bluuebunny/crossref_metadata_2025 huggingface dataset:
The 1988 Merck Frosst Award.: The role of ascending and descending noradrenergic and serotonergic pathways in opioid and non-opioid antinociception as revealed by lesion studies
Authors: Sawynok Jana
Published: April 2011

Both ascending and descending noradrenergic and serotonergic pathways have been implicated in mechanisms of antinociception produced by systemic administration of morphine and the non-opioid drugs, baclofen and clonidine. These agents affect the turnover and release of noradrenaline and 5-hydroxytryptamine in various brain regions and the spinal cord, and alter neuronal activity in regions from which ascending and descending aminergic pathways originate. The role of specific pathways in morphine analgesia has been examined by applying electrolytic lesions to discrete brain regions. However, this technique is limited because lesions are nonselective for a particular neuronal population. More recent studies have used microinjection of the neurotoxins 6-hydroxydopamine and 5, 7-dihydroxytryptamine to lesion specific noradrenergic and serotonergic pathways, respectively. Although more selective, this approach may be limited by the development of receptor supersensitivity or other mechanisms of compensation, as certain changes seen soon after microinjection (days) are no longer apparent at later intervals (weeks). Systemic drug administration reveals drug actions at predominant but not clearly identified sites of action. The role of a particular aminergic pathway can be revealed most clearly by combining microinjection of drugs into discrete brain sites with neurotoxin-induced lesions, and examining the effects of such lesions at a range of time intervals. A differential role of a particular pathway may become apparent following systemic or intracerebral administration.Key words: neurotoxin lesions, antinociception, morphine, noradrenaline, baclofen.
Renal serine production in vivo: effects of dietary manipulation of serine status
Authors: Brosnan John T. , Hall Beatrice
Published: April 2011

Renal serine production in rats was quantitated by simultaneously measuring renal blood flow and the renal arteriovenous difference for this amino acid. The rate of synthesis was 0.24 ± 0.02 μmol∙min−1∙100 g−1 in rats fed a diet containing 12% casein. This rate was not altered by the inclusion of an additional 1% serine in the diet for 7 days or by acute infusion of serine, although both protocols increased blood serine by 50%. When rats were fed a diet in which protein was entirely replaced by crystalline amino acids the rate of renal serine production was also 0.25 ±0.05 μmol∙min−1∙100 g−1. Omission of serine or both serine and glycine from this diet did not alter the rate of renal serine synthesis. Renal serine production does not respond to the serine content of the diet.Key words: serine, glycine, kidney, amino acid metabolism.
Biochemical mechanisms of atrial natriuretic factor action
Authors: Tremblay Johanne , Hamet Pavel
Published: April 2011

Since atrial natriuretic factor (ANF) is a natriuretic and vasodilatory hormone, its mechanisms of action expectedly involve so-called negative pathways of cell stimulation, notably cyclic nucleotides. Indeed, the guanylate cyclase–cyclic GMP (cGMP) system appears to be the principal mediator of ANF's action. Specifically, particulate guanylate cyclase, a membrane glycoprotein, transmits ANF's effects, as opposed to the activation of soluble guanylate cyclase by such agents as sodium nitroprusside. The stimulation of particulate guanylate cyclase by ANF manifests several characteristics. One of them is the functional irreversibility of stimulation with its apparent physiological consequences: the extended impact of ANF on diuresis and vasodilation in vivo lasts beyond the duration of increased plasma ANF levels and is accompanied by a prolonged elevation of cGMP. Another characteristic is the parallelism between guanylate cyclase stimulation and increases of cGMP in extracellular fluids. cGMP egression appears to be an active process, yet its physiological implications remain to be uncovered. In heart failure, cGMP continues to reflect augmented ANF levels, suggesting that in this disease, the lack of an ANF effect on sodium excretion is due to a defect distal to cGMP generation. In hypertension, where ANF levels are either normal or slightly elevated, probably secondary to high blood pressure, the ANF responsiveness of the particulate guanylate cyclase–cGMP system, the hypotensive effects, diuresis and natriuresis are exaggerated. The implications of this exaggerated responsiveness of the ANF–cGMP system in the pathophysiology of hypertension and its potential therapeutic connotations remain to be evaluated.Key words: ANF, cGMP, guanylate cyclase, hypertension, heart failure.
κ-Opioid agonist induced diuresis. Is it mediated by a blood-borne factor of adrenomedullary origin?
Authors: Borkowski Kazimierz R.
Published: April 2011

Intravenous administration of the κ-opioid agonists U50488H, tifluadom, and ethylketocyclazocine induced a characteristic diuresis in conscious, intact, saline-loaded rats. Naloxone pretreatment antagonized U50488H-induced diuresis. The diuretic response to the κ-opioid agonists was significantly attenuated in adrenal demedullated rats. However, basal urine output, the diuretic response to furosemide, and the antidiuretic response to the μ-opioid agonist buprenorphine were unaffected. Transfusion studies established that 1 mL of blood, from intact donor rats treated with U50488H, induced a diuretic response when administered to intact or demedullated recipient rats, whether or not the recipients had been pretreated with naloxone. However, blood from demedullated rats treated with U50488H was unable to induce diuresis in intact or demedullated recipients. The results indicate that κ-opioid agonist induced diuresis appears to be mediated by a nonopioid blood-borne "diuretic factor" of adrenomedullary origin and that this factor might be responsible for the dependence of the diuretic response upon an intact and functional adrenal medulla in conscious rats.Key words: kappa-opioid agonists, diuresis, adrenal medulla, conscious rats.
Ethosuximide affects both pentylenetetrazole- and kainate-induced clonic seizures but differentiates between tonic–clonic seizures
Authors: Velíšek Libor , Kulhánková Ivana , Roztočilová Lenka , Mareš Pavel , Velíšková Jana , Mirvaldová Helena
Published: April 2011

Young (25-day-old) and adult (90-day-old) rats pretreated with ethosuximide (62.5 or 125 mg/kg i.p.) were injected with either s.c. pentylenetetrazole (100 mg/kg) or i.p. kainate (10 or 14 mg/kg). The incidences and latencies of minor (clonic) and major (tonic–clonic) seizures were registered. Ethosuximide (125 mg/kg) completely blocked clonic seizures induced by the lower dose of kainate, and slightly suppressed or delayed those induced by the higher dose of kainate or pentylenetetrazole in both age groups. The effect of ethosuximide on major kainate-induced seizures (elicited in young rats only) was insignificant (ethosuximide only partially decreased the incidence of major seizures), whereas ethosuximide abolished major pentylenetetrazole-induced seizures in both age groups. Ethosuximide also failed to affect the latencies of kainate-induced automatisms (e.g., scratching, wet dog shakes). Similarities between kainate- and pentylenetetrazole-induced clonic seizures, as well as a similar action of ethosuximide on both, suggest a common generator for the pattern of clonic seizures.Key words: pentylenetetrazole, kainate, ethosuximide, seizures, rat.
Basal and stimulated ANF secretion: role of tissue preparation
Authors: Sonnenberg H. , Milojevic S. , Yip C. , Veress A. T.
Published: April 2011

Our previous results showed that addition of agonists, such as vasopressin and angiotensin, added to incubation medium with freshly excised rat atria caused marked release of atrial natriuretic factor (ANF). This release was in the form of prohormone rather than active peptide. Since others had difficulty reproducing these findings, in the present study we investigated ANF release with and without angiotensin addition in two sets of atrial tissue. In the first, tissue was blotted and carefully cleaned as previously described; in the second, atrial tissue was placed into incubation medium without prior preparation. ANF activity in the medium was measured by radioimmunoassay and receptor assay. Using the immunoassay, basal release of ANF was threefold greater from prepared vs. nonprepared atrial tissue; significant stimulation by angiotensin was seen only in the prepared atria. ANF release measured by radioreceptor assay was 1/5–1/10 of that measured by immunoassay. Taking the difference between the two measurements as an index of prohormone secretion, the results confirm that both basal and stimulated release was primarily in the form of proANF. Scanning electron microscopy revealed that cleaning of the atria had removed the endocardial lining of the tissue. The results thus indicate that an intact endocardium can prevent agonist-induced proANF secretion, suggesting that this tissue may be an important modulator of plasma ANF levels.Key words: atrial natriuretic factor, endocardium, proANF secretion.
Cardiovascular and renal effects of iso-rANP, a second natriuretic peptide from rat atria
Authors: Jennings D. B. , Flynn T. G.
Published: April 2011

Administration of a newly discovered second atrial peptide, iso-atrial natriuretic peptide (or iso-rANP(1–45) for the rat), caused hypotension, decreased heart rate, diuresis, and increased renal excretion of Na+, K+, and Cl− in the anesthetized rat. Bolus injections of chemically synthetic iso-rANP(1–45) had circulatory and diuretic activity equal to or greater than rANP(99–126) but, at low doses, a lesser effect on renal electrolyte excretion. The synthetic peptide fragment, iso-rANP(17–45), analogous in structure to rANP(99–126), had attenuated activity on the circulation, and at low doses, attenuated activity on the kidney. At higher doses, where renal responses to rANP(99–126) were less (downside of a biphasic response), both iso-rANP(1–45) and (17–45) had greater effects on water and electrolyte excretion than rANP(99–126). Injections of iso-rANP(1–45) and (17–45) increased hematocrit, whereas rANP(99–126) did not; furthermore, unlike rANP(99–126), iso-rANP did not affect arterial plasma Na+ concentration. The heart produces at least two genetically different atrial natriuretic peptides which affect the circulation and salt and water balance.Key words: blood pressure regulation, heart rate regulation, regulation of urine volume, regulation of renal electrolyte excretion, hemoconcentration.
Opioidergic control of gonadotropin secretion in the female rabbit: divergent effects of morphine on secretion of follicle-stimulating hormone and luteinizing hormone
Authors: YoungLai E. V. , Byrne A.
Published: April 2011

The nature of secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) was followed in female rabbits on a daily basis from age 36 to 60 days by sequential 5-min blood sampling over 1- to 2-h periods each day. Both LH and FSH were found to be secreted in a pulsatile manner. The mean LH pulse amplitude over the 25 days was 0.95 ± 0.32 ng/mL and for FSH it was 10.15 ± 1.11 ng/mL. Mean plasma LH levels were significantly increased from 1.46 ± 0.08 ng/mL in 36 to 42-day-old rabbits to 1.89 ± 0.12 ng/mL in 43 to 50-day-old rabbits and remained elevated from 50 to 60 days. FSH levels during the same periods also rose significantly from 14.93 ± 0.79 to 19.57 ± 2.05 ng/mL. To examine the influence of endogenous opioid peptides on the release of LH and FSH in 36 to 60-day-old female rabbits, morphine sulfate at 0.2, 0.5, 2.0, and 5.0 mg/kg was administered subcutaneously after 30 min baseline sampling, and blood was taken for another 60–120 min. Morphine at all doses and at all ages inhibited the amplitude and frequency of LH pulses but had no effect on FSH secretion. To determine whether the effects of morphine on LH secretion could be reversed with naloxone, females aged 82–114 days were used. Naloxone administered 1 h after morphine reversed the inhibitory effects of morphine, whereas the simultaneous administration of naloxone with morphine had variable effects but seemed to delay the LH increase. These data suggest that endogenous opioid peptides may have an acute inhibitory effect on the secretion of LH but not FSH.Key words: rabbit, follicle-stimulating hormone, luteinizing hormone, morphine, naloxone.
Adrenergic interactions in uterus and vascular smooth muscle in rats in vivo
Authors: Gazis Diana , Gonzalez Genevieve , Mendlowitz Milton
Published: April 2011

Simultaneous blood pressure and uterine responses to norepinephrine infusions were recorded in urethane-anesthetized, pentolinium–indomethacin treated rats in natural estrus under conditions in which no blockers or blockers of α1-, α2-, and β-adrenergic receptors or of "reuptake" of norepinephrine were present. The contributions of α1- and α2-adrenergic receptors to the blood pressure response were similar during the initial portion of the response. At later times, however, α1-adrenergic receptors were responsible for the major portion of the response. The tachyphylaxis of the pressor response that occurs during norepinephrine infusion could be prevented by preventing norepinephrine "reuptake" with imipramine. In the uterus, the initial small α-adrenergic contractile response (seen only at the lowest infusion rate) was quickly overwhelmed by a β-adrenergic relaxing component. Administration of the β-adrenergic receptor blocker, propranolol, during norepinephrine infusion caused similar increases in blood pressure in control, yohimbine-, and prazosin-treated rats. Uterine contractions, in contrast, were only significantly elevated during β-adrenergic receptor blockade when yohimbine or imipramine had also been administered.Key words: uterus, vascular smooth muscle, adrenergic receptors, rats.
Activity and energy expenditure
Authors: Dauncey M. J.
Published: April 2011

The influence of small changes in activity on energy expenditure and hence on energy requirements and energy balance is assessed. Evidence from direct and indirect calorimetry suggests that differences in spontaneous minor activity could readily alter 24-h energy expenditure by as much as 20%. This compares with values in the order of 10% for moderate overfeeding and somewhat less than this during mild cold exposure. Individual variability in 24-h energy expenditure can therefore be accounted for not only by differences in resting metabolism and the thermic responses to energy intake and temperature but also by differences in minor activity. Interactions between activity and environmental factors such as nutrition and temperature can modify the effect of activity on energy balance. Very little is known about mechanisms that could account for differences in spontaneous activity and these need to be the subject of future investigations.Key words: activity, energy balance, nutrition, temperature, thermogenesis.
Endothelial cells inhibit the vascular response to adrenergic nerve stimulation by a receptor-mediated mechanism
Authors: González Carmen , Martin Carmen , Hamel Edith , Galea Elena , Gómez Bernardino , Lluch Salvador , Estrada Carmen
Published: April 2011

Rabbit central ear arteries, with and without endothelium, were perfused at a constant flow rate and the perfusion pressure was measured as an index of the vessel resistance. Transmural nerve stimulation (TNS) induced a frequency-dependent increase in perfusion pressure in all vessels that was blocked by tetrodotoxin, phentolamine, and prazosin. Removal of endothelium significantly enhanced contractions induced by TNS. The inhibitory effect of endothelium was not modified by indomethacin but was abolished by hemoglobin, indicating that endothelium-derived relaxant factor (EDRF) was the vasodilator involved. The endothelium-dependent inhibitory effect (rubbed vessel minus control vessel contractions) increased with time during the first 10–20 s after the beginning of TNS, and was frequency dependent and inhibited by low doses of phentolamine, which suggest a receptor-mediated mechanism. To analyze whether amine neurotransmitters are able to permeate the artery wall and contact the endothelial cell membrane, the passage of [3H]acetylcholine from the abluminal side to the lumen was studied in intact vessels. [3H]acetylcholine readily permeated the vessel wall, as assessed by radioautography, and appeared in the perfusion fluid at a concentration that explains the relaxation induced by perivascular acetylcholine. These data suggest that endothelial cells modulate the effect of perivascular neurotransmitters by a receptor-mediated mechanism. In the case of the sympathetic innervation, such modulation would be more relevant at low levels of transmitter release and would be minimized during intense sympathetic stimulation.Key words: adrenergic innervation, endothelium-derived relaxant factor, endothelial receptors, endothelium, vascular innervation.
Flow-induced oxygen uptake by the perfused rat hindlimb is inhibited by vasodilators and augmented by norepinephrine: a possible role for the microvasculature in hindlimb thermogenesis
Authors: Ye Ji-Ming , Colquhoun Eric Q. , Hettiarachchi Manthinda , Clark Michael G.
Published: April 2011

Oxygen uptake in the perfused rat hindlimb was studied at 25 °C using an artificial perfusate, and the effects of perfusate flow rate, norepinephrine, and vasodilators were compared. Hindlimb oxygen uptake and perfusion pressure each increased as the flow rate was increased stepwise from 2 to 18.5 mL/min per hindlimb. At each flow rate, the rate of oxygen uptake was inhibited by the vasodilator nitroprusside (0.5 mM) and increased by norepinephrine (5 nM). A corresponding change in perfusion pressure also occurred, with norepinephrine leading to a marked increase and nitroprusside leading to a decrease; however, changes in oxygen uptake and pressure were not linearly related. The lactate/pyruvate ratio of the perfusate was used as an index of tissue perfusion and was determined at each flow rate. Lactate and pyruvate efflux increased as the flow rate was increased stepwise from 2 to 18.5 mL/min per hindlimb. At 2 mL/min per hindlimb, the lactate/pyruvate ratio was 15; at flow rates equal or greater than 4 mL/min per hindlimb, the ratio was constant at 9. Nitroprusside had no significant effect on the ratio at any flow rate even though a marked inhibitory effect on oxygen uptake was evident. Muscle content of high energy phosphates at 8 mL/min per hindlimb did not differ before and after treatment with vasodilators. In addition, the vasodilators had no apparent effect on skeletal muscle oxygen uptake or force development during electrical stimulation. The findings indicate that oxygen uptake by the hindlimb is not limited by inadequate perfusion and that oxygen uptake can be further increased by norepinephrine. The close association of the vasoconstrictive action of norepinephrine with the increase in oxygen uptake and the finding that the increase in oxygen uptake is minimal when nitroprusside is present suggest a central role of the vasculature in the control of muscle thermogenesis. The novel possibility that a significant proportion of oxygen uptake by the resting hindlimb is a consequence of the work done by cells contributing to vasoconstriction (i.e., thermogenesis from "hot pipes") is discussed.Key words: hindlimb oxygen uptake, oxygen uptake and vasoconstriction, norepinephrine, pressure-induced oxygen uptake, nitroprusside.
Animal models in the study of vomiting
Authors: King Gregory L.
Published: April 2011

The emetic responses to various pharmacological agents, cytotoxins, and radiation are compared among animal species. The species included for comparison are the human, nonhuman primate, dog, cat, and ferret. The categories of pharmacologic compounds include both those compounds that act on identified membrane receptors (e.g., cholinergic agonists, catecholamines, and neuroactive peptides) and those that act on unidentified receptors (e.g., cardiac glycosides and Veratrum alkaloids, among others). Emphasis is placed on emetic dose–response relations and threshold ED50 and ED100 values calculated from these relations, as indices of species sensitivity to emetic stimuli. For the more noxious emetics, the cytotoxins and radiation, the latency to the first emetic episode and duration of emesis are also compared across species. The effect that peripheral and central nerve lesions have on species differences in emetic responses to stimuli is also discussed.Key words: emesis, vomiting, ferret, dog, cat, nonhuman primate, model.
Effects of glucocorticoids on prostaglandin formation by human amnion
Authors: Gibb William , Lavoie Jean-Claude
Published: April 2011

The human amnion may be an important source of prostaglandins involved in the onset of human labor and therefore it is important to define the factors that regulate their formation in this tissue. In the present study we demonstrate that glucocorticoids inhibit prostaglandin production by freshly isolated amnion cells. The inhibitory action of the glucocorticoids, however, changes to a stimulatory action when the cells are maintained in primary culture for a few days. For both inhibition and stimulation, concentrations of 10−8 M dexamethasone or greater were required to give significant effects, and estradiol and progesterone had no effect on the prostaglandin output of the cells. Epidermal growth factor (EGF), which has previously been found to stimulate prostaglandin output by confluent amnion cells, did not alter prostaglandin output of cells initially placed in culture. Furthermore, the stimulatory action of EGF and dexamethasone appeared additive. The calcium ionophore A23187 stimulated prostaglandin output in freshly isolated cells and accentuated the inhibitory effect of dexamethasone. These studies indicate that prostaglandin formation by human amnion during pregnancy could be regulated by glucocorticoids. These steroids are easily available to the amnion by way of cortisone conversion to Cortisol by the maternal decidua. The results also indicate that amnion is capable of responding to glucocorticoids in both a stimulatory and inhibitory fashion and whether one or both actions are of importance in vivo is a question that is as yet unresolved.Key words: prostaglandins, amnion, fetal membranes, glucocorticoids, labor, pregnancy.
Regulation of hepatic cytochrome P-450 during Infectious disease
Authors: Renton Kenneth W. , Knickle Leah C.
Published: April 2011

During episodes of infectious disease the mixed function oxidase system is depressed and the capacity of the liver to metabolize drags can be compromised in both animals and humans. The depression that occurs during viral infections is mediated via the production of interferon. This action of interferon requires the synthesis of an intermediate protein(s) yet to be identified. Using an oligonucleotide probe for a unique sequence in cytochrome P-450LAω we have now shown that the mRNA for this isozyme is depressed following the administration of interferon inducers. The magnitude in the loss of mRNA corresponds to the magnitude of the loss in the levels of this isozyme. This depression is observed within 6 h of interferon exposure. It is concluded that the decrease in drag metabolism during viral infections is caused by an interferon-mediated loss in mRNA and subsequent cytochrome P-450 synthesis in the liver.Key words: cytochrome P-450, drug metabolism, mixed function oxidase, interferon, viral infection.
Reversibility of cold-induced hypertension after removal of rats from cold
Authors: Shechtman Orit , Papanek Paula E. , Fregly Melvin J.
Published: April 2011

Chronic exposure of rats to cold air induces hypertension, including elevation of blood pressure and cardiac hypertrophy. The present study was designed to assess reversibility of these changes after removal from cold. Five groups of six male rats each were exposed to cold (5 ± 2 °C) for 39 days, while six control rats were maintained at 26 ± 2 °C. Systolic blood pressures of the rats in one of the cold-treated groups, as well as the controls, were measured twice weekly throughout the experiment. Blood pressure of the cold-exposed rats (150 ± 3 mmHg; 1 mmHg = 133.3 Pa) became elevated significantly above that of controls (129 ± 3 mmHg) within 4 weeks. On day 39 of cold exposure, one group (six rats) of the cold-treated rats was sacrificed while still in the cold. The remaining four groups of cold-treated rats were than removed from cold and kept at 26 ± 2 °C. One group of cold-treated rats was sacrificed weekly thereafter. During the last week, the six control rats were also sacrificed. At death, the heart, kidneys, and adrenal glands were removed and weighed. Mean heart weight of the cold-treated group (346 ± 7 mg/100 g body weight), sacrificed prior to removal from cold, was significantly (p < 0.01) greater than that of controls (268 ± 5 mg/100 g body weight). The increased heart weight of the cold-treated group appeared to result mainly from an increase in left ventricular weight. The weights (mg/100 g body weight) of the kidneys and adrenal glands of cold-treated rats, measured prior to removal from cold, were significantly (p < 0.01) greater than those of controls. Two weeks after removal from cold, blood pressure, heart weight, and left ventricular weight decreased from the levels observed prior to removal from cold. However, they were still significantly greater than those of controls through the fourth week after removal from cold. Thus, the hypertension accompanying a 39-day exposure to cold appears to be only partially reversible at 4 weeks after removal from cold.Key words: cold exposure, hypertension, blood pressure, reversibility of hypertension, renal hypertrophy, cardiac hypertrophy.
Adenylate cyclase uncoupled β-adrenergic receptors in salamander proximal tubules
Authors: Morgunov Nikolas S. , Hirsch David J.
Published: April 2011

The isolated perfused proximal tubule of the neotenic salamander Ambystoma tigrinum responds with either a hyperpolarization or depolarization of both the basolateral cell membrane and transepithelial potentials following the addition of 10−5 M isoproterenol to the bath superfusate. Both responses were blocked by 10−6 M propranolol but neither response was mimicked by 10−4 M cAMP. β-Adrenergic binding studies of individual microdissected proximal tubules using (−)-[3H]CGP-12177 as a hydrophyllic radioligand and (±)-timolol (0.1 mM) as the displacer drug revealed two distinct populations of proximal tubules possessing either low (KD = 153.8 nM; Bmax = 110.2 fM/mm) or high affinity (KD = 12.0 nM; Bmax = 3.9 fM/mm) binding characteristics. Competition studies indicated that the bound (−)-[3H]CGP-12177 behaved as a typical β-adrenergic ligand, being displaced by (−)-isoproterenol but not by (+)-isoproterenol or (−)phenylephrine. However, neither appeared to be coupled to the adenylate cyclase system. These data suggest the presence of functional β-adrenergic receptors that do not appear to be coupled to the adenylate cyclase system.Key words: proximal tubule, β-receptors, adenylate cyclase.
Effects of caffeine ingestion on body fluid balance and thermoregulation during exercise
Authors: Falk Bareket , Burstein Ruth , Rosenblum Josef , Shapiro Yair , Zylber-Katz E. , Bashan N.
Published: April 2011

This study investigated the effects of caffeine supplementation on thermoregulation and body fluid balance during prolonged exercise in a thermoneutral environment (25 °C, 50% RH). Seven trained male subjects exercised on a treadmill at an intensity of 70–75% of maximal oxygen consumption to self-determined exhaustion. Subjects exercised once after caffeine and once after placebo ingestion, given in a double-blind crossover design. Five milligrams per kilogram body weight of caffeine followed by 2.5 mg∙kg−1 of caffeine were given 2 and 0.5 h before exercise, respectively. Rectal temperature was recorded and venous blood samples were withdrawn every 15 min. Water loss and sweat rate were calculated from the difference between pre- and post-exercise body weight, corrected for liquid intake. Following caffeine ingestion, when compared with placebo, no significant difference in final rectal temperature or in percent change in plasma volume were found. No significant differences were observed in total water loss (1376 ± 154 vs. 1141 ± 158 mL, respectively), sweat rate (12.4 ± 1.1 vs. 10.9 ± 0.7 g∙m−2 min−1, respectively), rise in rectal temperature (2.1 ± 0.3 vs. 1.5 ± 0.4 °C, respectively), nor in the calculated rate of heat storage during exercise (134.4 ± 17.7 vs. 93.5 ± 22.5 W, respectively). Thus, in spite of the expected rise in oxygen uptake, caffeine ingestion under the conditions of this study does not seem to disturb body fluid balance or affect thermoregulation during exercise performance.Key words: caffeine, physical exercise, thermoregulation, fluid balance, dehydration.
Rat heart organ culture for the study of trophic substances involved in the maintenance of normal sensitivity to norepinephrine: possible involvement of cAMP and search for other factors
Authors: Tanaka Hikaru , Shigenobu Koki
Published: April 2011

In organ culture conditions, in the absence of in vivo factors, the newborn rat right atria acquire a high sensitivity to agonists similar to that seen before sympathetic innervation and after denervation. In the present study, we examined the effects of various extracts and substances on the development of supersensitivity to norepinephrine (NE) to obtain information on the in vivo factors that regulate myocardial sensitivity. Addition of rat serum, right atrial extract, superior cervical ganglionic extract, vas deferens extract, carbachol, insulin, cortisone, thyroxin, and neuropeptide Y in the culture medium did not prevent the development of supersensitivity. Addition of NE completely inhibited the development of supersensitivity. This effect of NE was blocked by sotalol but not by phentolamine. Addition of calcitonin gene related peptide, forskolin, and 8-bromo-cAMP partially inhibited the development of supersensitivity. These results are consistent with the view that NE released from sympathetic nerve terminals in the newborn atria maintains myocardial sensitivity at normal level by acting on β-adrenergic receptors, and that the effect may be partially mediated by a rise in intracellular cAMP concentration.Key words: rat neonate cardiac muscle, organ culture, sympathetic innervation, norepinephrine, calcitonin gene related peptide, sensitivity, trophic control.
Recent studies of human calcium metabolism using stable isotopic tracers
Authors: Yergey Alfred L. , Abrams Steven A. , Vieira Nancy E. , Eastell Richard , Hillman Laura S. , Covell David G.
Published: April 2011

Stable isotopes of calcium are used safely as tracers for calcium in human populations ranging in age from infants to postmenopausal women. Thermal ionization mass spectrometry is used to measure calcium isotope ratios with relative accuracies of about 1% for natural abundance ratios at precisions of about 1% relative to the mean. Perturbations of natural abundance ratios are determined for the calcium in blood, urine, and feces with a limit of detection of about 2 Δ% excess. The mathematical rationale for clinical studies of fractional absorption of dietary calcium and the kinetics of calcium's internal distribution are presented.Key words: calcium, tracers, stable isotopes, mass spectrometry.
Increased thyroxine turnover after 3,3′,4,4′,5,5′-hexabromobiphenyl injection and lack of effect on peripheral triiodothyronine production
Authors: Spear P. A. , Higueret P. , Garcin H.
Published: April 2011

Juvenile male Wistar rats were injected i.p. with 0, 20, or 40 mg/kg 3,3′,4,4′,5,5′-hexabromobiphenyl and blood samples collected periodically up to 28 days. A dose-dependent depression of the serum thyroxine level was detected, while the circulating triiodothyronine concentration was not affected by the biphenyl congener. Thyroxine turnover in vivo 7 days after injection of the 20 mg/kg dose revealed significant increases of various clearance parameters relative to controls. The fractional clearance rate (day−1) increased by 84%, the daily metabolic clearance rate (mL∙kg−1∙day−1) increased by 128%, and the daily thyroxine disposal rate (ng∙kg−1∙day−1) increased by 41%. Also, the thyroxine distribution space (mL/kg) increased by 21%. These results indicated greater thyroxine binding in major organs as well as a marked increase in the peripheral metabolism of thyroxine. The increased thyroxine metabolism is explained by a 4.8-fold induction of uridine 5′-diphosphoglucuronyltransferase activity in liver microsomes. The type I 5′-deiodinase activity in liver homogenates and endogenous concentrations of the cofactor for this reaction, glutathione, were not affected by the biphenyl. This result means that homeostatic mechanisms involving thyroxine conversion to triiodothyronine do not explain the maintenance of serum T3 under these conditions.Key words: thyroxine, triiodothyronine, thyroxine turnover, deiodinase, 3,3′,4,4′,5,5′-hexabromobiphenyl, uridine 5′-diphosphoglucuronyltransferase, glutathione.
Relationship between sensitivity and density of muscarinic receptors in single smooth muscle cells of guinea pig taenia caecum prepared under three conditions
Authors: Koike Katsuo , Ohtsuki Hiroshi , Takayanagi Issei
Published: April 2011

The relationship between the sensitivity (the pD2 value) of carbachol and the density (the total concentration of receptors) of muscarinic receptors using single cells from the guinea pig taenia caecum prepared with a mixture of crude collagenase and trypsin inhibitor, purified collagenase alone, and a mixture of purified collagenase and papain was examined. The sensitivity of the single cells prepared with a mixture of purified collagenase and papain was about 10 times more effective than that of the single cells prepared under other conditions. The dissociation constant of [3H]quinuclidinyl benzilate (QNB) and Hill's coefficient did not change in the single cells prepared under the three conditions, though the maximum binding sites were significantly greater in the cells prepared with the mixture of purified collagenase and papain than in those prepared by other means. These results suggest that the increase in the sensitivity of carbachol obtained in the single cells prepared with this mixture is due to the increase in the density of muscarinic receptors and also suggest that the effects of this enzyme mixture may be due to an increase in the incorporation of newly synthesized receptors and (or) changes in receptor turnover.Key words: single smooth muscle cells, muscarinic receptors, sensitivity, density, guinea pig taenia caecum.
Dopamine and hepatic oxygen supply – demand relationship
Authors: Roytblat Leonid , Gelman Simon , Bradley Edwin L. , Henderson Todd , Parks Dale
Published: April 2011

The present study examined the effect of small, vasodilating doses of dopamine on the hepatic oxygen supply – uptake ratio. Thirteen miniature pigs weighing 18–27 kg were studied under sodium pentobarbital anesthesia. Hepatic arterial and portal blood flows were measured. Oxygen content in arterial, portal, and hepatic venous blood was determined. Dopamine was infused in doses of 5, 10, and 15 μg∙kg−1∙min−1. Dopamine infusion was associated with a dose-related increase in hepatic oxygen uptake and a dose-independent increase in hepatic oxygen delivery with a maximal increase (30%) in the hepatic oxygen delivery at 10 μg∙kg−1∙min−1. The hepatic oxygen delivery–uptake ratio remained unchanged during dopamine infusion in doses of 5 and 10 μg∙kg−1∙min−1 and significantly decreased during the dose of 15 μg∙kg−1∙min−1. The study demonstrated that an increase in cardiac output and hepatic oxygen delivery during dopamine administration was not associated with an improvement in hepatic oxygen supply – demand relationship since hepatic oxygen uptake also increased.Key words: dopamine, hepatic blood flow, hepatic oxygenation.
Characterization of platelet-activating factor receptors in porcine platelets
Authors: Duronio Vincent , Reany Anne , Wong Sandra , Bigras Chantal , Salari Hassan
Published: April 2011

Despite a large number of studies describing the properties and effects of platelet-activating factor (PAF), little is known about its receptor structure. The characterization of the PAF receptor from additional cell types and species is important for the design of strategies to purify and characterize the receptor molecule. Porcine platelets were shown to bind PAF with characteristics similar to several other species, based on receptor number, affinity, and the activity of PAF antagonists. We found that the affinity for binding was higher in porcine than in rabbit platelets (Kd = 0.68 ± 0.13 nM for rabbit and 0.29 ± 0.10 nM for porcine). Porcine platelets have approximately 281 ± 158 receptors per cell compared with 689 ± 229 receptors in rabbit platelets. Rabbit platelets respond to concentrations of PAF that are approximately 105-fold lower than those required for aggregation of porcine platelets, but this difference is probably not due to the differences in receptor number alone. When binding was compared between purified membranes from these two cell types, porcine platelets had 20-fold fewer receptors per milligram of membrane protein, but this difference may have been due to an artifact of the membrane preparation procedure. Binding of PAF was severely hindered at cold temperatures. It was undetectable in whole cells on ice and greatly reduced with purified membranes. This study is the first to characterize PAF receptors in porcine platelets, which represent a potentially useful source of receptor for further biochemical characterization.Key words: platelet activating factor, receptor, porcine, platelet, membrane.
Body growth, lung and heart weight, and DNA content in newborn rats exposed to different levels of chronic hypoxia
Authors: Mortola Jacopo P. , Xu Lijing , Lauzon Anne-Marie
Published: April 2011

To evaluate the contribution of maternal factors in the somatic underdevelopment of newborns exposed to chronic hypoxia we took advantage of the observation that, in the rat, daily changes of the mother did not alter the normal postnatal growth of the litter. Body growth and heart and lung development were studied in (a) normoxic litters nursed either by normoxic mothers or by mothers exposed to 24 h of hypoxia on alternate days, and (b) litters growing in hypoxia and raised by mothers which were either hypoxic at all times or normoxic on alternate days. From the results it is concluded that neonatal growth retardation during moderate (15% O2) or severe (10% O2) hypoxic exposure can be almost entirely attributed to the effects of hypoxia on the newborn, and is not mediated by the maternal response. Mild (19% O2) or moderate levels of 1-week hypoxic exposure had little or no inhibitory effects on somatic and lung growth, while cardiac weight and DNA content increased. Severe hypoxia (10% O2) resulted in important growth retardation with hypoplasia (decreased weight and DNA content) of heart and lungs, although the negative effects on the growth of these organs were not as marked as those of the extrapulmonary and extracardiac tissues.Key words: postnatal development, lung maturation, high altitude.
Comparative responses to endothelin-2 and sarafotoxin 6b in the pulmonary vascular bed of the cat
Authors: Minkes R. K. , Nossaman B. D. , Kvamme P. , Kadowitz P. J.
Published: April 2011

Pulmonary vascular responses to endothelin-2 and sarafotoxin 6b were investigated in the feline pulmonary vascular bed under natural flow and constant flow conditions. Injections of endothelin-2 and sarafotoxin 6b in a dose of 0.3 nmol/kg iv increased pulmonary arterial and left atrial pressures and cardiac output, and caused a biphasic change in calculated pulmonary vascular resistance. Endothelin-2 caused a biphasic change in systemic arterial pressure, while sarafotoxin 6b only decreased arterial pressure. Under constant flow conditions in the intact-chest cat, injections of endothelin-2 and sarafotoxin 6b in doses of 0.1–1 nmol into the perfused lobar artery increased lobar arterial pressure in a dose-related manner but were less potent than the thromboxane A2 mimic, U46619. An ET analog with only the Cys1–Cys15 disulfide bond and an amidated carboxy terminus had no significant activity in the pulmonary vascular bed. The present data show that endothelin-2 and sarafotoxin 6b have significant vasoconstrictor activity in the pulmonary vascular bed of the cat.Key words: pulmonary circulation, endothelin-2, sarafotoxin 6b.
Factors contributing to increased muscle fatigue with β-blockers
Authors: McKelvie R. S. , Jones N. L. , Heigenhauser G. I. F.
Published: April 2011

β-Adrenoceptor blockers are widely used clinically and can be classified as nonselective (β1 and β2) or selective (β1). Impairment of exercise performance is a well-known side effect of this group of drugs. This paper reviews mechanisms that could potentially be responsible for this impairment. In addition to cardiovascular and metabolic effects, β -blockade inhibits Na+–K+ ATPase pumps controlling ion movement between muscle and plasma and thus may contribute to muscle fatigue through this mechanism. To investigate the relationship between the change in plasma [K+] and exercise performance, we studied healthy male subjects taking propranolol. Eight subjects performed maximal incremental cycle ergometer exercise tests during control (no drug), low dose (LD) (40 mg daily), and high dose (HD) (265 ± 4.3 (SE) mg daily) of propranolol. The control plasma [K+] (5.8 ± 0.12 mequiv./L) during exercise was significantly lower than either the LD (6.4 ± 0.05 mequiv./L) or HD (6.1 ± 0.16 mequiv./L) values. There was no significant difference between plasma [K+] for the LD and HD of propranolol. However, maximum oxygen uptake was reduced only while taking the HD of propranolol. Six of the subjects also performed three 30-s bouts of high intensity exercise on an isokinetic cycle ergometer while taking the LD and HD of propranolol. There was no significant difference between doses for the increase in plasma [K+] (LD, 7.8 ± 0.35 mequiv./L vs. HD, 7.6 ± 0.36 mequiv./L) during exercise. However, exercise performance was significantly reduced during HD compared with LD. These results suggest that the increases in plasma [K+] with propranolol did not play a direct significant role in the reduced performance observed during the HD.Key words: exercise, potassium, performance, lactate.
Torque potentiation and myosin light-chain phosphorylation in human muscle following a fatiguing contraction
Authors: Houston Michael E. , Grange R. W.
Published: April 2011

Indices of electrically stimulated and maximal voluntary isometric muscle torque and the phosphate content of myosin phosphorylatable light chains (P light chains) were studied during recovery following a 60-s maximal voluntary isometric contraction (MVC) in 21 human subjects. Analysis of muscle biopsy samples revealed that immediately after the 60-s MVC there were significant decreases in ATP (−15%) and phosphocreatine (−82%), and lactate concentration increased by 17-fold. All indices of muscle torque production were reduced by the 60-s MVC, but the twitch torque and torque at 10 Hz were relatively less reduced compared with the torque at 20 and 50 Hz or a 1-s MVC. Between 3 and 6 min of recovery, twitch torque and torque at 10 Hz stimulation were significantly potentiated, reaching peak values of 125 and 134%, respectively, compared with rest. Phosphate content of the fast and two slow P light chains was significantly increased over rest levels immediately after and 4 min after the 60-s MVC. These results suggest that myosin P light-chain phosphorylation could provide a mechanism to increase human muscle torque under conditions of submaximal contractile element activation following fatigue.Key words: fatigue, human, muscle, torque, myosin phosphorylation.
Biochemical adaptations to training: implications for resisting muscle fatigue
Authors: McCully Kevin K. , Clark B. J. , Kent Jane A. , Wilson John , Chance Britton
Published: April 2011

Skeletal muscle activity is invariably associated with a decline in force-generating capacity (fatigue). The build-up of metabolic by-products such as intracellular H+ and inorganic phosphate (Pi) has been shown to be one of the potential mechanisms of muscle fatigue. The use of phosphorus magnetic resonance spectroscopy is a repeatable and useful tool to study the effect of pH and Pi on force development. When maximal exercise is preceded by submaximal exercise to reduce the starting muscle pH and increase Pi; the degree of muscle fatigue correlates more strongly with [Formula: see text] than pH or R alone. However, other studies in humans have found that [Formula: see text] does not always correlate well with fatigue. The use of ramp exercise protocols allow repeatable and sensitive measurement of changes in muscle metabolism in response to endurance training. Chronic electrical stimulation in dogs and endurance training in humans results in reduced pH and Pi changes at the same exercise intensities. This means that the effect of pH and Pi in depressing force development is reduced, which could partially explain the increased fatigue resistance seen following endurance training.Key words: magnetic resonance spectroscopy (31P-MRS), muscle metabolism, exercise, inorganic phosphate, pH.
Effect of decreased pH on force and phosphocreatine in mammalian skeletal muscle
Authors: Meyer Ronald A. , Adams Gregory R. , Fisher M. Jill , Dillon P. F. , Krisanda Joseph M. , Brown Truman R. , Kushmerick Martin J.
Published: April 2011

Phosphocreatine (PCr) and intracellular pH changes were monitored by 31P-NMR spectroscopy in isolated, arterially perfused cat biceps and soleus muscles, while the pH of the CO2–bicarbonate buffered perfusate was decreased from 7.1–7.4 to 6.4–6.7 by increasing the CO2 in the equilibrating gas from 5 to up to 70%. In biceps (fast twitch) muscles, intracellular pH decreased from 7.0 to 6.6 (30% CO2, 30 °C), peak tetanic force decreased by 8%, but the rise and relaxation times of tetani were not significantly changed. In soleus muscles, intracelluar pH decreased from 7.0 to 6.6 (30% CO2, 30 °C), peak tetanic force was unchanged, but the rise and relaxation times of tetani were increased by 27 and 112%, respectively. In both muscles greater decreases in tetanic force were observed during repetitive or ischemic stimulation, which resulted in intracelluar pH similar to that produced by hypercapnia. Contrary to previous reports, there was no significant decrease in PCr level in either muscle type with decreased intracellular pH. In the soleus at 30 °C there was a significant increase in PCr level with decreased pH.Key words: cat, biceps brachii, soleus, 31P-nuclear magnetic resonance spectroscopy, fatigue.