bluuebunny/crossref_metadata_2025 huggingface dataset:
Anesthesia rapidly suppresses insulin pulse mass but enhances the orderliness of insulin secretory process
Authors: Vore Stephen J. , Aycock E. Dale , Veldhuis Johannes D. , Butler Peter C.
Published: December 2017

Induction of anesthesia is accompanied by modest hyperglycemia and a decreased plasma insulin concentration. Most insulin is secreted in discrete pulses occurring at ∼6- to 8-min intervals. We sought to test the hypothesis that anesthesia inhibits insulin release by disrupting pulsatile insulin secretion in a canine model by use of direct portal vein sampling. We report that induction of anesthesia causes an abrupt decrease in the insulin secretion rate (1.1 ± 0.2 vs. 0.7 ± 0.1 pmol · kg−1 · min−1, P < 0.05) by suppressing insulin pulse mass (630 ± 121 vs. 270 ± 31 pmol, P < 0.01). Anesthesia also elicited an ∼30% higher increase in insulin pulse frequency ( P < 0.01) and more orderly insulin concentration profiles ( P < 0.01). These effects were evoked by either sodium thiamylal or nitrous oxide and isoflurane. In conclusion, anesthesia represses insulin secretion through the mechanism of a twofold blunting of pulse mass despite an increase in orderly pulse frequency. These data thus unveil independent amplitude and frequency controls of β-cells' secretory activity in vivo.
Sulfate production depicts fed-state adaptation to protein restriction in humans
Authors: Hamadeh Mazen J. , Schiffrin Alicia , Hoffer L. John
Published: December 2017

One feature of the adaptation to dietary protein restriction is reduced urea production over the hours after consumption of a test meal of fixed composition. This adaptation is impaired in conventionally treated insulin-dependent diabetes mellitus (Hoffer LJ, Taveroff A, and Schiffrin A. Am J Physiol Endocrinol Metab 272: E59–E67, 1997). We have now tested the response to a test meal containing less protein and included as a main outcome variable the production of sulfate, a specific indicator of sulfur amino acid catabolism. Six normal men consumed a mixed test meal containing 0.25 g protein/kg and 10 kcal/kg while adapted to high (1.5 g · kg−1· day−1) and low (0.3 g · kg−1· day−1) protein intakes. They followed the identical protocol twice. Six subjects with insulin-dependent diabetes consumed the test meal while adapted to their customary high-protein diet. Adaptation to protein restriction reproducibly reduced 9-h cumulative postmeal urea N and S production by 22–29% and 49–52%, respectively (both P < 0.05). Similar results were obtained for a postmeal collection period of 6 h. The response of the diabetic subjects was normal. We conclude that reductions in postmeal urea and sulfate production after protein restriction are reproducible and are evident using a postmeal collection period as short as 6 h. Sulfate production effectively depicts fed-state adaptation to protein restriction.
Effect of protein restriction on15N transfer from dietary [15N]alanine and [15N]Spirulina platensisinto urea
Authors: Hamadeh Mazen J. , Hoffer L. John
Published: December 2017

Six normal men consumed a mixed test meal while adapted to high (1.5 g · kg−1· day−1) and low (0.3 g · kg−1· day−1) protein intakes. They completed this protocol twice: when the test meals included 3 mg/kg of [15N]alanine ([15N]Ala) and when they included 30 mg/kg of intrinsically labeled [15N] Spirulina platensis([15N]SPI). Six subjects with insulin-dependent diabetes mellitus (IDDM) receiving conventional insulin therapy consumed the test meal with added [15N]Ala while adapted to their customary high-protein diet. Protein restriction increased serum alanine, glycine, glutamine, and methionine concentrations and reduced those of leucine. Whether the previous diet was high or low in protein, there was a similar increase in serum alanine, methionine, and branched-chain amino acid concentrations after the test meal and a similar pattern of15N enrichment in serum amino acids for a given tracer. When [15N]Ala was included in the test meal,15N appeared rapidly in serum alanine and glutamine, to a minor degree in leucine and isoleucine, and not at all in other circulating amino acids. With [15N]SPI, there was a slow appearance of the label in all serum amino acids analyzed. Despite the different serum amino acid labeling, protein restriction reduced the postmeal transfer of dietary15N in [15N]Ala or [15N]SPI into [15N]urea by similar amounts (38 and 43%, respectively, not significant). The response of the subjects with IDDM was similar to that of the normal subjects. Information about adaptive reductions in dietary amino acid catabolism obtained by adding [15N]Ala to a test meal appears to be equivalent to that obtained using an intrinsically labeled protein tracer.
Brain glucose-sensing mechanisms: ubiquitous silencing by aglycemia vs. hypothalamic neuroendocrine responses
Authors: Mobbs Charles V. , Kow Lee-Ming , Yang Xue-Jun
Published: December 2017

Interest in brain glucose-sensing mechanisms is motivated by two distinct neuronal responses to changes in glucose concentrations. One mechanism is global and ubiquitous in response to profound hypoglycemia, whereas the other mechanism is largely confined to specific hypothalamic neurons that respond to changes in glucose concentrations in the physiological range. Although both mechanisms use intracellular metabolism as an indicator of extracellular glucose concentration, the two mechanisms differ in key respects. Global hyperpolarization (inhibition) in response to 0 mM glucose can be reversed by pyruvate, implying that the reduction in ATP levels acting through ATP-dependent potassium (K-ATP) channels is the key metabolic signal for the global silencing in response to 0 mM glucose. In contrast, neuroendocrine hypothalamic responses in glucoresponsive and glucose-sensitive neurons (either excitation or inhibition, respectively) to physiological changes in glucose concentration appear to depend on glucokinase; neuroendocrine responses also depend on K-ATP channels, although the role of ATP itself is less clear. Lactate can substitute for glucose to produce these neuroendocrine effects, but pyruvate cannot, implying that NADH (possibly leading to anaplerotic production of malonyl-CoA) is a key metabolic signal for effects of glucose on glucoresponsive and glucose-sensitive hypothalamic neurons.
An osmotic-sensitive taurine pool is localized in rat pancreatic islet cells containing glucagon and somatostatin
Authors: Bustamante J. , Lobo M. V. T. , Alonso F. J. , Mukala N.-T. A. , Giné E. , Solís J. M. , Tamarit-Rodriguez J. , Martín Del Río R.
Published: December 2017

Previous reports have dealt with the hypoglycemic properties of taurine and its effects on insulin secretion by adult and fetal isolated islets. We have studied the presence and cellular distribution of taurine in rat islets, the conditions to evoke its release, and its possible modulatory action on insulin secretion. We localized taurine by techniques of double immunolabeling in most glucagon-positive cells and in some somatostatin-positive cells, whereas insulin-positive cells were not labeled with the taurine antibody. Although high-glucose stimulation did not evoke any taurine release, a hyposmotic solution (17% osmolarity reduction) induced a specific phasic release of taurine and GABA (34 and 52% increase on their basal release rate). On the other hand, taurine (10 mmol/l) application slightly reduced the second phase of insulin secretion induced by glucose stimulation. In conclusion, taurine is highly concentrated in glucagon-containing cells of the islet periphery. It is not liberated by glucose stimulation but is strongly released under hyposmotic conditions. All of these data suggest that taurine plays an osmoregulatory role in α-cells.
Adrenomedullin expression in rat uterus is correlated with plasma estradiol
Authors: Cameron Vicky A. , Autelitano Dominic J. , Evans John J. , Ellmers Leigh J. , Espiner Eric A. , Nicholls M. Gary , Richards A. Mark
Published: December 2017

Levels of expression of adrenomedullin (AM) in the uterus have been reported to vary with the reproductive cycle. This study examines the relationships among uterine AM mRNA, the stage of the estrous cycle, and circulating estradiol and progesterone in cycling rats and in ovariectomized (OVX) rats without or with estrogen replacement (ER). Strong AM mRNA, AM immunoreactivity, and pro-AM NH2-terminal 20 peptide (PAMP) immunoreactivity were observed in endometrial stroma by use of in situ hybridization and immunocytochemistry. Endometrial expression was particularly intense at proestrus and estrus, with weaker expression in the myometrium. By RNase protection assay, significant differences in AM mRNA between the stages of the estrous cycle could not be established. However, levels of AM mRNA were positively correlated with plasma estradiol in cycling rats ( r = 0.56, P < 0.005) and in OVX and ER rats ( r = 0.92, P < 0.001) and were not correlated with plasma progesterone. Levels of AM mRNA were significantly reduced after OVX compared with cycling rats, and ER restored AM mRNA to levels equivalent to those seen at the peak of the cycle (proestrus). In conclusion, although AM expression in the uterus varies throughout the estrous cycle, it is more closely correlated with circulating estradiol levels than with the stage of the cycle itself.
Effect of short-term exercise training on insulin-stimulated PI 3-kinase activity in middle-aged men
Authors: Tanner Charles J. , Koves Timothy R. , Cortright Ronald L. , Pories Walter J. , Kim Young-Bum , Kahn Barbara B. , Dohm G. Lynis , Houmard Joseph A.
Published: December 2017

The purpose of this study was to determine whether the improved insulin action with short-term exercise training in middle-aged individuals is associated with enhanced phosphatidylinositol (PI) 3-kinase activity in skeletal muscle. Nine men of ages 50–70 yr were studied before and after 7 consecutive days of supervised exercise (60 min/day, 70% peak O2 consumption). Insulin sensitivity was measured with a euglycemic hyperinsulinemic glucose clamp in the sedentary condition and 15–17 h after the final exercise session. Anti-phosphotyrosine-associated PI 3-kinase activity was determined from muscle samples obtained in the fasted condition and after 60 min of insulin infusion during the clamp. With exercise, the glucose infusion rate increased ( P < 0.001) by 33%, indicating enhanced insulin action (mean ± SE, 6.6 ± 0.6 vs. 8.7 ± 0.8 mg · kg−1 · min−1). Short-term exercise training did not, however, increase insulin-stimulated (insulin stimulated/fasting) PI 3-kinase activity (1.8 ± 0.8 vs. 1.8 ± 0.7-fold stimulation with insulin pre- vs. posttraining, respectively). There was also no change in insulin-stimulated protein kinase B activity (1.3 ± 0.1 vs. 1.4 ± 0.2-fold stimulation with insulin) with training. These data suggest that insulin action is enhanced with short-term exercise training via an adaptation distal to PI 3-kinase in middle-aged, insulin-resistant individuals.
Decreased endothelium-dependent relaxation in subarachnoid hemorrhage-induced vasospasm: role of ET-1
Authors: Zuccarello M. , Romano A. , Passalacqua M. , Rapoport R. M.
Published: December 2017

The purpose of this study was to test whether endothelium-dependent relaxation is decreased during acute vasospasm following subarachnoid hemorrhage (SAH) and the mechanism underlying the decrease. Basilar artery in situ was 35% constricted 3 days following injection of autologous arterial blood into the rabbit cisterna magna compared with vessels from control rabbits. In situ suffusion with the endothelium-dependent relaxant, acetylcholine (ACh; 10 microM), relaxed resting and serotonin (5-HT)-contracted control vessels but not vasospastic and 5-HT-contracted vasospastic vessels. In contrast, the relaxant potency and efficacy of ACh was similar in control and vasospastic vessels contracted with 5-HT in vitro. In situ suffusion with the ETA-receptor antagonist, BQ-123 (1 microM), reversed the vasospasm by 51% and restored the magnitude of ACh relaxation of vasospastic and 5-HT-contracted vasospastic vessels to that of controls. ACh in situ and in vitro relaxed endothelin-1 (ET-1)-contracted control vessels to a smaller magnitude than 5-HT-contracted control vessels. These results suggest, in contrast to previous studies, that endothelium-dependent relaxation is decreased during acute vasospasm following SAH. The decreased endothelium-dependent relaxation is secondary to the underlying ET-1-mediated spasm. The inhibition of endothelium-dependent relaxation observed in situ following SAH cannot be demonstrated in vitro, presumably due to loss of the ET-1-mediated vasospasm.
Polystyrene microspheres decrease bronchial artery resistance in anesthetized sheep
Authors: Pearse D. B. , Fessler H. E. , Wagner E. M.
Published: December 2017

The use of microspheres to measure tissue blood flow requires that the microspheres themselves do not alter regional arterial tone. To determine whether microspheres affected bronchial artery resistance, we cannulated and perfused the bronchial artery in anesthetized sheep. In seven sheep, the change in bronchial artery pressure at constant flow was recorded during infusion of 5 doses (1 x 10(5), 2 x 10(5), 5 x 10(5), 1 x 10(6), and 1.5 x 10(6)) of 15-microns microspheres. Microspheres produced a dose-dependent, self-limited decrease in bronchial artery pressure (1.5 x 10(6) microspheres decreased bronchial artery pressure by 36% for 31 min). This was a decrease in bronchial artery resistance, as evidenced by a shift in the slope, but not the intercept, of a pressure-flow curve (n = 4 sheep). Left atrial injection of 1 x 10(7) microspheres decreased bronchial artery resistance by 17% in six sheep with intact bronchial arteries in which flow was measured by ultrasound probe. The adenosine-receptor antagonist 8-phenyltheophylline attenuated the fall in resistance by 79% (n = 4 sheep). Cyclooxygenase inhibition by indomethacin attenuated the response by 37% (n = 4 sheep). These results suggest that microspheres caused the release of adenosine and a vasodilator prostaglandin. Repetitive measurements of bronchial blood flow by microspheres could overestimate true bronchial blood flow if the interval between measurements is < 30 min.
Characterization of Ca(2+)-release channels in fetal and adult rat hearts
Authors: Ramesh V. , Kresch M. J. , Katz A. M. , Kim D. H.
Published: December 2017

The goal of this study was to characterize the Ca(2+)-release channel in whole homogenates of left (LV) and right ventricles (RV) of fetal (22 days in gestation) and adult Sprague-Dawley rat hearts using [3H]ryanodine binding and 45Ca2+ fluxes. Although many features of the Ca(2+)-release channels were similar in fetal and adult hearts, biochemical assays revealed quantitative differences. Similar properties include 1) Ca(2+)-sensitive cooperative ryanodine binding to Ca(2+)-release channel, measured as Ca2+ concentration for half-maximal activation (fetal LV: 0.13 +/- 0.02 microM; adults LV: 0.15 +/- 0.02 microM) and Hill coefficient (fetal LV: 2.5 +/- 0.9; adult LV: 2.7 +/- 0.5), and 2) caffeine-sensitive ryanodine binding, measured as the percent increase in ryanodine binding induced by caffeine (fetal LV: 148.8 +/- 16.9% vs. adult LV: 171.4 +/- 34.9%). The distinguishing property was the lower Ca(2+)-release channel density in the fetal heart (LV: 0.22 +/- 0.03 pmol/mg protein) compared with adult heart (LV: 0.59 +/- 0.04 pmol/mg protein; P < 0.05), as determined by [3H]ryanodine binding. The lower density of Ca(2+)-release channel is supported by the finding that there is very low ryanodine-sensitive oxalate-supported 45Ca2+ uptake in the fetal heart. The tested characteristics of the Ca(2+)-release channel were similar between LV and RV in both fetal and adult rat hearts. Ou results indicate that expression of Ca2+-release channels in sarcoplasmic reticulum increases during postnatal growth in the rat heart. This is consistent with previous physiological reports that Ca2+ available for excitation-contraction coupling in the fetal heart is derived mainly from transsarcolemmal Ca2+ influx.
Enhanced role of K+ channels in relaxations of hypercholesterolemic rabbit carotid artery to NO
Authors: Najibi S. , Cohen R. A.
Published: December 2017

Endothelium-dependent relaxations to acetylcholine remain normal in the carotid artery of hypercholesterolemic rabbits, but unlike endothelium-dependent relaxations of normal rabbits, they are inhibited by charybdotoxin, a specific blocker of Ca(2+)-dependent K+ channels. Because nitric oxide (NO) is the mediator of endothelium-dependent relaxation and can activate Ca(2+)-dependent K+ channels directly or via guanosine 3',5'-cyclic monophosphate, the present study investigated the role of Ca(2+)-dependent K+ channels in relaxations caused by NO, sodium nitroprusside, and 8-bromoguanosine 3',5'-cyclic monophosphate (8-Brc-GMP) in hypercholesterolemic rabbit carotid artery. Isometric tension was measured in rabbit carotid artery denuded of endothelium from normal and hypercholesterolemic rabbits which were fed 0.5% cholesterol for 12 wk. Under control conditions, relaxations to all agents were similar in normal and hypercholesterolemic rabbit arteries. Charybdotoxin had no significant effect on relaxations of normal arteries to NO, sodium nitroprusside, or 8-BrcGMP, but the Ca(2+)-dependent K+ channel blocker significantly inhibited the relaxations caused by each of these agents in the arteries from hypercholesterolemic rabbits. By contrast, relaxations to the calcium channel blocker nifedipine were potentiated to a similar extent by charybdotoxin in both groups. In addition, arteries from hypercholesterolemic rabbits relaxed less than normal to sodium nitroprusside when contracted with depolarizing potassium solution. These results indicate that although nitrovasodilator relaxations are normal in the hypercholesterolemic rabbit carotid artery, they are mediated differently, and to a greater extent, by Ca(2+)-dependent K+ channels. These data also suggest that K+ channel-independent mechanism(s) are impaired in hypercholesterolemia.
Determinants of respiratory sinus arrhythmia in the vagotomized rabbit
Authors: Perlini S. , Solda P. L. , Piepoli M. , Sala-Gallini G. , Calciati A. , Finardi G. , Bernardi L.
Published: December 2017

After cardiac denervation, a small-amplitude respiratory sinus arrhythmia (RSA) has been described in animals and humans. Its mechanical and chemical determinants were investigated in 19 urethan-anesthetized, vagotomized, and mechanically ventilated rabbits. We measured the influence on RSA of arterial blood gases, beta-adrenergic blockade, and phasic and steady changes in right atrial pressure (RAP) induced by changes in tidal volume (VT, 20, 40, 60 ml), respiratory frequency (RF, 10, 20, 30 cycles/min), and dextran-induced RAP increases. Phasic changes in RAP during each recording were quantified as standard deviation of the first derivative of the RAP signal (dRAP) as a measure of magnitude of variations of the rate of change due to respiration. RSA was assessed by combined autoregressive power spectral analysis of R-R interval and respiration on sequences of 256 heart-beats. Despite vagotomy, RSA was present in all recordings in all animals. During room air breathing, RSA changes were dependent on RF and VT (P < 0.025 and P < 0.001, respectively) and correlated with dRAP (P < 0.001) and arterial PO2 (P < 0.001). beta-Adrenergic blockade did not change the amplitude of this residual RSA or its dependence on ventilatory mechanics. Dextran-induced increase in mean RAP from 2.9 to 11.9 mmHg did not modify RSA or dRAP. During 100% O2 inhalation, RSA changes were no longer significantly linked to RF and VT, and also the correlation of RSA with dRAP was reduced (P < 0.05). Changing the arterial PCO2 from 28 to 79 mmHg (induced by increasing dead space at fixed ventilation) did not modify RSA.(ABSTRACT TRUNCATED AT 250 WORDS)
Coronary flow stimulates auricular-ventricular transmission in the isolated perfused guinea pig heart
Authors: Rubio R. , Ceballos G. , Suarez J.
Published: December 2017

In the heart in situ coronary flow stimulates oxygen consumption, glycolytic flux, myocardial contractility, and the release of bioactive substances. Studies have indicated that the coronary flow-enhanced contraction is similar to a hormonelike effect because the enhanced contraction results from an elevation in intracellular free calcium. In fact, if extracellular calcium is raised sufficiently, the contraction amplitude rises and remains constant and independent of coronary flow. We hypothesized that coronary flow could also stimulate other calcium-dependent cardiac functions such as auricular-ventricular (A-V) transmission. This hypothesis was tested in isolated guinea pig hearts perfused at constant flow. Our results show that increases in coronary flow (6-25 ml/min range) decrease the A-V delay solely as a result of reduced propagation time in the A-V node and not in atrial or ventricular propagation. When coronary vascular resistance was altered by dilation (nitroglycerin, bradykinin, nitroprusside, and adenosine) or by constriction (angiotensin II), this dromotropic effect of flow remained the same despite wide changes in perfusing pressure. Also, this dromotropic effect of flow was not altered by energy-altering substrates in the perfusate or by perfusion of adenosine receptor blockers. Furthermore, the effectiveness of flow as a dromotropic stimulus varied inversely with changes in calcium entry caused either by elevation or reduction of extracellular calcium. In addition, enhanced viscosity of the perfusing medium amplifies the positive dromotropic effect of flow. These results suggest that coronary flow is a stimulus that exerts a positive dromotropic effect mediated by shear stress.
Ca(2+)-dependent K+ current in arterial smooth muscle cells from aldosterone-salt hypertensive rats
Authors: Liu Y. , Jones A. W. , Sturek M.
Published: December 2017

Aorta from aldosterone-salt hypertensive rats (AHR) demonstrates an increased basal 42K efflux. We investigated the cellular mechanisms of this alteration by measuring 42K efflux from aortic segments as well as myoplasmic Ca2+ concentration ([Ca2+]m) and K+ current in aortic smooth muscle cells from AHR and normotensive control-salt rats (CSR). Both diltiazem and nisoldipine attenuated but did not normalize the increase in basal 42K efflux in AHR. The resting [Ca2+]m was elevated in cells from AHR (148 +/- 15 vs. 91 +/- 12 nM for CSR, P < 0.05). The rate of Mn2+ quenching under basal conditions was also increased in cells from AHR, and the increase was abolished by Cd2+. However, the resting membrane potential did not differ between CSR and AHR (-49 +/- 5 vs. -50 +/- 4 mV). The steady-state, whole cell K+ current was also increased in cells from AHR. This increase was abolished by charybdotoxin, tetraethylammonium, La3+, and by clamping [Ca2+]m at zero or 100 nM with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. The single-channel conductance of the large conductance Ca(2+)-activated, voltage-dependent K+ (KCa) channels was not altered in AHR. Further, 33% of cells from AHR vs. 1% from CSR showed spontaneous transient outward K+ currents, which reflect activation of KCa channels by Ca2+ released from caffeine-sensitive stores. While the acute caffeine-induced [Ca2+]m response was similar between CSR and AHR, the outward current and 42K efflux responses to caffeine were greater in AHR. After continued exposure to caffeine, the basal 42K efflux was attenuated more in AHR than in CSR. Charybdotoxin resulted in a greater depolarization in AHR cells than in CSR cells (9.8 +/- 2.2 vs. 3.5 +/- 1.6 mV, P < 0.05). These results indicate that the increases in both 42K efflux and K+ current reflect an increased activity of KCa channels that is associated with an increased Ca2+ influx and resting [Ca2+]m and altered Ca2+ handling by the sarcoplasmic reticulum in aortic smooth muscle cells from AHR.
Activation of angiotensin-converting enzyme expression in infarct zone following myocardial infarction
Authors: Passier R. C. , Smits J. F. , Verluyten M. J. , Studer R. , Drexler H. , Daemen M. J.
Published: December 2017

In the present study we quantified angiotensin-converting enzyme (ACE) mRNA and localized ACE mRNA and protein in the infarcted rat heart. Wistar rats underwent ligation of the left descending coronary artery, resulting in myocardial infarction (MI) or a sham operation. At different times (1-90 days) after surgery (n = 3 each), the heart was removed and divided into the right ventricle (RV), septum (Se) and left ventricle (LV). ACE mRNA was quantified by competitive reverse transcriptase-polymerase chain reaction (RT-PCR). At 4 and 7 days after MI, we found a 2.8-fold increase of ACE mRNA (n = 3; P < or = 0.05) in the infarcted LV compared with the LV of the sham group. No increases of ACE mRNA were found in the noninfarcted hypertrophied compartments. ACE activity increased 2.6- and 3.6-fold in the infarcted LV at 7 and 90 days after MI, respectively. In situ hybridization and immunohistochemistry showed increased ACE mRNA and protein density in the border zone of the infarcted area, predominantly in the endothelial cells lining capillaries. In the noninfarcted myocardium ACE mRNA and protein were confined to endothelial cells of the larger vessels. From these data we conclude that the intracardiac RAS is involved in the healing of the scar after MI in the rat, possibly giving rise to neovascularization. Furthermore, the data suggest that the intracardiac ACE is not necessarily associated with hypertrophy in the rat heart after MI.
Abnormalities of K+ and Ca2+ currents in ventricular myocytes from rats with chronic diabetes
Authors: Wang D. W. , Kiyosue T. , Shigematsu S. , Arita M.
Published: December 2017

Ionic mechanisms related to the prolongation of cardiac action potential in rats with chronic diabetes mellitus were studied using whole cell voltage-clamp techniques. Diabetes was induced by injection of streptozotocin (STZ; 65 mg/kg body wt) into the tail vein, and ventricular myocytes were isolated from STZ-injected rats (24-30 wk) and from age-matched normal rats. The current densities of transient outward current (Ito), a steady-state outward current, and L-type Ca2+ current (ICa) were significantly smaller in cells from diabetic animals. In addition, the kinetics of Ito of diabetic cells were modified. 1) The decay of Ito was well fitted by a sum of two exponential components in normal cells; there was only one (slow) component in the diabetic cells. 2) The steady-state inactivation curve of Ito in diabetic cells shifted by 5 mV in the negative direction. 3) Recovery from inactivation of Ito was slower in cells from diabetic animals. These alterations in Ito and the steady-state outward current can account for most of the action potential prolongation heretofore documented. The decrease of ICa may possibly be related to the depressed contraction seen in chronic diabetic mellitus.
Preconditioning accelerates contracture and ATP depletion in blood-perfused rat hearts
Authors: Kolocassides K. G. , Galinanes M. , Hearse D. J.
Published: December 2017

We investigated the effect of preconditioning on the ischemia-induced depletion of ATP in the blood-perfused rat heart. Isolated hearts (n = 5/group) were aerobically perfused with whole blood from a support rat and subjected to zero-flow global ischemia (37 degrees C) for periods up to 35 min. Frozen hearts were taken for metabolic analysis. Ischemic contracture was assessed with an isovolumic intraventricular balloon. The study groups were 1) control (C) with unprotected ischemia, 2) preconditioning (PC; 2 cycles of 3-min ischemia/3-min reperfusion), and 3) cardioplegia (CP; St. Thomas') before ischemia. Preconditioning accelerated, whereas cardioplegia delayed, ischemic contracture (time to peak contracture: PC = 8.1 +/- 0.3 and CP = 25.1 +/- 0.2 min vs. C = 15.6 +/- 0.3 min, P < 0.05). The ischemia-induced decline in ATP was delayed by cardioplegia but accelerated by preconditioning (P < 0.05). In a parallel study, preconditioning and cardioplegia protected postischemic contractile function to a similar extent. Thus, in the blood-perfused rat heart, preconditioning accelerated ischemic contracture and depletion of ATP. In contrast, cardioplegia slowed ischemic contracture and ATP depletion.
Activation delay in healed myocardial infarction: a comparison between model and experiment
Authors: Maglaveras N. , De Bakker J. M. , Van Capelle F. J. , Pappas C. , Janse M. J.
Published: December 2017

Conduction delay in healed myocardial infarction, facilitating reentry, is frequently based on an increased path length the activation has to travel in a matrix of merging and diverging bundles that survive in the infarcted area. Additional delay occurs at sites where bundles bifurcate. The purpose of this study was to investigate conduction delay at sites where bundles bifurcate. A computer model was developed to simulate spread of activation in a two-dimensional sheet of excitable elements. A structure consisting of two isolated bundles merging into a single one was modeled. Extracellular electrograms calculated in the model were comparable to electrograms obtained in a superfused infarcted papillary muscle model. A zone of crowded isochrones or local conduction delay was found at the site where an isolated bundle bifurcated. The position of the isochrones in this area depended on the way activation times were determined. Lines of activation delay were mainly perpendicular to the fiber direction. In conclusion, the results have enabled us to better understand extracellular electrograms at pivoting points and show that activation sequences at a microscopic level can best be constructed on the basis of Laplacian signals.
Scatter in input impedance spectrum may result from the elastic nonlinearity of the arterial wall
Authors: Stergiopulos N. , Meister J. J. , Westerhof N.
Published: December 2017

We have examined the role of the nonlinear elastic properties of the arterial wall on the human aortic input impedance obtained at different heart rates and different pressure and flow wave shapes. Pressure and flow were taken from a computer model that provides realistic simulations of the nonlinear distributed systemic arterial tree. Different wave shapes of ascending aorta pressure and flow and different heart rates were used to derive input impedance moduli and phase angles via Fourier analysis. The results show that the nonlinear elastic properties of the arterial wall are responsible for significant variations in the input impedance spectrum when changes in heart rate and aortic flow wave shape take place. This finding may explain the scatter often observed in experimentally determined input impedance data using different heart rates obtained by pacing.
Albumin reduces basement membrane hydraulic conductance in part due to arginyl side groups
Authors: Katz M. A. , La Marche M. L.
Published: December 2017

Albumin reduces capillary hydraulic conductance (Lp) even at low concentrations. To determine if part of this barrier protective effect might be extracellular, we studied the effects of bovine serum albumin (BSA) on Lp of self-assembled basement membrane (Matrigel). Lp with tris(hydroxymethyl)aminomethane (Tris) buffer superfusate was stable at 1.77 +/- 0.22 x 10(-5) (SE) cm.s-1.cmH2O-1 over several hours. At 0.1 g/dl BSA, experimental/control (Tris) Lp fell to 83.1 +/- 6.0% (2P < 0.025), with decreases to 72.4 +/- 3.7% at 1 g/dl (2P < 0.005), 45.3 +/- 5.1% at 2.5 g/dl (2P < 0.001), and 45.0 +/- 4.8% at 4.0 g/dl (2P < 0.001). In separate experiments, BSA arginine groups were neutralized by 1,2-cyclohexanedione (CHD), and experimental/control Lp values were measured. At 2.5 g/dl, CHD-BSA depressed Lp to 54.4 +/- 4.8%, while unmodified BSA reduced Lp to 40.8 +/- 3.5% of Tris control (2P = 0.05). Finally, soluble arginine at three- and sixfold the arginine in BSA was added to BSA superfusate. For threefold, Lp rose to 120 +/- 8% of BSA level and for sixfold to 129 +/- 9% (2P < 0.05). We conclude that some part of the albumin protective effect is very likely due to consequences on extracellular matrix and that at least 18-22% of this effect is related to arginine groups on albumin when computed from Lp, and up to 34% when viscosity is taken into account. Membrane-saturable arginine-binding sites can be unbound with arginine, thus nullifying part of the barrier protective effect of BSA.
Role of K+ATP channels and EDRF in reactive hyperemia in the hindquarters vascular bed of cats
Authors: Minkes R. K. , Santiago J. A. , McMahon T. J. , Kadowitz P. J.
Published: December 2017

The mechanism underlying reactive hyperemia was investigated in the feline hindquarters vascular bed under natural- and constant-flow conditions. A 30-s occlusion of the distal aorta produced a marked hyperemic increase in distal aortic blood flow that was attenuated by the ATP-sensitive K+ (K+ATP) channel blocking agent, glibenclamide. When blood flow to the hindquarters vascular bed was held constant with a pump, interruption of blood flow for 5- to 90-s periods produced reactive vasodilator responses that increased in magnitude and duration as the period of ischemia increased. The magnitude and duration of the reactive vasodilator responses were reduced by K+ATP channel antagonists and an inhibitor of nitric oxide synthase, whereas indomethacin had no significant effect. In the pulmonary vascular bed, under constant-flow, elevated tone conditions, a 30-s period of ischemia produced a small reactive vasodilator response and a larger secondary vasoconstrictor response. The present data suggest that reactive hyperemia in the hindquarters vascular bed is mediated by the opening of K+ATP channels and nitric oxide release and that the reactive hyperemic response is not pronounced in the pulmonary circulation.
Autonomic and ventilatory components of heart rate and blood pressure variability in freely behaving rats
Authors: Perlini S. , Giangregorio F. , Coco M. , Radaelli A. , Solda P. L. , Bernardi L. , Ferrari A. U.
Published: December 2017

The relative role of parasympathetic, sympathetic, and ventilatory influences in the genesis of blood pressure and R-R interval variability is controversial. In 13 freely behaving WKY rats instrumented with venous and arterial catheters and chest electrodes, mean arterial pressure (MAP, mmHg), R-R interval (ms), and respiratory fluctuations were monitored for 90 min in the control condition and after intravenous atropine (0.75 mg/kg) and/or propranolol (1 mg/kg). Spectral power (pw) in the 0.25- to 0.75-Hz (midfrequency, MF) and the 0.75- to 3.0-Hz (high-frequency, HF, respiratory-synchronous) bands was computed in sequences of 400 heartbeats by use of a combined autoregressive analysis. Atropine reduced but did not abolish HF R-R interval pw (from 1.73 +/- 0.50 to 0.39 +/- 0.27 ms2, P < 0.01) and halved HF MAP pw (from 0.41 +/- 0.30 to 0.21 +/- 0.12 mmHg2, P < 0.05), whereas propranolol did not affect HF pw of the R-R interval or MAP. Propranolol also failed to significantly modify MF R-R interval pw (from 0.48 +/- 0.44 to 0.40 +/- 0.34 ms2, P = NS) or MF MAP pw (from 0.54 +/- 0.39 to 0.42 +/- 0.20 mmHg2, P = NS), whereas atropine virtually abolished MF R-R interval pw (from 0.48 +/- 0.44 to 0.01 +/- 0.01 ms2, P < 0.01) and also significantly reduced MF MAP pw (from 0.54 +/- 0.39 to 0.33 +/- 0.24 mmHg2, P < 0.01). The effects of combined blockade were similar to those of atropine alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of acadesine treatment on postischemic damage to small intestine
Authors: Schoenberg M. H. , Poch B. , Moch D. , Marzinzig M. , Marzinzig E. , Mattfeldt T. , Gruber H. , Beger H. G.
Published: December 2017

Hemorrhagic mucosal lesions are produced during intestinal ischemia and after reperfusion due at least in part to the accumulation and activation of polymorphonuclear leukocytes in the tissue. It has been shown in vitro that adenosine is instrumental in attenuating this pathophysiological process. Acadesine [5-amino-4-imidazolecarboxamide (AICA) riboside], a purine nucleoside analogue, increases the availability of adenosine in the tissue. The aim of the study was therefore to assess the influence of acadesine treatment on neutrophil accumulation, purine metabolism, and mucosal damage after intestinal ischemia and reperfusion. Intestinal ischemia was induced in cats by partial occlusion of the superior mesenteric artery for 2 h. Samples of the small intestine were exercised before and at the end of the hypotensive period as well as 10 and 60 min after reperfusion. Conjugated dienes, myeloperoxidase, and reduced and oxidized glutathione, as well as the purine metabolites, were determined in the tissue samples. The tissue was also examined histologically. Six cats received saline, and six cats were treated initially before ischemia with acadesine (2.5 mg/kg body wt i.v.) over 5 min as a bolus. Thereafter, acadesine (0.5 mg.kg-1.min- i.v.) was given continuously during ischemia and 30 min after reperfusion. Acadesine treatment significantly attenuated the mucosal lesions seen during reperfusion. This improvement was due at least in part to the inhibition of neutrophil accumulation, as judged by low myeloperoxidase levels. The prevention of neutrophil activation resulted most likely from increased adenosine concentrations in the intestinal tissue in the early reperfusion period.(ABSTRACT TRUNCATED AT 250 WORDS)
Pulmonary vascular extraction and distribution of antipyrine with alveolar flooding
Authors: Cua W. O. , Bower V. , Tice C. , Chinard F. P.
Published: December 2017

Transport characteristics of antipyrine (AP), 22Na+, and tritiated water (THO) were assessed in dog lungs by multiple indicator-dilution experiments in vivo with anesthesia and in isolated perfused preparations before and after alveolar flooding. In controls, outflow patterns of AP and THO were nearly identical. In flooding, AP and THO patterns separated. THO upslopes decreased and mean (t) and modal (tmax) transit times increased as flooding increased; AP initial upslopes remained relatively unchanged but t increased, whereas tmax decreased. Patterns of 22Na+ were unchanged. The results indicate 22Na+ limitation at the endothelium, AP limitation only at the epithelium, and no THO limitation. A mathematical model is based on axial and orthogonal distribution of AP and THO. With alveolar flooding, diffusional distance may be a limiting factor in this distribution.
Myocardial electrophysiological effects of vasoactive intestinal peptide in dogs
Authors: Kralios Alexandros C. , Anderson Fred L. , Kralios Fany A.
Published: December 2017

Pages H1559–H1565: Alexandros C. Kralios, Fred L. Anderson, and Fany A. Kralios. “Myocardial electrophysiological effects of vasoactive intestinal peptide in dogs.” On p. H1562, the columns of Fig. 4 were identified in reverse in the legend. The correct sentence should read as follows. Columns represent means ± SD of data from 32 sites in each experiment with epicardial (filled bars) (n = 16) and endocardial (hatched bars) (n = 12) mapping.
Reactive oxidants mediate TNF-alpha-induced leukocyte adhesion to rat mesenteric venular endothelium
Authors: Morita Y. , Clemens M. G. , Miller L. S. , Rangan U. , Kondo S. , Miyasaka M. , Yoshikawa T. , Bulkley G. B.
Published: December 2017

We investigated the role of reactive oxygen metabolites (ROMs) as potential mediators of tumor necrosis factor-alpha (TNF-alpha)-stimulated neutrophil adhesion to rat mesenteric venules in vivo, using intravital microscopy and fixed whole mount preparations of mesentery. Intraperitoneal injection of TNF-alpha significantly increased leukocyte rolling, adhesion, and emigration in a dose- and time-dependent manner. Leukocyte adhesion and emigration, but not rolling, were significantly attenuated by prior intravenous administration of monoclonal anti-intercellular adhesion molecule-1 (ICAM-1). Rolling leukocyte flux was significantly attenuated by intravenous preadministration of superoxide dismutase (SOD), catalase, or both. Only catalase or SOD plus catalase significantly inhibited leukocyte adhesion. Catalase alone inhibited emigration. Moreover, postadhesive treatment with catalase but not SOD, 4 h after TNF-alpha administration reduced the flux of rolling (but not adherent) leukocytes that had previously increased in response to TNF-alpha. Intragastric allopurinol (50 mg/kg at 3 and 18 h before TNF-alpha administration) or 3 wk of a tungsten-enriched diet substantially inhibited xanthine oxidase activity but had no significant effects on the above parameters of neutrophil dynamics. In parallel experiments using fixed whole mount preparations of the mesoappendix stained specifically for neutrophil esterase, neutrophil adhesion 2 h after TNF-alpha administration was also inhibited by continuous intravenous administration of catalase but not by SOD, intragastric allopurinol, or tungsten diet. These findings suggest that ROMs, apparently not from xanthine oxidase, are important mediators of TNF-alpha-induced upregulation of neutrophil adhesion in rat mesenteric venules.
Contraction and endothelium-dependent relaxation in mesenteric microvessels from pregnant rats
Authors: Pascoal I. F. , Lindheimer M. D. , Nalbantian-Brandt C. , Umans J. G.
Published: December 2017

We assessed KCl- and phenylephrine (PE)-induced vasoconstriction as well as acetylcholine (ACh)-induced endothelium-dependent vasodilation in small, isometrically mounted mesenteric arteries from virgin and gravid rats, studied in the absence and presence of NG-nitro-L-arginine (L-NNA). Neither maximal vasoconstriction nor PE potency differed significantly between vessels from virgin and pregnant rats, either in the absence or presence of L-NNA. L-NNA resulted in similar twofold leftward shifts in the PE dose-response curves for both groups. ACh-induced relaxation was potentiated in vessels from gravid rats (half-maximum effective concentration = 0.25 vs. 0.04 microM, virgin and gravid rats, respectively). After L-NNA, maximal relaxation was inhibited significantly more in vessels from gravid rats (62 vs. 31%). Likewise, maximal slope of ACh dose-response curves and ACh potency were decreased in this group so that values no longer differed from those in virgins. We conclude that pregnancy does not alter basal nitric oxide (NO) synthesis in these isolated microvessels, but it does enhance ACh-induced NO release, while apparently inhibiting the action of a NO-independent, endothelium-derived vasodilator.
Assessment and modeling of the physical components of human corporovenous function
Authors: Venegas J. G. , Sullivan M. P. , Yalla S. V. , Vickers M. A.
Published: December 2017

To understand and quantify specific causes of venoocclusive dysfunction, an analog model of penile hemodynamics, including a mechanism of flow limitation by subtunical veins, was developed and a detailed analytic study was conducted in patients with erectile dysfunction. Computer simulations for steady-state and transient intracavernosal conditions were carried out to study graded changes in cavernosal smooth muscle tone, subtunical venular resistance, and cavernosal and tunical compliances. The model predicted a steady-state cavernosal pressure (Pca)-infusion flow relationship with two phases: an initial phase characterized by a gradual slope up to a critical flow and a second phase characterized by a much steeper slope after limitation of subtunical venular flow. Model predictions were compared with clinical data obtained during incremental saline cavernosometry (SaC) and pharmacocavernosometry (PhC) in 13 patients with erectile dysfunction with use of a computer-controlled infusion system that automatically changed from constant-flow to constant-pressure feedback control when Pca reached the threshold of 80 mmHg. Steady-state pressure-flow and pressure-circumference relationships of the penis were analyzed and interpreted in terms of specific components of the electrical analog model. These clinical studies demonstrated that patients with a functional venoocclusive mechanism (i.e., those able to achieve 100 mmHg Pca with infusion flow rates < 60 ml/min during PhC) had a steeper initial slope of the pressure-flow relationship during SaC and a greater increase in penile circumference and Pca after intracavernosal injection of papaverine-phentolamine than those with an impaired venoocclusive mechanism. From the electrical analog model, initial steepness of the pressure-flow relationship (slope) during SaC mainly represented subtunical venular resistance, whereas maintenance of flow during PhC depended on overall function of the different components, i.e., subtunical venular resistance, cavernosal and subtunical compliances, and full relaxation of cavernosal smooth muscle. We conclude that the proposed analog model can be used to interpret and characterize clinical penile hemodynamic data and may provide guidelines for more successful management of patients with erectile dysfunction.
NMDA receptor blockade in cat dorsal horn blunts reflex pressor response to muscle contraction and stretch
Authors: Hand G. A. , Meintjes A. F. , Keister A. W. , Ally A. , Wilson L. B.
Published: December 2017

The role of N-methyl-D-aspartate (NMDA) receptors in the reflex pressor response to static muscle contraction and passive stretch was examined by microdialyzing the NMDA receptor antagonist DL-2-amino-5-phosphonovalerate (AP-5) into the L7 or L6 and S1 levels of the dorsal horn of anesthetized cats. Contraction, elicited by electrical stimulation of the cut L7 and S1 ventral roots, increased mean arterial pressure (MAP) and heart rate (HR). Passive stretch at tensions similar to those generated by contraction also increased these variables. These cardiovascular changes were unaffected by dialyzing AP-5 (10 mM) into the dorsal horn at L7. Increasing the syringe concentration of AP-5 to 100 mM attenuated the pressor and HR responses from 62 +/- 8 to 31 +/- 6 mmHg and 18 +/- 4 to 12 +/- 4 beats/min, respectively. AP-5 blunted the increase in MAP (59 +/- 10 vs. 41 +/- 10 mmHg) evoked by muscle stretch. Simultaneously microdialyzing AP-5 (10 or 100 mM) into the dorsal horn at the L6 and S1 spinal levels also blunted the MAP and HR responses to contraction and stretch. These results suggest that NMDA receptors play a role in mediating the MAP and HR responses to static muscle contraction at the spinal level of the central nervous system. Furthermore, these data demonstrate that collaterals from muscle afferents partially mediate the reflex cardiovascular responses evoked by muscle contraction and stretch.
Myocardial relaxation in regionally stunned left ventricle
Authors: Leite-Moreira A. F. , Gillebert T. C.
Published: December 2017

Load regulation of pressure fall was analyzed in regionally stunned left ventricles (LV) of anesthetized dogs. Stunning delayed and slowed pressure fall. When partial aortic occlusions elevated systolic pressure by 12.5 +/- 0.4 mmHg, the rate of pressure fall remained unchanged at baseline but slowed after stunning. This different response after stunning could be attributed entirely to decreased contractility and decreased development of peak isovolumetric pressure. Total aortic occlusions were then performed at various timings during ejection. With early occlusions and isovolumetric heartbeats, systolic pressure was lower after stunning, but pressure fall slowed to the same extent. With midocclusions the stunned LV developed relatively more systolic pressure, and pressure fall slowed more. This suggested a delayed transition from contraction to relaxation. With late occlusions pressure fall did not slow as with earlier occlusions, but initial pressure fall accelerated both at baseline and after stunning. The data suggested that load dependence was preserved with stunning and that, even if myocardial inactivation might be delayed, this delay did not contribute to the observed slowing of pressure fall.