STZ) induced diabetic (DIA) rats. Urine flow and sodium excretion were measured before and after ANF from innervated and denervated kidneys in anesthetized (Inactin 0.1 g/kg, i.p.) control and DIA rats (Sprague–Dawley rats injected with vehicle or STZ 65 mg/kg, i.p., respectively, 2 weeks prior to the experiment). Blood glucose levels were significantly elevated in the DIA group compared with the control group. ANF produced a significantly blunted diuresis and natriuresis in DIA rats compared with control rats. In addition, reducing the hyperglycemia in DIA rats by treatment with insulin (third group) reversed the blunted urine flow and sodium excretion responses to ANF. This study demonstrates that (i) there is a blunted natriuresis and diuresis to ANF in the STZ-induced DIA rats, and (ii) restoring the glucose levels to normal by insulin treatment in the DIA rats normalized the renal responses to ANF.Key words: diuresis, natriuresis, renal nerves, atrial natriuretic factor.
Stereoselective and nonstereoselective inhibition exhibited by the enantiomers of verapamil
Authors: Piascik Michael T. , Collins Roslynn , Butler Brent T.
Published: April 2011

The interaction of the isomers of verapamil with sites on the calcium channel and α1-adrenergic receptor has been examined. The inhibitory potency of these enantiomers differ with respect to the agonist. KCl- or clonidine-induced contractions of rabbit aortic rings were inhibited in a stereoselective manner by the enantiomers of verapamil with the (−)-isomer being more potent than the (+)-isomer. Similarly, (−)-verapamil was also more potent at displacing (−)-[N-methyl-3H]desmethoxyverapamil than was the (+)-isomer. In contrast, the inhibition of norepinephrine- or phenylephrine-induced aortic contractions was not stereoselective. Differences in enantiomer potency were also observed in vivo. The ability of clonidine to increase blood pressure in the anesthetized rat was blocked in a stereoselective manner by the verapamil enantiomers, while inhibition of the pressor actions of phenylephrine was not. In summary, for agents that rely heavily on calcium channel function (KCl, clonidine), stereoselective inhibition was observed. Stereoselective inhibition was not observed against high efficacy α1-agonists. This difference in stereochemistry argues that verapamil does not act at the same site when inhibiting clonidine or KCl action when compared with norepinephrine or phenylephrine.Key words: calcium channels, phenylalkylamines, α-receptors, vascular smooth muscle, stereochemistry.
Atrial natriuretic peptide – cyclic GMP coupling and urinary sodium excretion during acute volume expansion in man
Authors: Sagnella Giuseppe A. , Singer Donald R. J. , Markandu Nirmala D. , MacGregor Graham A. , Shirley David G. , Tremblay Johanne , Hamet Pavel
Published: April 2011

The present study examines hormonal and renal responses to acute volume expansion in normal man, with particular emphasis on the atrial natriuretic peptide (ANP) – cyclic GMP coupling. Two liters of isotonic saline were infused into eight normotensive male subjects over a 1-h period. Plasma and urinary measurements were made before, during, and up to 300 min after the start of the saline infusion. With the initial increase in urinary sodium excretion there were increases in plasma ANP and plasma cyclic GMP, which reached maximum levels at 15 min after the end of the saline infusion. Urinary cyclic GMP increased gradually during saline infusion up to approximately 60 min after the end of the infusion. Plasma ANP and plasma and urinary cyclic GMP excretion gradually declined thereafter. By contrast, urinary sodium excretion remained elevated up to the end of the observation period. The saline infusion was associated with marked reductions in plasma renin activity and aldosterone, which persisted up to the end of the study. These results suggest a coupling between the increases in plasma ANP, the production of cyclic GMP, and urinary sodium excretion, in particular during the initial renal response to acute volume expansion. However, other mechanisms including the suppression of the rennin–angiotensin–aldosterone system may become increasingly important in the later natriuretic response to acute volume expansion.Key words: atrial natriuretic peptide, cyclic GMP, sodium, renal, human.
Potassium currents in rat cortical neurons in culture are enhanced by the antiepileptic drug carbamazepine
Authors: Zona C. , Tancredi V. , Palma E. , Pirrone G. C. , Avoli M.
Published: April 2011

We report that carbamazepine (Tegretol), a drug that is useful for the treatment of complex partial seizures, enhances outward, voltage-dependent K+ currents generated by rat neocortical cells in culture and recorded with patch-clamping techniques. This effect is seen in the presence of therapeutic concentrations of carbamazepine (10–20 μM). Furthermore, at these doses carbamazepine does not influence voltage-dependent inward Na+ and Ca2+ currents recorded in these cells. The action exerted by carbamazepine on K+ currents is a novel finding and might represent an important mechanism for controlling neocortical excitability and thus the generation of epileptiform activity.Key words: potassium currents, antiepileptic drugs, carbamazepine, rat neocortex.
Threshold of hormonal and biophysical responses to acute hypoxemia in fetal sheep at different gestational ages
Authors: Akagi Kozo , Challis John R. G.
Published: April 2011

We examined whether there was a threshold for change in fetal arterial [Formula: see text] to elicit alterations in plasma adrenocorticotropic hormone, arginine vasopressin, or cortisol, or to affect the incidence of fetal breathing movements or eye movements and we determined whether such a threshold changed with gestational age. Fetal sheep were exposed to two levels of hypoxemia, mild (4.6–5.3 mmHg [Formula: see text] drop) and moderate (8.3–8.8 mmHg [Formula: see text] drop) (1 mmHg = 133.322 Pa) for 1 h without pH change at 125–129 or 134–147 days of gestation within 7 days of spontaneous labor. Hypoxemia was induced by altering the inspired percent oxygen of the mother. No significant hormonal and biophysical changes were observed in mild hypoxemia at either age. In moderate hypoxemia at 125–129 days of gestation, there were significant increases of fetal adrenocorticotropic hormone, arginine vasopressin, and cortisol concentrations, and a decreased incidence of fetal breathing movements and eye movements. At 134–147 days of pregnancy, moderate hypoxemia induced a significant increase in adrenocorticotropic hormone, but the response was less than at 125–129 days of gestation. The arginine vasopressin response was similar to that at 125–129 days and there was no significant change in cortisol. There was a significant decrease in fetal breathing movements but not in eye movements. We conclude that a threshold of fetal arterial [Formula: see text] drop exists between 5 and 8 mmHg to elicit endocrine or biophysical responses to hypoxemia in fetal sheep at 125–129 days of gestation. There was a similar threshold for hypoxemia effects at 134–147 days of gestation within 7 days of spontaneous labor on adrenocorticotropic hormone, arginine vasopressin, and fetal breathing movements, but not on cortisol and fetal eye movements.Key words: fetal sheep, hypoxemia, adrenocorticotropic hormone, arginine vasopressin, cortisol, fetal breathing movements, fetal eye movements.
Serotonin agonist and antagonist actions in hippocampal CA1 neurons
Authors: Gurevich Natasha , Wu Peter H. , Carlen Peter L.
Published: April 2011

The actions of serotonin (5-HT) and its putative agonists and antagonists were examined in vitro on hippocampal CA1 neurons using intracellular recordings, demonstrating that the cellular pharmacological effects can not necessarily be predicted from binding characteristics alone. The first response following 5-HT application was often a long-lasting (several minutes) hyperpolarization associated with decreased input resistance. Subsequent 5-HT applications caused only brief hyperpolarizations (30–120 s) and associated decreased input resistance, often followed by membrane depolarization. The post-spike train afterhyperpolarization (AHP) was prolonged for several minutes following the 5-HT induced hyperpolarization. 5-HT1 agonists (8-hydroxy-2-(di-n-propylamino)tetralin, 5-methoxytryptamine, MK-212) caused a prolonged hyperpolarization, decreased input resistance, and enhancement of the AHP. 5-HT applied following agonist application elicited only short-lasting hyperpolarizations. The 5-HT2 antagonists, cyproheptadine and mianserin, and a nonspecific 5-HT antagonist, methysergide, also caused a prolonged hyperpolarization with decreased input resistance. Spiperone, a nonspecific 5-HT antagonist, and ritanserin, a putative specific 5-HT2 receptor antagonist, depolarized CA1 neurons with little or no change in input resistance. The 5-HT-induced short-lasting hyperpolarization was not affected by drop application of 5-HT antagonists, except for methysergide, but perfusion of methysergide, ritanserin, and spiperone attenuated this response. The long-lasting 5-HT hyperpolarization might be mediated by 5-HT1A receptor activation, and the short-lasting hyperpolarization by another serotonergic receptor subtype.Key words: 5-hydroxytryptamine agonists, 5-hydroxytryptamine antagonists, CA1 neurons, intracellular recording, rat hippocampus.
The effect of ferrous sulfate and pH on L-dopa absorption
Authors: Campbell Roderick R. A. , Hasinoff Brian , Chernenko Gary , Barrowman James , Campbell Norman R. C.
Published: April 2011

Ferrous sulfate decreases L-dopa bioavailability in humans probably as a result of binding of L-dopa by iron in the gastrointestinal tract. This study was conducted to determine if iron by binding L-dopa decreases L-dopa absorption and to investigate the effect of different pH buffers on intestinal absorption of L-dopa in the presence and absence of ferrous sulfate. A rat model developed to examine drug absorption was used. Control animals had buffered [14C]L-dopa solutions injected into two in vivo closed segments of intestine; a 5-cm duodenal and a 5-cm proximal jejunal segment. These studies were conducted using solutions buffered at pH 5.5, 6.5, 7.5, and 8.5. An identical procedure was followed for experimental animals except ferrous sulfate was injected with the buffered L-dopa solutions. Ferrous sulfate resulted in a reduction in L-dopa absorption in the buffers at all pHs in both the duodenum and jejunum. The average reduction in L-dopa absorption in the presence of iron was 22.6% in the duodenum and 23.9% in the jejunum. There was a tendency for ferrous sulfate to cause a greater reduction in L-dopa absorption as the buffer pH increased. There was also a decrease in L-dopa absorption in the higher pH buffers in the absence of iron. Despite this latter result, in the jejunum there was an increase in the percent reduction in L-dopa absorption associated with ferrous sulfate as pH increased. Although this tendency was not as consistent in the duodenum as the jejunum, the combined results are compatible with the chemical model of increased L-dopa–iron binding as pH increases.Key words: L-dopa, ferrous sulfate, complex formation, chelation, drug absorption.
A growth-stimulating activity derived from the proximal small intestine is associated with an adaptive response
Authors: Grey V. L. , Morin C. L.
Published: April 2011

Luminal nutrition is important for the maintenance of small intestinal structure and function. The equilibrium between crypt cell production and villous cell loss in the mucosal epithelium of the small intestine is altered under certain conditions such as after a small bowel resection. Immediately after resection, there is a marked increase in crypt cell proliferation giving rise to an adaptive hyperplasia in the remnant intestine and for this response luminal nutrition is a critical factor. We have previously demonstrated the presence of a growth-stimulating (GS) activity in a heat-stable acidic extract of the rat proximal intestine 24, 48, and 96 h after resection, which is coincidental with an increase in crypt cell proliferation as measured by thymidine kinase activity. Eight days after resection when the GS activity is no longer detectable, the thymidine kinase activity returns to control values. The molecular weights of the peptides associated with this GS activity are 4500 and 1500, as determined by Sephadex gel filtration. Of note is that the oral intake of food is necessary for the appearance of the GS activity postoperatively. The presence of the GS activity has also been demonstrated upon refeeding after a fast, as well as at weaning in the rat, two physiological situations known to be associated with increased proliferation in the small intestine. This GS activity in the proximal intestine first detected in the resection model may represent a general mechanism by which food controls the cell renewal pattern of the small intestine.Key words: stimulating activity, proximal intestine, adaptation.
Quantitative integration of the cardiovascular system and synthesis of drug actions: another attempt
Authors: Greenway C. V. , Scott G. D.
Published: April 2011

This article describes the latest version of a computer program, first published in 1982, that attempts to integrate quantitatively the physiological and pharmacological knowledge of the cardiovascular system. This new version incorporates pressure-induced autoregulation of arterioles, distensibility of venous and pulmonary resistances, and some aspects of pericardial constraint on cardiac function. The program allows the researcher or student to explore the complex interactions resulting from changes in a wide variety of cardiovascular parameters and to synthesize the cardiovascular actions of drugs in the human, dog, or cat. The program can be run on an IBM-compatible computer with math coprocessor and with DOS® as the operating system. The program can be modified by licenced users of QuickBasic®. The program is available on diskette from the authors. This model represents our attempt to put together some of the complex interactions within the cardiovascular system. Every relationship, every initialized parameter, and every drug action can be questioned and alternatives can be proposed. However, the model allows these alternatives to be tested and their consequences to be predicted. We believe that the value of the model lies in the thought, discussion, and experiments that can be generated by this process.Key words: computer model, vascular resistance, blood pressure, cardiac output, capacitance, blood volume, catecholmines, heart failure.
Induction of rhythmic contraction in canine tracheal smooth muscle
Authors: Kong Siow-Kee , Stephens Newman L.
Published: April 2011

Na+ –K+ ATPase activity of the canine tracheal smooth muscle membrane is responsible for the electrogenic pumping of Na+ and K+ ions. It has been shown that this activity results in muscle relaxation. Based on the results of the current study, we suggest that prolonged electrical stimulation induces increased Na+–K+ ATPase activity in isolated tracheal smooth muscle. Tracheal smooth muscle pretreated with prolonged electrical stimulation developed graded mechanical activity when subsequently treated with histamine, serotonin, acetylcholine, or 80 mM K+. This increased isometric tension was interrupted by rhythmic activity, which was elicited by histamine or serotonin but not by acetylcholine or 80 mM K+ stimulation. The spontaneous phasic activity was not inhibited by atropine or propranolol but was totally inhibited by 10−6 M ouabain. These results suggested that the relaxation phase of rhythmic contraction in response to histamine and serotonin stimulation could be the result of stimulated Na+–K+ ATPase activity.Key words: smooth muscle, histamine, serotonin, rhythmic phasic activity, Na+–K+ ATPase.
Esmolol: effects on isoprenaline- and exercise-induced cardiovascular stimulation in conscious dogs
Authors: Fischer G. , Grohs J. G. , Raberger G.
Published: April 2011

Esmolol, a recently developed ultra-short acting β-adrenoceptor blocking agent, was evaluated in 12 conscious chronically instrumented dogs with intact autonomic reflexes. The significance of its β1-adrenoceptor selectivity was examined at various cardiovascular activation levels established by either incremental isoprenaline infusion or graded treadmill exercise. The observed parameters were heart rate, systolic and diastolic arterial blood pressure, left ventricular dp/dtmax, and left ventricular end-diastolic pressure. Intravenous infusion of esmolol (25 and 250 μg∙kg−1∙min−1) led to a dose-dependent reduction of the isoprenaline-induced increase in positive dp/dtmax. The concomitant increase in heart rate was suppressed to a lesser extent. Characteristically of a β1-selective agent, esmolol had only a slight effect on the isoprenaline-induced reduction in diastolic blood pressure. The impact of esmolol on exercise-induced hemodynamic activation was much smaller. Exercise-induced increase in positive dp/dtmax was more sensitive to β-adrenoceptor blockade than the concomitant increase in heart rate. Diastolic blood pressure was not influenced significantly. β-Adrenoceptor blockade was virtually reversed within 20 min of discontinuation of esmolol infusion.Key words: esmolol, β1-adrenoceptor selectivity, dogs, treadmill exercise, isoprenaline stimulation.
Characterization of myometrial desensitization to β-adrenergic agonists
Authors: Dayes Brian A. , Lye Stephen J.
Published: April 2011

Continuous exposure of ovine myometrial strips exposed to isoproterenol (10 μM) resulted in only transient inhibition with contractions returning within 60 min. Rechallenging these strips with isoproterenol failed to induce inhibition, confirming the occurrence of desensitization. In contrast, exposure of myometrial tissue to isoproterenol for only 5 min did not result in desensitization. Myometrial strips exposed to isoproterenol demonstrated a significant increase in cAMP content associated with inhibition of contractile activity and a subsequent fall in cAMP content upon desensitization. Elevation of endogenous cAMP levels by either inhibition of cAMP-dependent phosphodiesterase activity (0.5 mM isobutylmethylxanthine, in ovine strips) or direct activation of adenylyl cyclase (10 μM forskolin, in rat strips) induced a rapid and significant inhibition of myometrial contractile activity in desensitized tissue. Scatchard analysis of the binding of the β-adrenoceptor antagonist, [125I]iodocyanopindolol, revealed a significant reduction in the concentration of β-adrenergic receptors (but no change in binding affinity) in desensitized myometrial tissue. Incubation of desensitized tissue with fresh buffer for 3 h induced only a partial recovery in responsiveness to isoproterenol. These data suggest that prolonged, but not acute, exposure of the myometrium to β-adrenergic agonists induces a state of desensitization that is associated with a down-regulation of β-adrenoceptors but maintenance of postreceptor function.Key words: myometrium, contraction, β-adrenergic receptors, β-antagonists.
Neuromuscular structures specific to the submucosal border of the human colonic circular muscle layer
Authors: Faussone-Pellegrini M. S. , Cortesini C. , Pantalone D.
Published: April 2011

The circular muscle layer of the human caecum and ascending colon is clearly subdivided into two portions: an outer one which includes the bulk of the circular muscle layer, and an inner one made up of only six to eight rows of cells. In the right transverse colon no demarcation can be observed, but a difference exists between the innermost and the outermost cells, since those of the two innermost rows possess some peculiarities with regard to the sarcoplasmic reticulum, glycogen particles, caveolae, and intercellular junctions. In the left part of the colon, the circular muscle layer is also divided into two portions. In fact, the innermost smooth muscle cells still possess peculiar morphologies, progressively increase in number, and become separate from each other making up a superficial muscle network. A fibrous lamella, along and inside which a ganglionated nerve plexus runs, is strictly apposed to the submucosal border of the circular muscle layer of the entire colonic length. A second nerve plexus runs between the two portions of the circular muscle layer. Both these plexuses are accompanied by interstitial cells of Cajal in the right colon only. The peculiar organization of the entire submucosal border of the human colonic circular muscle layer distinguishes it from other parts of the gut and probably represents a structural basis for control of human colonic motility. The presence of putative pacemaker cells (interstitial cells and peculiar smooth muscle cells) indicates that the inner border of human colonic circular muscle layer possesses pacemaking activities. Moreover, the interstitial cell – smooth muscle cell ratio differs depending on the colonic level; two main regions can be identified: the right and the left colon. Consequently, we might expect regional variation in pacemaking.Key words: smooth muscle cells, interstitial cells of Cajal, human colon, ultrastructure.
Changes of β-adrenoceptors in the aortic muscle cells of spontaneously hypertensive rats
Authors: Kwan C. Y. , Lee R. M. K. W.
Published: April 2011

The characteristics of [125I]monoiodocyanopindolol (ICYP) binding to β-adrenoceptors of cultured aortic smooth muscle cells derived from 4-week-old spontaneously hypertensive rats (SHR) and the Wistar–Kyoto normotensive rats (WKY) were examined. During optimization of the binding assays, we found that the specific binding of ICYP by intact cells was masked by a high level of nonspecific ICYP accumulation in intact cells presumably owing to the lipophilic nature of ICYP. Optimal specific ICYP binding requires that the cells be gently lysed with hypotonic dilution followed by a freeze-and-thaw cycle. Under most experimental conditions tested, the total number of ICYP binding sites in WKY aortic muscle cells was considerably and consistently smaller than that in SHR cells. There was no difference in the Kd values for ICYP binding to SHR and WKY cells. However, when ICYP binding was carried out using crude membrane fractions with well-defined plasma-membrane content isolated from aortic muscle strips of adult rats, we found no difference in the number of β-adrenoceptor sites between SHR and WKY. Morphological evidence indicated that cultured SHR aortic muscle cells contained a greater proportion of larger cells with multinuclear features. These results suggest that an increase in the number of β-adrenoceptor density per cell in SHR may be associated with cellular hypertrophy of aortic smooth muscle cells. We conclude that under cultured conditions, a higher incidence of polyploid smooth muscle cells in the SHR as compared with WKY was expressed earlier than under in vivo conditions. Therefore, the interpretation of results obtained from cultured cell studies in relation to under in vivo conditions should be exercised with caution.Key words: β-adrenoceptor, vascular smooth muscle, aorta, cell membranes, hypertension, hypertrophy.
Biochemical analysis of L-type calcium channels from skeletal and cardiac muscle
Authors: Tuana Balwant S. , Murphy Brian J.
Published: April 2011

The development of specific pharmacological agents that modulate different types of ion channels has prompted an extensive effort to elucidate the molecular structure of these important molecules. The calcium channel blockers that specifically modulate the L-type calcium channel activity have aided in the purification and reconstitution of this channel from skeletal muscle transverse tubules. The L-type calcium channel from skeletal muscle is composed of five subunits designated α1, α2, β, γ, and σ. The α1-subunit is the pore-forming polypeptide and contains the ligand binding and phosphorylation sites through which channel activity can be modulated. The role of the other subunits in channel function remains to be studied. The calcium channel components have also been partially purified from cardiac muscle. The channel consists of at least three subunits that have properties related to the subunits of the calcium channel from skeletal muscle. A core polypeptide that can form a channel and contains ligand binding and phosphorylation sites has been identified in cardiac preparations. Here we summarize recent biochemical and molecular studies describing the structural features of these important ion channels.Key words: dihydropyridine receptor, calcium channel, muscle, molecular structure.
Composition, structure, functionality, and chemical modification of legume starches: a review
Authors: Hoover R. , Sosulski F. W.
Published: April 2011

The major carbohydrate of the legume seed is starch, which represents up to 45% of the total seed weight. In recent years, substantial progress has been made in understanding the relationship between starch structure and functionality. However, these studies have been mainly on cereal and tuber starches. The present status of knowledge on the composition, structure, functionality, digestibility, and chemical modification of legume starches is reviewed. In addition present concepts of granule structure, gelatinization, retrogradation, and rheology are also reviewed. Future research needs in the area of legume starch chemistry are discussed.Key words: legume starch, structure, functionality, modification, digestibility.
The 1990 James A. F. Stevenson Memorial Lecture. Gonadotropin-releasing hormone and its actions
Authors: Braden Tim D. , Conn P. Michael
Published: April 2011

Gonadotropin-releasing hormone (GnRH) stimulates the release and biosynthesis of gonadotropins, luteinizing hormone, and follicle-stimulating hormone from the pituitary gland. Additionally, GnRH regulates the number of its own receptors on pituitary gonadotropes causing both up- and down-regulation of receptors as well as biosynthesis of GnRH receptors. After exposure to GnRH, gonadotropes become desensitized to further stimulation by GnRH. The mechanisms through which these actions of GnRH are mediated appear to differ. Effects dependent upon extracellular calcium include gonadotropin biosynthesis and release as well as up-regulation of GnRH receptors. Additional actions of GnRH, such as down-regulation of receptors, biosynthesis of receptors, and desensitization, appear to be independent of extracellular calcium. Subsequent studies have ascribed roles for calmodulin and protein kinase C in mediating specific effects of GnRH.Key words: pituitary, gonadotropin-releasing hormone, receptor, protein kinase C, calmodulin.
Effect of cicletanine on reperfusion-induced arrhythmias and its relation to 6-keto-PGF1α and thromboxane B2 release
Authors: Tosaki Arpad , Viossat Isabelle , Braquet Pierre
Published: April 2011

Isolated hearts, excised from spontaneously hypertensive male rats treated orally with cicletanine, a new furopyridine antihypertensive drug, were subjected to 30 min of global ischemia followed by 10 min of reperfusion. The effect of cicletanine on reperfusion-induced arrhythmias in relation to 6-keto-PGF1α and thromboxane (TXB2) release was studied. After 30 min of global ischemia, the incidence (total) of ventricular fibrillation (VF) and ventricular tachycardia (VT) was reduced by 2-week pretreatment of the rats with 30 and 100 mg/kg of cicletanine (VF, 33% at 30 mg/kg and 25% at 100 mg/kg vs. 91% in untreated rats; VT, 42% at 30 mg/kg and 42% at 100 mg/kg vs. 100% in untreated rats), while lower doses of cicletanine (3 and 10 mg/kg) failed to reduce the incidence of reperfusion-induced rhythm disturbances. Reperfusion of the ischemic myocardium resulted in a fivefold increase of 6-keto-PGF1α and TXB2 release in the perfusion effluent of fibrillated hearts but not in the perfusion effluent of nonfibrillated hearts. Cicletanine failed to influence the reperfusion-stimulated release of 6-keto-PGF1α and TXB2. These results indicate that the anti-arrhythmic effect of cicletanine in the reperfused myocardium is not related to PGI2 and thromboxane A2 release.Key words: cicletanine, reperfusion arrhythmias, 6-keto-PGF1α, thromboxane B2, rat heart.
Developmental changes in inotropic actions of neurotoxins observed in ventricular muscle of rat heart
Authors: Temma Kyosuke , Kondo Hiroshi , Akera Tai
Published: April 2011

Developmental changes in functions of myocardial sodium channels were examined from inotropic effects of several neurotoxins in ventricular muscle preparations obtained from prenatal (20–22 day gestation) or adult (3–4 months old) rat hearts. Tetrodotoxin caused a negative inotropic effect in low concentrations and a loss of muscle responsiveness to electrical stimulation in high concentrations in preparations obtained from either prenatal or adult rat heart. The tetrodotoxin concentration that caused a 50% decrease in developed tension was higher in prenatal rats. Anemonia sulcata toxin, Androctonus australis toxin, veratridine, and Centruroides sculpturatus toxin all produced positive inotropic effects in adult rat heart. The effects were largest with A. sulcata and A. australis toxins, intermediate with veratridine, and smallest with C. sculpturatus toxin. Prenatal heart required higher concentrations of either veratridine, or A. sulcata or A. australis toxins to produce comparable positive inotropic effects. With C. sculpturatus toxin, no significant positive inotropic effect was observed in prenatal heart muscle preparations. These results indicate that cardiac sodium channels undergo significant functional changes during development and that negative and positive inotropic effects of neurotoxins resulting from inhibition and enhancement of fast Na+ channels reflect developmental changes in the cardiac sodium channels.Key words: sodium channels, sodium channel toxins, cardiac inotropic agents.