bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of calcium in secretory and metabolic effects of substrates in the gastric mucosa
Authors: Chacin J. , Cardenas P. , Lobo P. , Subero O.
Published: December 2017

The role of extracellular Ca2+ in the effects and oxidation of metabolic substrates was investigated in the isolated toad gastric mucosa. In the presence of lipoate, the stimulating effect of 10 mM glucose on spontaneous acid secretion was significantly reduced by 76% in Ca2+-free solutions. The inhibition was overcome by addition of 5 mM Ca2+. The increment in respiration induced by glucose was also blocked in the absence of external Ca2+. The effect of 10 mM pyruvate on acid secretion was inhibited by 37% in Ca2+-free solutions. The secretory responses induced by 10 mM butyrate and 10 mM octanoate were not significantly affected by Ca2+-free solutions. The rates of oxidation of [14C]-glucose and [14C]pyruvate were significantly reduced by incubating in Ca2+-free solutions containing 0.1 mM of EGTA. When O2 uptake and glucose oxidation were measured simultaneously in the same preparation, the increment in the rate of glucose oxidation accounted for by 43% of the total increase of respiration observed in the presence of Ca2+. The rates of oxidation of [14C]butyrate and [14C]acetate were not significantly affected by Ca2+-free solutions. The rate of oxidation of [14C]glucose exhibited saturation kinetics versus concentration and was lower in the absence of external Ca2+ under a range of glucose concentrations. Similar results were observed when the experiments were performed in the absence of external potassium to block the acid secretory process. Ca2+ stimulated the rate of glucose oxidation in a dose-dependent manner. The kinetics of 45Ca2+ efflux and 45Ca2+ uptake were not significantly affected by glucose and butyrate.(ABSTRACT TRUNCATED AT 250 WORDS)
Muscarinic receptor size on smooth muscle cells and membranes
Authors: Collins S. M. , Jung C. Y. , Grover A. K.
Published: December 2017

The loss of [3H]quinuclidinyl benzilate ([3H]QNB) binding following high-energy radiation was used to compare the muscarinic receptor size on single smooth muscle cells isolated by collagenase digestion from the canine stomach and on plasma membranes derived from intact gastric smooth muscle without exposure to exogenous proteolysis. Radiation inactivation of galactose oxidase (68 kdaltons), yeast alcohol dehydrogenase (160 kdaltons), and pyruvate kinase (224 kdaltons) activities were used as molecular-weight standards. Radiation inactivation of [3H]QNB binding to rat brain membranes, which gave a target size of 86 kdaltons, served as an additional control. In isolated smooth muscle cells, the calculated size of the muscarinic receptor was 80 +/- 8 kdaltons. In contrast, in a smooth muscle enriched plasma membrane preparation, muscarinic receptor size was significantly smaller at 45 +/- 3 kdaltons. Larger molecular sizes were obtained either in the presence of protease inhibitors (62 +/- 4 kdaltons) or by using a crude membrane preparation of gastric smooth muscle 86 +/- 7 kdaltons).
Mechanism of induction of mucosal ornithine decarboxylase by food
Authors: Tabata K. , Johnson L. R.
Published: December 2017

Refeeding fasted rats dramatically increases ornithine decarboxylase (ODC) activity in the mucosa of the small intestine and colon. The agents responsible for that activation and pathways leading to activation, however, have not been identified. The current work examines whether stimulation of ODC activity is mediated humorally or directly and whether dietary amines might be in part responsible for activation. Male Sprague-Dawley rats were used 1 wk after they were surgically prepared with Thiry-Vella jejunal loops. Two hours after refeeding rats fasted for 48 h, ODC activity increased 40-fold in mucosa from the intact jejunum and 4-fold in the mucosa of the bypassed segments. The injection of intestinal contents (obtained from additional fed rats) into the bypassed loop caused a 10-fold increase in ODC activity in the loop measured 2 h later. Injection of gut contents, lyophilized to remove dietary amines, produced no change in enzyme activity. The addition of 400 mol dimethylamine to lyophilized gut contents restored enzyme activation to 80% of the previous level. These data allow the following conclusions: following a meal mucosal ODC is activated by both humoral and direct mechanisms, direct stimulation by dietary constituents appears to be the predominant mechanism involved, and dietary amines may be one of the agents involved in directly increasing enzyme activity.
Structural features of various proglumide-related cholecystokinin receptor antagonists
Authors: Jensen R. T. , Zhou Z. C. , Murphy R. B. , Jones S. W. , Setnikar I. , Rovati L. A. , Gardner J. D.
Published: December 2017

Thirteen proglumide derivatives that varied in the length of the di-n-alkyl group and in the substitutions on the benzoyl moiety were tested for their ability to interact with guinea pig pancreatic cholecystokinin (CCK) receptors. Each derivative was more potent than proglumide. There was a close correlation between their abilities to inhibit CCK-stimulated amylase release and to inhibit binding of 125I-CCK. For the di-n-alkyl derivatives the relative potency was n-pentyl greater than n-hexyl greater than n-butyl greater than n-propyl. For the benzoyl moiety, adding two electron-withdrawing groups increased potency more than adding a single electron-withdrawing group or adding electron-donating groups. The 3,4-dichloro-di-n-pentyl derivative of proglumide was 1,300 times more potent than proglumide, and its action was specific, competitive, and it functioned as a CCK receptor antagonist in rat, mouse, and guinea pig pancreas. For all proglumide derivatives there was a good correlation (r = 0.84, P less than 0.001) between their abilities to inhibit CCK-stimulated amylase release and that previously reported for their abilities to inhibit CCK-induced gallbladder contraction. However, certain proglumide derivatives had a much higher affinity for the pancreatic CCK receptor than for the CCK receptor mediating gallbladder contraction. For other proglumide derivatives the pattern was reversed. These results demonstrate that both the di-n-alkyl group and the substitution on the benzoyl moiety of proglumide are equally important determinants of affinity and that derivatives such as the di-n-pentyl 3,4-dichloro analogue can be produced that are 1,300 times more potent than proglumide.(ABSTRACT TRUNCATED AT 250 WORDS)
Differing transport maxima values for taurine-conjugated bile salts in rats and hamsters
Authors: Kitani K. , Kanai S. , Ohta M. , Sato Y.
Published: December 2017

It was recently suggested that the apparent biliary transport maximum (Tm, secretory maximum) for bile salts is primarily determined by their degree of cytotoxicity (the cytotoxicity hypothesis), based on experiments on male rats [Hardison, W. G., D. E. Hatoff, K. Miyai, and R. G. Weiner. Am. J. Physiol. 241 (Gastrointest. Liver Physiol. 4): G337-G343, 1981]. To confirm this hypothesis, we determined the Tm of three different bile salts, taurocholate (TC), taurochenodeoxycholate (TCDC), and tauroursodeoxycholate (TUDC) in female rats and hamsters. The order of Tm values in female rats was the same as that reported for male rats (TUDC greater than TC greater than TCDC), whereas in female hamsters it was TC greater than TCDC greater than TUDC. On the other hand, in hamsters, the order of cytotoxicity, evaluated in vivo by the biliary excretion of hepatocyte enzymes such as lactate dehydrogenase and alkaline-phosphatase and an increase in plasma lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase levels under a fixed rate infusion (0.6 and 1.2 mumol X min-1 X 100 g body wt-1) of bile salts, was inverse to the order of Tm values (TCDC greater than TC greater than TUDC) in rats, but in hamsters, too, TCDC was most cytotoxic. The order of Tm value in hamsters thus does not correspond to the order of cytotoxicity of these bile salts, suggesting that the cytotoxicity of bile salts may not be the sole determinant of bile salt Tm.
Effects of Na+ replacement and amiloride on ursodeoxycholic acid-stimulated choleresis and biliary bicarbonate secretion
Authors: Lake J. R. , Van Dyke R. W. , Scharschmidt B. F.
Published: December 2017

In these studies, we have tested the hypothesis that bile acid-dependent bile formation is attributable, in part, to the stimulation of active bicarbonate secretion and have further explored the cellular mechanism(s) possibly involved in this process using the isolated perfused rat liver. Under control conditions, ursodeoxycholic acid (UDCA) infusion (3 mumol/min X 20 min) produced a 3.7-fold increase in bile flow and a 7.4-fold increase in HCO3- output. Amiloride (an inhibitor of Na+-H+ exchange) decreased UDCA-stimulated bile flow by 20.6% and decreased biliary HCO3- output by 24.9% but increased biliary UDCA output by 42.9%. Thus amiloride decreased UDCA choleretic efficiency (microliter UDCA-stimulated bile/mumol UDCA output) by 45% and UDCA-stimulated increase in HCO3- output per unit UDCA secreted by 48%. Substitution of Li+ for Na+ in perfusate virtually abolished (greater than 95% decrease) both the UDCA choleresis and increase in biliary HCO3- output but modestly decreased (39.6%) biliary bile acid output. Li+ substitution thus decreased UDCA choleretic efficiency by 98% and the UDCA-stimulated increase in HCO3- output by 96%. Amiloride had no effect and Li+ substitution produced a modest decrease in basal bile flow (26.0%) and HCO-3 output (33.5%). Neither amiloride nor Li+ substitution significantly affected UDCA uptake by cultured hepatocytes or by perfused liver. Amiloride (1 mM) also decreased taurocholate (TC)-stimulated choleresis by 48.5%, biliary TC output by 7.2%, and the choleretic efficiency of TC by 45%.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypercholeresis induced by norchenodeoxycholate in biliary fistula rodent
Authors: Palmer K. R. , Gurantz D. , Hofmann A. F. , Clayton L. M. , Hagey L. R. , Cecchetti S.
Published: December 2017

The biliary recovery and effect on bile flow and biliary bicarbonate secretion of infused norchenodeoxycholate (nor-CDC), the synthetically prepared C23 homologue of chenodeoxycholate (CDC), were defined in the anesthetized biliary fistula hamster, rat, and guinea pig and compared with those of its taurine conjugate as well as those of the natural C24 bile acid, CDC. In the hamster and rat, nor-CDC was recovered slowly in bile in contrast to its taurine conjugate or CDC. Hepatic biotransformation of nor-CDC was complex. Little amidation with glycine or taurine occurred and the compound was recovered in bile in unchanged form, in the form of hydroxylated derivatives as well as glucuronates and sulfates, the proportion varying in the different species. In contrast, CDC was efficiently amidated with glycine or taurine. The taurine conjugate of nor-CDC was secreted largely unchanged. Nor-CDC infusion caused a striking hypercholeresis in the hamster (108 microliters bile/mumol bile acid in bile) and in the rat (220 microliters/mumol); these values for bile acid-dependent flow far exceed those reported for any other natural bile acid to date in these species. The induced hypercholeresis was of canalicular origin and was accompanied by an enrichment in bicarbonate ion concentration as well as increased bicarbonate output. The taurine conjugate of nor-CDC did not display hypercholeretic properties in the hamster. In the guinea pig, whose native bile is bicarbonate-rich relative to other species, nor-CDC was only mildly hypercholeretic relative to CDC and caused no change in bicarbonate concentration. Thus shortening the side chain of a natural dihydroxy bile acid by a single carbon atom formed a compound that underwent a different hepatic biotransformation than that of most natural bile acids and induced a bicarbonate-rich canalicular choleresis far greater than that which can be explained by current theories of bile formation.
Mechanisms of enhanced canine enteric absorption with intestinal pacing
Authors: Bjorck S. , Kelly K. A. , Phillips S. F.
Published: December 2017

Electrical pacing enhances absorption from the canine small bowel, but the mechanism of this effect is unknown. To explore the mechanism, conscious dogs with two Vella loops, a proximal jejunal and a distal ileal, each 50 cm long, were studied. Pacing the jejunal loop with 15–18 pulses/min entrained the pacesetter potentials of the jejunal loop and increased water, sodium, and glucose absorption from the jejunal loop. Jejunal pacing also increased water absorption from the unpaced, ileal loop. Conversely, ileal pacing did not entrain the ileal loop or enhance absorption from the ileal loop. However, it did enhance water absorption in the unpaced jejunal loop. After alpha-blockade with phentolamine or celiac and superior mesenteric ganglionectomy, jejunal pacing did not increase jejunal or ileal absorption. In contrast, after beta-blockade with propranolol, pacing still enhanced jejunal absorption in three out of four dogs. Vagotomy alone enhanced jejunal but not ileal absorption, but the enhancement was not further increased by pacing. In conclusion, electrical pacing of the small bowel elicited a local and distant increase in net water absorption; the effect was mediated in part by an alpha-adrenergic mechanism.
Characteristics of transient lower esophageal sphincter relaxation in humans
Authors: Mittal R. K. , McCallum R. W.
Published: December 2017

Transient lower esophageal sphincter relaxations (TLESR) were studied in 10 normal healthy subjects. Electrical activity of mylohyoid muscle measured by an electromyogram (MEMG), pressures from pharynx, three esophageal sites, lower esophageal sphincter, and stomach were simultaneously recorded for 1 h, while fasting and 3 h after an 850 kcal meal. Reflux of acid into esophagus and/or occurrence of belching accompanying a TLESR was also monitored. TLESRs occurred with an equal frequency in fasting and postprandial state (6.2 vs. 6.4 h). However, frequency of an acid reflux during a TLESR was much greater postprandially than after fasting (44.8 vs. 9.6%). Belching coincided with 8% of TLESRs. A small MEMG complex and a small pharyngeal complex were present at onset of TLESR in 41.6 and 26.9% of instances, respectively. TLESRs were then categorized as either postswallow, if it occurred within 10 s of a preceding swallow-induced LES relaxation, or isolated, if its onset to previous swallow was greater than 10 s. Esophageal contractions were noticed at onset of 84% of isolated TLESRs. When present at two distal sites, this contraction was always of a simultaneous nature. Esophageal contractions at onset of postswallow TLESR were less frequent (33.3%) but when present were usually observed at the proximal esophageal site. At completion of a TLESR, the LES never recovered without an associated esophageal contraction, the latter was either swallow mediated or a spontaneous simultaneous esophageal contraction. Our data indicate that 1) MEMG and pharyngeal motor events may accompany TLESRs; and 2) esophageal contraction frequently heralds the onset, and it always occurs at completion of a TLESR.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of bethanechol and the octapeptide of cholecystokinin on colonic smooth muscle in the cat
Authors: Snape W. J. , Tan S. T. , Kao H. W.
Published: December 2017

The aim of this study is to compare the action of the cholinergic agonist, bethanechol, with the action of the octapeptide of cholecystokinin (CCK-OP) on feline circular colonic smooth muscle membrane potential and isometric tension, using the double sucrose gap. Depolarization of the membrane greater than 10 mV by K+ or bethanechol increased tension and spontaneous spike activity. CCK-OP (10(-9) M) depolarized the membrane (6.1 +/- 1.3 mV) without an increase in tension or spike activity. Depolarization of the membrane by increasing [K+]o was associated with a decrease in the membrane resistance. The slow-wave duration (2.3 +/- 0.2 s) was unchanged by administration of K+ or bethanechol but was prolonged after increasing concentrations of CCK-OP. The maximum effect occurred at a 10(-10) M concentration of CCK-OP (4.5 +/- 0.4 s, P less than 0.01). At higher concentrations of CCK-OP (greater than 10(-10) M), the slow-wave pattern became disorganized. Addition of increasing concentrations of [K+]o or bethanechol, but not CCK-OP, stimulated a concentration-dependent increase in the maximum rate of rise (dV/dtmax) of an evoked spike potential. These studies suggest 1) bethanechol decreased the membrane potential without altering the slow-wave activity, whereas CCK-OP has a minimal effect on the membrane potential but distorted the slow-wave shape; 2) an increased amplitude of the spike and dV/dtmax of the spike were associated with an increase in phasic contractions after bethanechol or increased [K+]o; 3) the lack of an increase in the spike amplitude and the dV/dtmax to CCK-OP was associated with no increase in phasic contraction.
Alterations in protein transport events in rat liver after estrogen treatment
Authors: Goldsmith M. A. , Jones A. L. , Underdown B. J. , Schiff J. M.
Published: December 2017

The effects of 17 alpha-ethynylestradiol (EE) treatment on the hepatic processing of rat polymeric immunoglobulin A (IgA) and human asialoorosomucoid (ASOr) were studied. After 5 days of treatment with EE (5 mg/kg) or solvent alone, male rats were anesthetized and injected with tracer doses of the test proteins. Bile flow rates had been reduced by greater than 60% in the EE-treated animals. A previously reported radiolabeling strategy was used to monitor both the transport of intact protein to bile and the degradation of protein in lysosomes. Transport of intact IgA to bile was reduced by 43%, with transport peaking 27 min later in EE-treated animals compared with controls. There was a corresponding impairment of uptake of labeled IgA from blood. EE induced no kinetic change in the uptake or processing of ASOr. However, there was an increase in the proportion of ASOr reaching bile intact from 3% to 15-23% of the injected dose. The data indicate that EE disables the transport pathway for IgA and causes a partial change in the routing of ASOr after endocytosis in favor of direct transport to the bile canaliculus. These findings may have implications for the importance of membrane composition in protein transport events.
Nitric oxide: mediator of nonadrenergic noncholinergic responses of opossum esophageal muscle
Authors: Murray J. , Du C. , Ledlow A. , Bates J. N. , Conklin J. L.
Published: December 2017

Nonadrenergic noncholinergic (NANC) nerves of the opossum esophagus mediate relaxation of circular muscle from the lower esophageal sphincter (LES) and the off contraction of circular esophageal muscle. The latencies between the end of the stimulus and the off contraction describe a gradient so that the latency is longest in muscle from the caudad esophagus. NG-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide (NO) synthase, and NO were used to test the hypothesis whether NO is a mediator of these nerve-induced responses. Both electrical field stimulation (EFS) of intrinsic esophageal nerves and exogenous NO relaxed LES muscle. Only EFS-induced relaxation was inhibited by L-NNA [half-maximal response (EC50) = 60.0 +/- 20.0 microM]. L-Arginine, the substrate for NO synthase, reversed the inhibitory effect of L-NNA. Exogenous NO did not contact circular esophageal muscle. Both the amplitude (EC50 = 14.7 +/- 4.0 microM) and the latency of the off contraction (EC50 = 41.1 +/- 5.6 microM) were diminished by L-NNA. L-Arginine prevented the action of L-NNA. NG-nitro-L-arginine also attenuated the gradient in the latency of the off response by shortening latencies in muscle from the caudad esophagus. It had no effect on cholinergic nerve-induced contraction of longitudinal esophageal muscle. These data support the hypothesis that NO or an NO-containing compound may be a mediator of NANC nerve-induced responses of the esophagus and LES.
Inhibition of peptidases potentiates enkephalin-stimulated contraction of gastric muscle cells
Authors: Menozzi D. , Gu Z. F. , Maton P. N. , Bunnett N. W.
Published: December 2017

Cell surface peptidases degrade enkephalins and thereby restrict the number of molecules available to activate receptors. The effects of peptidase inhibitors on degradation of enkephalins and on enkephalin-stimulated contraction of gastric smooth muscle cells were examined. Muscle cells dispersed from the guinea pig stomach degraded [Tyr1-3H] [Leu5]enkephalin (41.6 +/- 9.0% degradation at 60 min incubation, mean +/- SD, n = 4 animals). Amastatin (10 microM, an aminopeptidase inhibitor) inhibited degradation by 72.1 +/- 1.5% The residual peptidase activity was inhibited by phosphoramidon (1 microM, an endopeptidase EC 3.4.24.11 inhibitor) by 58.0 +/- 11.0%. [Tyr1-125I] [Met5]enkephalin was similarly degraded. Phosphoramidon (1 microM) inhibited the degradation of the aminopeptidase-resistant peptide [Tyr1-3H] [D-Ala2]-[Leu5]enkephalin by greater than 95%. [Met5]enkephalin, incubated with cells for 30 s, stimulated contraction [50% maximal contraction (EC50) 120 +/- 50 nM, n = 6]. Pretreatment of cells with phosphoramidon alone, amastatin alone, or phosphoramidon plus amastatin, caused 20-fold (EC50 6.5 +/- 1.1 nM), 2-fold (EC50 63 +/- 23 nM), and 100-fold (EC50 1.1 +/- 0.3 nM) increase in potency of [Met5]enkephalin, respectively. The results show that endopeptidase EC 3.4.24.11 and aminopeptidases contribute to degradation of enkephalins by gastric muscle cells. The rapidity and magnitude of the potentiating effects of the inhibitors on enkephalin-stimulated contraction suggest a close physical relationship between the peptidases and the enkephalin receptors.
Role of gastrin, histamine, and acetylcholine in the gastric phase of acid secretion in anesthetized rats
Authors: Lloyd K. C. , Raybould H. E. , Tache Y. , Walsh J. H.
Published: December 2017

To determine the relative contributions of gastrin, histamine, and cholinergic stimulation to the gastric phase of acid secretion, peptone-stimulated acid output was measured in urethan-anesthetized pylorus-ligated rats after intravenous administration of gastrin monoclonal antibody, cimetidine, and atropine. Intragastric peptone stimulated acid secretion four-fold over basal, which was associated with a significant increase in plasma gastrin levels. Gastrin immunoneutralization and simultaneous H2- and muscarinic-receptor blockade demonstrated that approximately 40% of peptone-stimulated acid output as attributed to endogenous gastrin through a histamine-dependent pathway, whereas 20% of acid output was accounted for by a cholinergic component. Another 10% of titratable acid was omeprazole-insensitive and presumably due to intragastric digestion of peptone. Therefore, approximately 30% residual acid output in response to peptone could not be accounted for by known acid stimulatory mechanisms. In rats given somatostatin monoclonal antibody to block the tonic inhibitory effect of endogenous somatostatin, residual acid output was a similar fraction of meal-stimulated acid output. In contrast, gastric distension induced by intragastric instillation of saline stimulated acid secretion to 1.5-fold over basal. Although 60% of distension-induced acid secretion could be inhibited by either H2 blockade or gastrin immunoneutralization, acid output returned to basal levels after simultaneous muscarinic blockade. These results indicate that gastrin, through a histaminergic pathway, is the principal mediator of meal-stimulated acid secretion in anesthetized rats. Approximately 30% of acid output was due to other unidentified mechanisms, such as chemical secretagogues, a direct effect of amino acids, or novel peptides.
Dephosphorylation of cAMP-dependent protein kinase regulatory subunit in stimulated parietal cells
Authors: Goldenring J. R. , Asher V. A. , Barreuther M. F. , Lewis J. J. , Lohmann S. M. , Walter U. , Modlin I. M.
Published: December 2017

The phosphorylation of endogenous proteins was investigated in subcellular fractions prepared from isolated rabbit parietal cells incubated with either cimetidine (unstimulated) or a combination of histamine and forskolin (maximally stimulated). Phosphorylation of endogenous proteins in subfractions was then assessed in a post hoc assay using [gamma-32P]ATP as a phosphate donor in vitro. The Mg(2+)-dependent incorporation of [32P]phosphate into a 52-kDa protein (pp52M) was observed in the 4,000 g membrane fraction from stimulated but not unstimulated cells. The pp52M protein was identified as the type II regulatory subunit of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase (RII) by isoelectric focusing, comigration with cAMP-binding proteins, and immunoprecipitation. Incorporation of [32P]phosphate into RII in the in vitro assay in the presence of Zn2+ was apparent in the 4,000 g membrane from stimulated but not unstimulated cells. The results thus suggested that, on stimulation, RII in membrane was dephosphorylated. Incorporation of [32P]phosphate into membrane-associated RII was completely abolished in the presence of 10 microM cAMP. The decrease in RII phosphorylation in membrane from stimulated cells assayed in the presence of cAMP was due to a phosphoprotein phosphatase activity that was completely inhibited by okadaic acid (1 microM). The results indicate that stimulation of parietal cells with histamine and forskolin results in the dephosphorylation of membrane bound RII by a protein phosphatase that is also membrane associated. Furthermore, okadaic acid inhibited histamine-stimulated accumulation of [14C]aminopyrine into isolated parietal cells without altering stimulated increases in cAMP. Thus protein phosphatase may be a significant regulator of parietal cell function.
Motor cycles with phase III in antrum are associated with high motilin levels and prolonged gallbladder emptying
Authors: Stolk M. F. , van Erpecum K. J. , Smout A. J. , Akkermans L. M. , Jansen J. B. , Lamers C. B. , Peeters T. L. , vanBerge-Henegouwen G. P.
Published: December 2017

We examined the relationship of interdigestive gallbladder emptying with the different phases of the migrating motor complex (MMC) and with plasma levels of cholecystokinin (CCK) and motilin. In 10 volunteers 20 cycles of the MMC were recorded. In 11 cycles phase III occurred in antrum and duodenum (group 1). In nine cycles phase III was observed only in duodenum (group 2). In group 1 gallbladder emptying started at 30% of total cycle length and continued until the end of the cycle. Maximal gallbladder emptying was 33.3 +/- 3.3% (SE). In group 2 gallbladder emptying also started at 30% of total cycle length but ended at 60%. Maximal gallbladder emptying in this group was 24.3 +/- 3.1% (P < 0.05). Motilin levels were higher in group 1 than in group 2 during phase IIB (240.1 +/- 28.5 and 142.1 +/- 30.9 pg/ml, respectively, P < 0.05) and during phase III (210.8 +/- 24.3 and 93.5 +/- 12.5 pg/ml, respectively, P < 0.05). We conclude that: 1) phase III activities starting in the antrum are preceded by greater and prolonged gallbladder emptying, higher motilin levels, and higher intraduodenal bile acid concentrations than phase III activities starting in the duodenum and 2) no relationship between interdigestive gallbladder motility and CCK levels could be demonstrated.
From ionic to cellular variability in human atrial myocytes: an integrative computational and experimental study
Authors: Muszkiewicz Anna , Liu Xing , Bueno-Orovio Alfonso , Lawson Brodie A. J. , Burrage Kevin , Casadei Barbara , Rodriguez Blanca
Published: December 2017

Variability refers to differences in physiological function between individuals, which may translate into different disease susceptibility and treatment efficacy. Experiments in human cardiomyocytes face wide variability and restricted tissue access; under these conditions, computational models are a useful complementary tool. We conducted a computational and experimental investigation in cardiomyocytes isolated from samples of the right atrial appendage of patients undergoing cardiac surgery to evaluate the impact of variability in action potentials (APs) and subcellular ionic densities on Ca2+ transient dynamics. Results showed that 1) variability in APs and ionic densities is large, even within an apparently homogenous patient cohort, and translates into ±100% variation in ionic conductances; 2) experimentally calibrated populations of models with wide variations in ionic densities yield APs overlapping with those obtained experimentally, even if AP characteristics of the original generic model differed significantly from experimental APs; 3) model calibration with AP recordings restricts the variability in ionic densities affecting upstroke and resting potential, but redundancy in repolarization currents admits substantial variability in ionic densities; and 4) model populations constrained with experimental APs and ionic densities exhibit three Ca2+ transient phenotypes, differing in intracellular Ca2+ handling and Na+/Ca2+ membrane extrusion. These findings advance our understanding of the impact of variability in human atrial electrophysiology.

NEW & NOTEWORTHY Variability in human atrial electrophysiology is investigated by integrating for the first time cellular-level and ion channel recordings in computational electrophysiological models. Ion channel calibration restricts current densities but not cellular phenotypic variability. Reduced Na+/Ca2+ exchanger is identified as a primary mechanism underlying diastolic Ca2+ fluctuations in human atrial myocytes.
Cardiac pacemakers in absence of the SA node: responses to exercise and autonomic blockade
Authors: Randall W. C. , Talano J. , Kaye M. P. , Euler D. , Jones S. , Brynjolfsson G.
Published: December 2017

Surgical excision of the sinoatrial node, verified histologically, is followed by a supraventricular (atrial) rhythm in both resting and exercising dog whether anesthetized or conscious. The ECG is characterized by a definitive P wave and associated atrial electrograms. Waxing and waning in heart rate, generally referred to as sinus arrhythmia continues in the awake animal after complete excision of the SA node. This arrhythmia is responsive to both adrenergic and cholinergic interventions, thus indicating the presence of both sympathetic and parasympathetic regulation of subsidiary atrial pacemaking tissues.
A reproducible model of moderate to severe concentric left ventricular hypertrophy
Authors: Kleinman L. H. , Wechsler A. S. , Rembert J. C. , Fedor J. M. , Greenfield J. C.
Published: December 2017

A reproducible model for the production of moderate to severe concentric left ventricular hypertrophy has been developed in this laboratory. Coarctation-banding of the ascending aorta was performed successfully in 10 puppies. There were no late deaths related to aortic rupture, and in the dogs surviving for 1 yr no evidence of congestive heart failure was present. A second operative procedure was performed in seven dogs for chronic instrumentation, and all survived. Severe supravalvular aortic stenosis with a marked peak systolic pressure gradient was noted in each dog. Postmortem examination revealed a substantial increase in left ventricular mass and in the ratio of left ventricular to body weight.
Cardiac output changes during neonatal growth
Authors: Woods J. R. , Dandavino A. , Brinkman C. R. , Nuwayhid B. , Assali N. S.
Published: December 2017

Changes in resting cardiac output (CO), stroke volume (SV), and systemic vascular resistance (SVR) during neonatal growth were studied in chronically instrumented lambs from the 1st to 5th wk of age; adult nonpregnant sheep values measured simultaneously were used as standard reference. Neonatal responses to autonomic agonists and antagonists were also investigated. Total CO increased linearly with neonatal growth, but decreased strikingly when expressed per weight unit; at 5 wk of age, CO/kg was still significantly higher than the adult value. SV also increased with neonatal growth but did not change when related to body weight; at 5 wk of age, SV/kg values were still higher than those of adult sheep. SVR changed reciprocally to CO. The decrease in CO/kg during neonatal growth paralleled the progressive decline in heart rate (HR). Beta receptor stimulation increased neonatal CO markedly and the increment was the same from the first through the fifth neonatal week. Beta blockade had insignificant effects, but cholinergic blockade produced moderate CO increases.
Blood flow distribution in dogs during hypothermia and posthypothermia
Authors: Anzai T. , Turner M. D. , Gibson W. H. , Neely W. A.
Published: December 2017

Blood flow distribution in tissues of mongrel dogs during hypothermia was studied with radionuclide-tagged microspheres. The animals were cooled at 21 degrees C and rewarmed under thiamylal sodiuni anesthesia. During hypothermia, cardiac output fell to 20% of the control; the highest rate of blood flow relative to normothermic values was observed in the subendocardium of the left ventricle, and the lowest in the hypophysis. Each tissue showed specific reactions to hypothermia. During hypothermia the myocardial and brain-stem blood flows were about 40% of the control; almost all of the digestive tract, striated muscle, adrenal gland, and hypophysis blood flows were maintained at 20% or less of the control. After rewarming, cardiac output recovered to values significantly lower than control. The myocardium, brain, renal cortex, and striated and smooth muscle recovered to control levels; however, blood flow to the digestive organs, bronchial artery flow to the lung, and flow to the endocrine organs did not completely recover by 2 after rewarming.
Regional blood flows measured in conscious rats by combined Fick and microsphere methods
Authors: Tsuchiya M. , Ferrone R. A. , Walsh G. M. , Frohlich E. D.
Published: December 2017

Regional blood flow measurements made by the radioactive microsphere technique were studied in conscious rats. A femoral arterial reference sample blood flow was measured directly, and at the same time indirectly by the combined use of direct Fick cardiac output and microsphere techniques. A significant correlation (r = .81, P less than .01) was obtained between direct and indirect blood flow values when 200--400 microspheres were trapped in the reference sample. When 100--200 microspheres were trapped, regional blood flow was 32% below true flow (P less than .01); and cardiac output, calculated by the reference sample method, was 57% greater than Fick cardiac output (P less than .01). When three consecutive Fick determinations and microsphere injections (20,000 per injection, 15 micrometer diam) were made in conscious rats, significant correlations were obtained among the first, second, and third regional blood flow measurements (r = .95, P less than .01). The results have demonstrated that cardiac output and reference blood flow can be measured with accuracy and precision in the conscious rat by the radioactive microsphere procedure.
Vasopressin in the rat with spontaneous hypertension
Authors: Crofton J. T. , Share L. , Shade R. E. , Allen C. , Tarnowski D.
Published: December 2017

Because vasopressin is one of the most potent naturally occurring pressor agents, and because of its importance in the regulation of blood volume and composition, we have undertaken a study of the role of vasopressin in the pathogenesis of the hypertension in the Okamoto-Aoki spontaneously hypertension (SH) rat. In SH rats, systolic blood pressure increased from 135 +/- 3 (SE) mmHg at age 33 days to 184 +/- 3 mmHg at age 75 days (P less than 0.01). In the Wistar-Kyoto (WKY) control rats, blood pressure increased from 100 +/- 2 to 120 +/- 2 mmHg (P less than 0.01). The differences in blood pressure between the SH and WKY rats at all ages were significant (P less than 0.01). During the age period 33-75 days, the 24-h urinary excretion of vasopressin in the SH rat was consistently more than twofold greater (P less than 0.01) than in the WKY rat. Plasma vasopressin concentration and pituitary vasopressin content were also elevated in the SH rat (P less than 0.01 and P less than 0.02, respectively). Changes in systolic blood pressure in the SH rat, however, were not paralleled by changes in the urinary excretion of vasopressin. The data indicate that the secretion of vasopressin is elevated in the SH rat. However, the magnitude of this elevation, in and of itself, may not be sufficient to account for the rising blood pressure in the young SH rat.
Effect of indomethacin on coronary vascular response to increased myocardial oxygen consumption
Authors: Harlan D. M. , Rooke T. W. , Belloni F. L. , Sparks H. V.
Published: December 2017

We tested the hypothesis that arachidonic acid metabolites mediate the coronary vascular response to changes in cardiac activity. Isoproterenol was administered intravenously to five chloralose-anesthetized, open-chest dogs. Left anterior descending coronary artery blood flow, systemic arterial blood pressure, and great cardiac vein O2 content were continuously measured, and blood gas determination (including O2 content) were made before and after infusions. From these data, coronary vascular conductance, coronary O2 delivery, and myocardial O2 consumption were calculated. Isoproterenol increased conductance, O2 delivery, and O2 consumption. Indomethacin, a blocker of prostaglandin synthesis, was administered, and the isoproterenol infusions were repeated. The changes in conductance, O2 delivery, and O2 consumption associated with isoproterenol were not different after indomethacin was administered than before indomethacin was administered. Neither were the relations between conductance or O2 delivery and O2 consumption affected by indomethacin. We conclude that, in this preparation and with this stimulus, prostaglandins do not appear to mediate or modulate the coronary vascular response to changes in cardiac activity.
Flexible valinomycin electrodes for on-line determination of intravascular and myocardial K+
Authors: Hill J. L. , Gettes L. S. , Lynch M. R. , Hebert N. C.
Published: December 2017

Flexible electrode systems capable of monitoring in vivo changes in venous and myocardial extracellular potassium activity were constructed using valinomycin-polyvinyl chloride matrix membrane and polyvinyl chloride tubing. Electrode impedance was 1--30 Momega, time constant 10--200 ms, drift less than 1 mV/h, and shelf life approximately 3 days (intramyocardial electrode) and approximately 6 wk (venous electrode). In vitro and in vivo accuracy were determined in 5 dogs and 18 pigs, anesthetized with sodium pentobarbital (35 mg/kg iv), with normal and elevated K+ levels. Serum and venous K+ concentration, determined using a K+ electrode with tip diameter of 1.5 mm, correlated well to serum K+ values determined by flame photometry (r = 0.997). Steady-state myocardial extracellular K+ concentration determined using double-barrel electrodes with total tip diameter of 0.6 mm also correlated well to the serum K+ concentration (r = 0.992). These electrode assemblies permit on-line, virtually instantaneous in vivo determination of intravascular and local myocardial extracellular K+ activity, a capability not previously available.
Interrelations between contracting striated muscle and precapillary microvessels
Authors: Gorczynski R. J. , Klitzman B. , Duling B. R.
Published: December 2017

Arterioles and capillaries in the hamster cremaster muscle were observed during electrical stimulation of striated muscle fibers in order to characterize the microcirculatory basis of functional hyperemia. When contraction was restricted to single muscle fibers, responses were variable and frequently transient. Stimulation of either small bundles of muscle fibers or the entire cremaster muscle resulted in reproducible responses typified by: 1) a latency period, 2) an early, often transient phase of dilation, and 3) a second, slower phase of dilation. The latency varied inversely with contraction frequency, and the magnitude of the dilation varied directly with contraction frequency over the range 1--8/s. With stimulation of single fibers and small groups of fibers, arteriolar vasodilation was highly localized to regions of the arterioles that were in close apposition to the stimulated fibers. The number of capillaries with red blood cell flow increased during contraction, and the increase was graded with contraction frequency. The changes observed suggest that the vascular response during functional hyperemia is a two-part process and that the control processes are influenced by contraction frequency.
Cellular electrophysiological marker of irreversible ischemic myocardial injury
Authors: McGee J. , Singer D. H. , Eick R. E. , Kloner R. , Belic N. , Reimer K. , Elson J.
Published: December 2017

Glass microelectrode studies on posterior papillary muscle (PPM) slice preparations from 20 pentobarbital-anesthetized dogs (15 subjected to prior circumflex coronary artery ligation, 5 to sham ligation) have resulted in the definition of an electrophysiological marker of irreversible ischemic injury, namely, findings of areas composed of cells unable to generate a significant resting potential (less than -25) mV), designated "electrically inactive areas." Electrically inactive areas were essentially confined to PPM from dogs with circumflex coronary ligation; the incidence and distribution of the areas was related to duration of ischemia. Correlative phase- and light-microscopic studies demonstrated close correspondence between such areas and morphological evidence of irreversible ischemic injury. Analysis of frequency and distribution of electrically inactive areas permits quantitative assessment of the extent and spatial distribution of irreversible injury. This method has been used to quantitate injury in PPM from dogs that had been subjected to ligation for varying time periods. The potential utility of this method for evaluation of interventions designed to protect against ischemic injury and to assess electrical properties of surviving cells is considered.
Increased reactivity of venous smooth muscle by small decreases in extracellular sodium
Authors: Beaty O. , Lorenz R. R. , Shepherd J. T.
Published: December 2017

In dog saphenous vein strips, decreases in extracellular sodium from 5% to 23% did not alter basal tension, but progressively increased tension developed during electrical stimulation (1.0 to 10 Hz). The augmentation did not occur with similar reductions in chloride ions. When osmolality was maintained with sucrose, the response to electrical stimulation also was enhanced with a 5% reduction in sodium ions, but did not increase further with larger sodium reductions. The enhancement was due to some effect on the smooth muscle cells, because the overflow of [7-3H]norepinephrine during electrical stimulation was unaffected by the sodium reduction, whereas contractions caused by norepinephrine and barium chloride were potentiated. The potentiation did not depend on increased influx of extracellular calcium, because contractions induced by acetylcholine were unaffected by sodium reduction; and after blocking calcium influx with verapamil, the norepinephrine contractions still were augmented. It was concluded that a decrease in extracellular sodium by 5% (from the normal value of 143.3--131.1 meq/1) can enhance the response of venous smooth muscle to adrenergic stimuli.
Dextran as a radioactive microsphere suspending agent: severe hypotensive effect in rat
Authors: Flaim S. F. , Morris Z. Q. , Kennedy T. J.
Published: December 2017

The effects of different commercially available radioactive microsphere suspending solutions were studied on the cardiovascular hemodynamics of male, Sprague-Dawley rats. Single left ventricular injections of carbonized radioactive microspheres (15 +/- 5 micron diam) totaling 850,000 spheres, suspended in 10% dextran (mol wt, 73,000) solution with Tween, caused reductions in arterial pressure (control, 101; postinjection, 74 mmHg; P less than 0.001), with no change in heart rate. Identical injections made with isotonic saline solution plus Tween had no effect on either heart rate or arterial pressure. Independent studies were conducted to examine the effects of 1-ml injections of four suspending solutions without microspheres on the cardiovascular hemodynamics of rats. Isotonic saline had no hemodynamic effect, and isotonic saline plus Tween decreased only heart rate. Ten percent dextran soluton with Tween decreased arterial pressure, heart rate, peak left ventricular systolic pressure, and left ventricular end-diastolic pressure. Similar changes occurred when dextran solution without Tween was administered. These data demonstrate that 10% dextran solution used as a microsphere suspending agent induces a severe hypotensive response in rats. Furthermore, injections of up to 850,000 microspheres in isotonic saline solution do not alter arterial pressure in the rat.
Myocardial perfusion and function during acute right ventricular systolic hypertension
Authors: Manohar M. , Bisgard G. E. , Bullard V. , Will J. A. , Anderson D. , Rankin J. H.
Published: December 2017

Hemodynamics, myocardial function, and regional myocardial blood flow (MBF) were measured in 6 closed-chest ponies anesthetized with ketamine hydrochloride before (control) and after creation of acute right ventricular systolic hypertension (RVSH) during normoxia and isocapnic hypoxia. The right ventricular (RV) systolic pressure during each RVSH approached 90 mmHg. There were significant alterations in the pattern of total ventricular MBG distribution in favor of the RV. Because RV myocardium received proportionate increments to its endocardium as well as epicardium, it is concluded that autoregulation in the RV coronary vascular bed had not been abolished even during hypoxia + RVSH. Marked increase in MBF to the right side of the septum during each RVSH with little change in perfusion to other regions suggests that RV contraction is supported by the right side of the septum. Because these increments occurred with decreased RV coronary driving pressure they were the consequence of compensatory coronary vasodilatation. The slow heart rate of the pony in the presence of a large coronary vasodilatory reserve may have been the major factor in allowing large increments in MBF to the stressed regions despite decreased coronary driving pressure.
Ventricular performance and myocardial water content during hemodilution in dogs
Authors: Geffin G. A. , Vasu M. A. , O'Keefe D. D. , Pennington D. G. , Erdmann A. J. , Lowenstein E. , Powell W. J. , Daggett W. M.
Published: December 2017

In dogs anesthetized with chloralose-urethan on right heart bypass, left ventricular (LV) performance was assessed at constant LV stroke work before and for up to 2.5 h after crystalloid hemodilution was established. Lowering the hematocrit from 43.3 +/- 1.3% to 13.6 +/- 1.7% (SE) did not significantly change LV end-diastolic pressure (LVEDP) initially. After 80 min LVEDP increased slightly by 1.7 +/- 0.6 cmH2O (P less than 0.05) at a stroke work of 17.3 +/- 2.3 g.m. The value of dP/dt did not change significantly throughout. When LV function curves were generated by increasing cardiac output, the stroke work attained at an LVEDP of 10 cmH2O decreased with hemodilution from 23.9 +/- 3.5 to 20.8 +/- 3.9 g.m (NS). LV wall water content increased with hemodilution, from which it could be calculated that there was an 18.6% increase in LV mass. Thus, despite an increase in LV external girth demonstrated by LV circumferential gauges, it is possible that increased wall thickness due to the water gain resulted in little change or an actual decrease in LV end-diastolic volume. Thus, profound hemodilution can be attained with only slight depression of LV performance.