bluuebunny/crossref_metadata_2025 huggingface dataset:
Overexpression of CYP27 in hepatic and extrahepatic cells: role in the regulation of cholesterol homeostasis
Authors: Hall E. , Hylemon P. , Vlahcevic Z. , Mallonee D. , Valerie K. , Avadhani N. , Pandak W.
Published: December 2017

In the liver, sterol 27-hydroxylase (CYP27) participates in the classic and alternative pathways of bile acid biosynthesis from cholesterol (Chol). In extrahepatic tissues, CYP27 converts intracellular Chol to 27-hydroxycholesterol (27OH-Chol), which may regulate the activity of 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA-R). This study attempts to better define the role of CYP27 in the maintenance of Chol homeostasis in hepatic and extrahepatic cells by overexpressing CYP27 in Hep G2 cells and Chinese hamster ovary (CHO) cells through infection with a replication-defective recombinant adenovirus encoding for CMV-CYP27. After infection, CYP27 mRNA and protein levels increased dramatically. CYP27 specific activity also increased two- to fourfold in infected cells ( P ≤ 0.02), with a marked increase in conversion of [14C]Chol to [14C]27OH-Chol (∼150%; P ≤ 0.01). Accumulation of 27OH-Chol in CHO cells was associated with a 50% decrease in HMG-CoA-R specific activity ( P ≤ 0.02). In infected Hep G2 cells, the significant increase in bile acid synthesis (46%; P ≤ 0.006), which prevented the accumulation of intracellular 27OH-Chol, resulted in increased HMG-CoA-R activity (183%; P ≤ 0.02). Overexpression of CYP27 in Hep G2 cells also increased acyl CoA-cholesterol acyltransferase (71%, P ≤ 0.02) and decreased cholesteryl ester hydrolase (55%, P ≤ 0.02). In conclusion, CYP27 generates different physiological responses depending on cell type and presence or absence of bile acid biosynthetic pathways.
Nifedipine modulation of biliary GSH and GSSG/ conjugate efflux in normal and regenerating rat liver
Authors: Yang Bo , Hill Ceredwyn E.
Published: December 2017

Canalicular glutathione secretion provides the major driving force for bile acid-independent bile flow (BAIF), although the pathways involved are not established. The hypothesis that GSH efflux proceeds by a route functionally distinct from the high-affinity, low-capacity, mrp2-mediated pathway was tested by using perfused rat liver and three choleretic compounds that modify biliary secretion of GSH (the dihydropyridine nifedipine and organic anion probenecid) or GSSG [sodium nitroprusside (SNP)]. Whereas nifedipine (30 μM) stimulated GSH secretion and blocked SNP-stimulated GSSG efflux and choleresis, SNP (1 mM) was ineffective against nifedipine-stimulated GSH efflux or BAIF, suggesting that most GSSG exits through a GSH-inhibitable path independent of high-affinity GSSG/glutathione conjugate transport. Three observations support this proposal. SNP, but not nifedipine, significantly inhibited bromosulfophthalein (BSP, 1 μM) excretion. Probenecid (1 mM) blocked resting or nifedipine-stimulated GSH secretion but only weakly inhibited BSP excretion. Glutathione, but not BSP, efflux capacity was reduced following partial hepatectomy. We suggest GSH efflux is mediated by a high-capacity organic anion pathway capable of GSSG transport when its high-affinity route is saturated.
Nonselective cation channel as a Ca2+ influx pathway in pepsinogen-secreting cells of bullfrog esophagus
Authors: Kimura Seiichiro , Mieno Hiroshi , Tamaki Kenji , Inoue Masaki , Chayama Kazuaki
Published: December 2017

In pepsinogen-secreting cells of bullfrog ( Rana catesbeiana), recent evidence suggests that Ca2+ release from internal stores followed by Ca2+ influx across the plasma membrane elicits pepsinogen secretion. Such a Ca2+ influx could be carried by a background current, potentiated by bombesin, that was found in these cells using the whole cell patch-clamp technique. The permeability ratio of Cs+-Rb+-K+-Na+-Li+- N-methyl-d-glucamine+-Ca2+was 1.01:1:1:0.86:0.72:0.54:0.34. The current was almost totally blocked by the nonselective cation channel blockers La3+(0.1 mM) and Gd3+ (0.1 mM) and was activated by intracellular Ca2+. These properties demonstrated that the current, which was activated by bombesin, was a nonselective cation current. At the same time, Gd3+ suppressed pepsinogen secretion by 29 ± 5.6% in isolated pepsinogen-secreting glands. These results are in accord with the idea that a nonselective cation channel in pepsinogen-secreting cells plays a role as a Ca2+ influx pathway leading to secretion of pepsinogen in bullfrog esophageal mucosa.
Viscoelastic properties of the human colon
Authors: Bharucha Adil E. , Hubmayr Rolf D. , Ferber Irene J. , Zinsmeister Alan R.
Published: December 2017

Our objectives were to characterize colonic viscoelastic properties of the human descending colon by assessing pressure-volume (P-V) relationships during barostatic balloon distension. In 16 healthy subjects, a balloon was inflated to 44 mmHg and then deflated to 0 mmHg in 4-mmHg steps at 10, 30, and 60 ml/min, allowing volume fluctuations to stabilize at each pressure increment. Thereafter, these “quasi-static” P-V curves were compared with “dynamic” distensions to 300 ml, at 1 and 10 ml/s, before and after intravenous atropine in another five subjects. During quasi-static curves, balloon volume stabilized at each pressure increment. Quasi-static P-V curves were reproducible within individuals and approximated to a power exponential function and revealed hysteresis, indicative of viscoelasticity. Body mass index influenced quasi-static P-V curves during inflation but not during deflation. The colon was less compliant during dynamic distensions at 10 ml/s than during quasi-static distensions. Atropine increased quasi-static compliance and attenuated differences between quasi-static and rapid distensions. We conclude that colonic viscoelastic properties can be assessed by quasi-static P-V curves. Rapid colonic distension activated neural reflexes, thereby reducing colonic compliance compared with quasi-static distensions.
Regulation of cholangiocyte bicarbonate secretion
Authors: Kanno Noriatsu , LeSage Gene , Glaser Shannon , Alpini Gianfranco
Published: December 2017

The objective of this review article is to discuss the role of secretin and its receptor in the regulation of the secretory activity of intrahepatic bile duct epithelial cells (i.e., cholangiocytes). After a brief overview of cholangiocyte functions, we provide an historical background for the role of secretin and its receptor in the regulation of ductal secretion. We review the newly developed experimental in vivo and in vitro tools, which lead to understanding of the mechanisms of secretin regulation of cholangiocyte functions. After a description of the intracellular mechanisms by which secretin stimulates ductal secretion, we discuss the heterogeneous responses of different-sized intrahepatic bile ducts to gastrointestinal hormones. Furthermore, we outline the role of a number of cooperative factors (e.g., nerves, alkaline phosphatase, gastrointestinal hormones, neuropeptides, and bile acids) in the regulation of secretin-stimulated ductal secretion. Finally, we discuss other factors that may also play an important role in the regulation of secretin-stimulated ductal secretion.
Glutamine transporter in crypts compensates for loss of villus absorption in bovine cryptosporidiosis
Authors: Blikslager Anthony , Hunt Elaine , Guerrant Richard , Rhoads Marc , Argenzio Robert
Published: December 2017

Cryptosporidium parvum infection represents a significant cause of diarrhea in humans and animals. We studied the effect of luminally applied glutamine and the PG synthesis inhibitor indomethacin on NaCl absorption from infected calf ileum in Ussing chambers. Infected ileum displayed a decrease in both mucosal surface area and NaCl absorption. Indomethacin and glutamine or its stable derivative alanyl-glutamine increased the net absorption of Na+in infected tissue in an additive manner and to a greater degree than in controls. Immunohistochemical and Western blot studies showed that in control animals neutral amino acid transport system ASC was present in villus and crypts, whereas in infected animals, ASC was strongly present only on the apical border of crypts. These results are consistent with PGs mediating the altered NaCl and water absorption in this infection. Our findings further illustrate that the combined use of a PG synthesis inhibitor and glutamine can fully stimulate Na+and Cl−absorption despite the severe villous atrophy, an effect associated with increased expression of a Na+-dependent amino acid transporter in infected crypts.
Identification of a VIP-specific receptor in guinea pig tenia coli
Authors: Teng B.-Q. , Grider J. R. , Murthy K. S.
Published: December 2017

Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) interact with VPAC2 receptors in rabbit and guinea pig (GP) gastric muscle but with functionally distinct VIP and PACAP receptors in GP tenia coli. This study examined whether selectivity for VIP was determined by two residues (40, 41) in the extracellular domain that differ in the VIP receptors of GP gastric and tenial muscle. A mutant rat VPAC2 receptor (L40F, L41F), and two chimeric receptors in which the NH2-terminal domain of rat VPAC2 receptor was replaced with that of GP gastric (chimeric-G) or tenia coli (chimeric-T) VIP receptors, were constructed and expressed in COS-1 cells. VIP and PACAP bound with equal affinity to wild-type and mutant rat VPAC2 receptors and to chimeric-G receptor (IC50: VIP 0.3 ± 0.1 to 1.5 ± 0.4 nM, PACAP 0.4 ± 0.1 to 2.5 ± 0.1 nM) and stimulated cAMP with equal potency (EC50: VIP 13 ± 5 to 48 ± 8 nM, PACAP 8 ± 3 to 31 ± 14 nM). VIP bound with high affinity also to chimeric-T receptor (IC50: 0.5 ± 0.1 nM) and stimulated cAMP with high potency (EC50: 3 ± 1 nM). In contrast, PACAP exhibited >1,000-fold less affinity for binding or potency for stimulating cAMP. We conclude that GP tenia coli express a VIP-specific receptor and that selectivity is determined by a pair of extracellular phenylalanine residues.
Time-dependent intestinal adaptation and GLP-2 alterations after small bowel resection in rats
Authors: Ljungmann K. , Hartmann B. , Kissmeyer-Nielsen P. , Flyvbjerg A. , Holst J. J. , Laurberg S.
Published: December 2017

Existing data on morphological adaptation after small bowel resection are obtained by potentially biased methods. Using stereological techniques, we examined segments of bowel on days 0, 4, 7, 14, and 28 after 80% jejunoileal resection or sham operation in rats and correlated intestinal growth with plasma levels of glucagon-like peptide-2 (GLP-2). In the jejunum and ileum of the resected rats, the mucosal weight increased by 120 and 115% during the first week, and the weight of muscular layer increased by 134 and 83%, compared with sham-operated controls. The luminal surface area increased by 190% in the jejunum and by 155% in the ileum after 28 days. The GLP-2 level was increased by 130% during the entire study period in the resected rats. Small bowel resection caused a pronounced and persistent transmural growth response in the remaining small bowel, with the most prominent growth occurring in the jejunal part. The significantly elevated GLP-2 level is consistent with an important role of GLP-2 in the adaptive response.
Phosphatidylinositol is essential determinant for K+permeability involved in gastric proton pumping
Authors: Omi Noriaki , Nagao Taku , Urushidani Tetsuro
Published: December 2017

Gastric vesicles purified from acid-secreting rabbit stomach display K+permeability manifested by the valinomycin-independent proton pumping of H+-K+-ATPase as monitored by acridine orange quenching. This apparent K+permeability is attenuated by the treatment of the membrane with 5 mM Mg2+, and this phenomenon has been attributed to membrane-bound phosphoprotein phosphatase. However, with the exception of the nonspecific inhibitor pyrophosphate, protein phosphatase inhibitors failed to inhibit the loss of K+permeability. Preincubation of the membrane with neomycin, a phospholipase C inhibitor, surrogated the effect of Mg2+, whereas another inhibitor, U-73122, did not. Phosphatidylinositol 4,5-bisphosphate (PIP2) restored the attenuated K+permeability by treatment with either Mg2+or neomycin. Furthermore, either phosphatidylinositol bound to phosphatidylinositol transfer protein or phosphatidylinositol 4,5,6-trisphosphate (PIP3) surrogated the effect of PIP2. Mg2+and neomycin reduced K+permeability in the membrane as determined by Rb+influx and K+-dependent H+diffusion. Treatment with Mg2+reduced the contents of PIP2and PIP3in the membrane. These results suggest that PIP2and/or PIP3maintain K+permeability, which is essential for proton pumping in the apical membrane of the secreting parietal cell.
Pressure-geometry relationship in the antroduodenal region in humans
Authors: Faas Henryk , Hebbard Geoffrey S. , Feinle Christine , Kunz Patrik , Brasseur James G. , Indireshkumar K. , Dent John , Boesiger Peter , Thumshirn Miriam , Fried Michael , Schwizer Werner
Published: December 2017

Understanding of the control mechanisms underlying gastric motor function is still limited. The aim of the present study was to evaluate antral pressure-geometry relationships during gastric emptying slowed by intraduodenal nutrient infusion and enhanced by erythromycin. In seven healthy subjects, antral contractile activity was assessed by combined dynamic magnetic resonance imaging and antroduodenal high-resolution manometry. After intragastric administration of a 20% glucose solution (750 ml), gastric motility and emptying were recorded during intraduodenal nutrient infusion alone and, subsequently, combined with intravenous erythromycin. Before erythromycin, contraction waves were antegrade (propagation speed: 2.7 ± 1.7 mm/s; lumen occlusion: 47 ± 14%). Eighty-two percent (51/62) of contraction waves were detected manometrically. Fifty-four percent of contractile events (254/473) were associated with a detectable pressure event. Pressure and the degree of lumen occlusion were only weakly correlated ( r 2 = 0.02; P = 0.026). After erythromycin, episodes of strong antroduodenal contractions were observed. In conclusion, antral contractions alone do not reliably predict gastric emptying. Erythromycin induces strong antroduodenal contractions not necessarily associated with fast emptying. Finally, manometry reliably detects ∼80% of contraction waves, but conclusions from manometry regarding actual contractile activity must be made with care.
IGFBP mRNA expression in small intestine of rat during postnatal development
Authors: Shoubridge C. A. , Steeb C.-B. , Read L. C.
Published: December 2017

In contrast to the adult gut, the immature intestine is refractory to subcutaneously infused insulin-like growth factor I (IGF-I). IGF binding protein (IGFBP) mRNA expression was characterized in intestinal tissues from 6-, 19-, and 90-day-old rats to determine if changes in local expression could account for this age-related change in IGF-I potency. For all age groups, IGFBP-3 to -6, but not IGFBP-1 or -2, were detected by Northern blot analysis. IGFBP-3, -4, and -5 were more intensely expressed in the 6-day-old rat intestine compared with weanling or adult tissue. In contrast, IGFBP-6 expression peaked at the time of weaning. In situ hybridization showed IGFBP-3 to -6 expression was confined to cells of the lamina propria and submucosa and also in the muscularis layer for IGFBP-5. Furthermore, the pattern of IGFBP-5 localization in the intestine changed with development. The findings indicate that the expression of IGFBP-3 to -6 is higher in the immature intestine compared with the adult intestine, suggesting locally produced IGFBPs may inhibit systemically derived IGF-I action in the intestine. Therefore, changes to local IGFBP expression may contribute to the varying response of the rat intestine to IGF-I peptides during postnatal development.
Role of T cells in development of chronic pancreatitis in male Wistar Bonn/Kobori rats: effects of tacrolimus
Authors: Yamada Tamaki , Hashimoto Takashi , Sogawa Mitsue , Kobayashi Sawako , Kaneda Kenji , Nakamura Soichi , Kuno Atsushi , Sano Hitoshi , Ando Tomoaki , Kobayashi Shinya , Aoki Shigeru , Nakazawa Takahiro , Ohara Hirotaka , Nomura Tomoyuki , Joh Takashi , Itoh Makoto
Published: December 2017

We assessed T cell association with acinar cell apoptosis and a preventive effect of tacrolimus, a T cell suppressant, on the development of chronic pancreatitis in male Wistar Bonn/Kobori rats. At 15 wk, cellular infiltrates composed of F4/80-positive cells (monocytes/macrophages), CD4-positive cells, and CD8-positive cells were extensive in the interlobular connective tissue and parenchyma. In particular, CD8-positive cells invaded pancreatic lobules and formed close associations with acinar cells, some of which demonstrated features of apoptosis. At 20 wk, CD8-positive cells were still abundant in the fibrotic tissue formed with loss of acinar cells. Repeated subcutaneous injection of 0.1 mg · kg−1· day−1but not 0.025 mg · kg−1· day−1of tacrolimus for 10 wk completely prevented the occurrence of acinar cell apoptosis, infiltration of CD4- and CD8-positive cells, and development of pancreatitis at the age of 20 wk, but these maneuvers did not recover the decreased plasma corticosterone levels, which may be responsible for the development of disease. We demonstrated that T cells, possibly CD8-positive cells, are involved in inducing apoptosis of acinar cells, raising the possibility that tacrolimus might find clinical application in the treatment of autoimmune chronic pancreatitis.
Helicobacter pyloricytotoxin VacA increases alkaline secretion in gastric epithelial cells
Authors: Debellis Lucantonio , Papini Emanuele , Caroppo Rosa , Montecucco Cesare , Curci Silvana
Published: December 2017

Human infection by the bacterium Helicobacter pylori (Hp) may lead to severe gastric diseases by an ill-understood process involving several virulence factors. Among these, the cytotoxin VacA is associated with higher tissue damage. In this study, the isolated frog stomach model was used to characterize the acute effects of VacA on the gastric epithelium. Our results show that VacA partially inhibits gastric acid output by increasing HCO[Formula: see text] efflux. Experiments conducted with double-barrelled pH or Cl−-selective microelectrodes on surface epithelial gastric cells (SECs) and single gastric glands show that VacA does not impair the activity of the oxyntic cells but renders the apical membrane of SECs more permeable to HCO[Formula: see text] and Cl−. Inhibition of this permeation by 5-nitro-2-(3-phenylpropylamino) benzoic acid indicates that this may be due to the formation of anion-selective pores by the toxin. We suggest that VacA-dependent HCO[Formula: see text] efflux from SECs improves the environmental conditions (pH, CO2concentration) of the niche parasitized by Hp, that is the gastric surface. This may favor Hp persistence in the tissue and the secondary development of a chronic inflammation.
Effects of an α2-adrenergic agonist on gastrointestinal transit, colonic motility, and sensation in humans
Authors: Viramontes Blanca E. , Malcolm Allison , Camilleri Michael , Szarka Lawrence A. , McKinzie Sanna , Burton Duane D. , Zinsmeister Alan R.
Published: December 2017

To characterize α2-adrenergic control of motor and sensory functions of gastrointestinal tract and colon, we studied dose-related effects of clonidine (placebo or up to 0.3 mg po) by random assignment in 55 healthy humans. Gastrointestinal transit was measured in all subjects; in 35, we assessed colonic compliance, tone, and sensations of gas and pain during phasic distensions. Clonidine did not significantly alter gastrointestinal or colonic transit, but it increased colonic compliance and reduced fasting tone without altering colonic response to a meal. Clonidine significantly reduced aggregate sensation to distensions overall and had significant linear dose-related sensory effects at 8- and 24-mmHg distensions. Effect on pain (including dose-response relationship) was due to 0.3-mg dose for distensions at 24 mmHg. We confirmed that clonidine relaxes fasting colonic tone and reduces sensation of pain. In this study, gut transit was not altered by clonidine, and novel dose-response characteristics and clonidine's effect on gas sensation are provided. Doses as low as 0.05 mg may be effective and potentially useful in reducing colonic tone and gas sensation.
Luminal CCK-releasing factor stimulates CCK release from human intestinal endocrine and STC-1 cells
Authors: Wang Yu , Prpic Vera , Green Gary M. , Reeve Joseph R. , Liddle Rodger A.
Published: December 2017

CCK is secreted into the blood from intestinal endocrine cells following ingestion of a meal. Recently, it has been demonstrated that the ability of certain foods to stimulate CCK release is mediated by endogenously produced CCK-releasing factors. A newly discovered luminal CCK-releasing factor (LCRF) is secreted into the intestine, where it stimulates CCK secretion. However, the mechanism whereby LCRF affects intestinal epithelial cells is unknown. The current study was designed to determine whether LCRF has a direct effect on CCK cells to stimulate hormone secretion. In dispersed human intestinal mucosal cells, LCRF (5–200 nM) significantly stimulated CCK release in a concentration-dependent manner. This stimulatory effect was absent in calcium-free media and was inhibited by the L-type calcium-channel blockers diltiazem and nifedipine. To examine direct cellular effects of LCRF on CCK cells, further studies were conducted in the CCK-containing enteroendocrine cell line STC-1. As in native cells, LCRF significantly stimulated CCK release from STC-1 cells in a calcium-dependent manner. In cells loaded with a calcium-sensitive dye, LCRF stimulation produced a rapid increase in intracellular calcium. To examine the electrophysiological basis for this stimulation, whole cell recordings were made from STC-1 cells. Whole cell calcium currents were identified under basal conditions; moreover, calcium-channel activity was increased by LCRF. These studies demonstrate that 1) LCRF has a direct effect on human intestinal cells to stimulate CCK secretion, 2) stimulated hormone release is calcium dependent, and 3) LCRF activates calcium currents in CCK cells, which leads to CCK secretion.
Glutamine promotes triglyceride absorption in a dose-dependent manner
Authors: Schwimmer Jeffrey B. , Ee Looi , Zheng Shuqin , Tso Patrick
Published: December 2017

Dietary proteins may play a role in lipid absorption. Whether amino acids are specifically involved is unknown. We hypothesized that enterally administered l-glutamine (l-Gln) given with a lipid meal increases triglyceride (TG) absorption in rats. Mesenteric lymph fistulae and gastroduodenal feeding tubes were placed in adult male Sprague-Dawley rats. The animals received an enteral bolus of Intralipid (5 ml) followed by enteral infusion of increasing concentrations of l-Gln in saline (0, 85, 170, or 340 mM) or equimolar concentrations of the inactive isomer d-Gln or an essential amino acid mixture without Gln. Lymph was collected continuously for 6 h and analyzed for TG content. Animals infused with 85 mM l-Gln had a 64% increase in total TG output vs. controls ( P < 0.05) despite no difference in lymph flow rate. Total TG output for animals infused with 340 mMl-Gln declined by 43% vs. controls ( P < 0.05). The effect of Gln in promoting lymphatic fat transport is specific to l-Gln and not shared by d-Gln or an equivalent amino acid mixture. l-Gln is capable of either promoting or impairing lymphatic TG transport in a dose-dependent manner.
Estrogen and prothrombin synthesis: effect of estrogen on absorption of vitamin K1
Authors: Jolly D. W. , Craig C. , Nelson T. E.
Published: December 2017

Intact male and female albino rats fed a vitamin K-deficient diet develop a plasma prothrombin-proconvertin deficiency. Male rats respond with a precipitous drop to approximately 20–30% of normal plasma levels within 2–5 days, whereas female rats respond at a slower rate. Ethynylestradiol, 5–10 mug/day, or castration, reduces the progressive decline of plasma prothrombin-proconvertin seen in nonsupplemented intact male rats. The response of castrate females differs little from the response of intact females. Ethynylestradiol, 5–10 mug/day, affects both castrate males and females similarly, limiting the prothrombin-proconvertin decrease to about 13% below control value after 14 days. Intestinal absorption of vitamin K1 measured in the thoracic duct lymph of pentobarbital-anesthetized castrate male and female rats was shown to increase significantly after estrogen treatment. Estrogen-treated castrate male and female rats absorbed 25.8 mug and 11.8 mug vitamin K1, respectively. Nontreated control castrate male and female rats absorbed 0.0 mug and 1.2 mug, respectively, during a 240-min collection period. Use of radioactive vitamin K1 in similar experiments confirmed these results. Estrogen-treated castrate males absorbed vitamin K1 at the rate of 30-40 mug/g lymph whereas nontreated control males absorbed only about 6 mug/g lymph.
Effects of atrial pacing on regional myocardial gas tensions with critical coronary stenosis
Authors: O'Riordan J. B. , Flaherty J. T. , Khuri S. F. , Brawley R. K. , Pitt B. , Gott V. L.
Published: December 2017

Changes in myocardial carbon dioxide (PmCO2) and oxygen tension (PmO2) measured by mass spectrometry have been shown to reflect quantitatively progressive degrees of regional myocardial ischemia associated with stepwise reduction in coronary blood flow. The present study utilized mass spectrometry to assess the severity of regional myocardial ischemia developing during atrial pacing in the presence of a flow-limiting proximal critical coronary artend subendocardial layers was measured by the radioactive microsphere technique. Application of a “critical stenosis” resulted in a 6-mmHg decrease in PmO2 and a 17-mmHg increase in PmCO2 in the region of the myocardium supplied by the stenosed vessel. The addition of atrial pacing resulted in a 3-mmHg further decrease in Pmo2 and a 40-mmHg further increase in PmCO2. In the region of myocardium supplied by the critically stenosed vessel MBF increased in the subepicardial layer, but decreased or remained unchanged in the subendocardial layer. The failure of myocardial blood flow to increase in deeper myocardial layers in response to the increased myocardial oxygen demand of atrial pacing would provide a mechanism for the development of subendocardial ischemia in the presence of a critical coronary stenosis.
Influence of mannitol on contractile responses of isolated perfused arteries
Authors: Krishnamurty V. S. , Adams H. R. , Smitherman T. C. , Templeton G. H. , Willerson J. T.
Published: December 2017

The influence of hyperosmotic mannitol on vascular smooth muscle contractile responses was examined in isolated arterial preparations. Vasoconstrictor effects of norepinephrine (NE) and potassium chloride (K+) in the perfused central artery of the rabbit's ear and in perfused mesenteric arteries of cats were significantly inhibited by infusion with Krebs bicarbonate solution made hyperosmotic with mannitol (50–200 mosM increase). Similarly, the magnitude and duration of vasoconstrictor responses to transmural stimulation of the central ear artery of the rabbit were decreased by hyperosmotic mannitol (50 mosM). Mannitol (50 mosM) produced a decrease in perfusion pressure when perfusion pressure was maintained at an increased level by K+ (60 mM). Mannitol-induced vasodilatation was not affected by ethacrynic acid (1.5 X 10(-5) M), beta adrenergic blockade or by the development of tachyphylaxis to the vasodilator effects of nitroglycerin. The concentration of cyclic adenosine-monophosphate was not changed by mannitol. Isotonic mannitol also inhibited NE-induced contractile responses. These data indicate that hyperosmotic mannitol produces vasodilatation in isolated arterial smooth muscle by a mechanism(s) that appears dissimilar from that of several other vasodilator substances and suggest that hypertonicity may not be the only factor involved in the vasodilator effect of mannitol.
Elevated systolic pressure following chronic low-level cadmiun feeding
Authors: Perry H. M. , Erlanger M. , Perry E. F.
Published: December 2017

Groups of 16 female Long-Evans rats received 0, 1, 2.5, 5, 10, 25, and 50 mg cadmium/liter dringking water (parts per million (ppm)), from the time they were weaned until they were 30 mo old. Systolic pressure was measured indirectly in triplicate at 6-mo intervals. Both 2.5 and 5 ppm cadmium consistently induced significant elevations in mean systolic pressure, ranging from 13 to 33 mmHg. At 6 mo, 10 and 25 ppm cadmium also induced significant elevations, whereas at 12 mo and subsequently 1 ppm cadmium induced significant elevations. With 10 ppm cadmium or less weight gain was normal and there was no evidence of cadmium toxicity. With 25 and 50 ppm cadmium weight gain was diminished, suggesting toxicity. Five rats with each level of exposure were sacrificed every 6 mo from a second population of similarly handled rats in order to determine renal cadmium concetrations. Cadmium intakes that had induced hypertension were associated with mean renal cadmium concentrations ranging from 5 to 50 mug/g kidney.
Evidence for the presence of adrenergic receptors in 3-day-old chick embryo
Authors: Petery L. B. , Van Mierop L. H.
Published: December 2017

Effects of sympathomimetic amines without and with alpha and beta-adrenergic blocking agents on the heart rate and arterial and venous blood pressures in the 3-day-old chick embryo were studied. No chronotropic effect was observed. Norepinephrine caused a biphasic change in systolic and diastolic arterial pressures, the lower doses effecting a fall, and the higher doses a rise in these pressures. With phenylephrine a sharp rise in systolic, diastolic, and pulse pressures was seen. Isoproterenol caused a dramatic fall in systolic, diastolic, and pulse pressures. In the presence of phenoxybenzamine, the pressor effect of high doses of norepinephrine was reversed, the pressor effect of phenylephrine was abolished, and the hypotension with isoproterenol was enhanced. After propranolol, the hypotensive effect of low doses of norepinephrine was reversed, the pressor response to phenylephrine was unchanged, and the depressor effect of isoproterenol was abolished. These findings suggest the presence of functioning alpha- and beta-receptors in the 3-day-old chick embryo. Additionally, they suggest that the alpha-receptors develop more slowly in the chick embryo.
Actions of bradykinin on isolated cerebral and peripheral arteries
Authors: Toda N.
Published: December 2017

The addition of bradykinin (BK) caused a dose-related contraction in helical strips of canine cerebral, internal carotid, external carotid, and femoral arteries, while the peptide elicited a relaxation in canine coronary, renal, and mesenteric arteries contracted with 5+ or prostaglandin F2alpha. In contrast to canine cerebral arteries, human cerebral arteries contracted with K+ or prostaglandin relaxed with BK. Contractile responses of canine cerebral arteries to BK were not influenced by phentolamine, diphenhydramine, and methysergide, but were attenuated by aspirin and indomethacin. Contractions induced by K+ were not or only slightly inhibited by these anti-inflammatory agents. Polyphloretin phosphate failed to reduce BK-induced contractions. Relaxing effects of BK on canine coronary arterial strips were not altered by atropine, propranolol, metiamide, and aminophylline, but were inhibited by aspirin and indomethacin. Adenosine-induced relaxation was unaffected by the latter two agents. It may be concluded that adrenergic, cholinergic, histaminergic, and adenosine-related mechanisms are not involved in the genesis of BK-induced contraction and relaxation. Contractile responses of canine cerebral arteries to BK do not appear to derive from prostaglandins released, but rather from a direct action on vascular smooth muscle cells.
An analysis of interstitial fluid pressure in the web of the bat wing
Authors: Salathe E. P.
Published: December 2017

A mathematical theory of interstitial fluid motion and capillary exchange is developed in order to understand and explain measurements of capillary and interstitial fluid pressure in the bat wing, in which a high degree of vasomotor activity occurs. As a result of precapillary sphincter activity, fluid is alternately filtered and reabsorbed from the capillary, and previous studies of related steady problems by the author suggest that the interstitial fluid pressure should oscillate with time. Wiederhielm and Weston did not observe such fluctuations when they measured tissue pressures near the capillaries. This apparent paradox is resolved in the present paper by including unsteady effects. It is shown that pressure oscillations are predicted, but because of the very high vasomotor frequency they die out within a very short distance from the capillary wall. The capillary pressure measurements of Wiederhielm and Weston are also explained in terms of precapillary sphincter activity.
Cardiovascular effects of radioactive microsphere suspensions and Tween 80 solutions
Authors: Millard R. W. , Baig H. , Vatner S. F.
Published: December 2017

The cardiovascular effects of two concentrations of Tween 80 (polyoxyethylene sorbitan mono-oleate), a surface-active agent commonly used to prevent aggregation of radionuclide-labeled microspheres, were examined in conscious dogs. Two types of adverse reactions were noted. The first (Type A) consisted of reductions in cardiac dimensions as well as hypotension and tachycardia. The second (Type B) was less severe and involved only a decrease in cardiac dimensions with no change in left ventricular systolic pressure or heart rate. A 10% dextran solution with .05 +/- .02% Tween 80 injected into the left atrium caused systemic and/or cardiac alterations in all four dogs studied. Administration of a lower concentration of Tween 80 (0.01 +/- 0.005%), which was the minimum concentration necessary to prevent aggregation of microspheres, induced adverse reactions in 6 of 41 dogs studied. Subsequent administration of this concentration of Tween 80 on the same day rarely induced adverse reactions. Thus, care must be exercised in application of microsphere techniques to organ blood flow measurements when Tween 80 is used to prevent microsphere aggregation, since this surface-active agent causes profound alterations in cardiac dynamics in concentrations normally employed in experiments involving microsphere techniques.
Selective coronary embolization in closed-chest dogs
Authors: Chagrasulis R. W. , Downey J. M.
Published: December 2017

A method is described for occluding a branch of the canine left coronary arterial system, without the use of X-ray equipment or the need for a surgical thoracotomy. For the creation of experimental myocardial infarction, either a solid embolus or a diffusible medium is introduced into the coronary vessels via a rigid cannula which is inserted through a carotid artery. This technique produces infarcts of reproducible size with a minimum of equipment and surgical complication.
Bone extraction and blood clearance of diphosphonate in the dog
Authors: Hughes S. P. , Davies D. R. , Bassingthwaighte J. B. , Knox F. G. , Kelly P. J.
Published: December 2017

The transcapillary extraction of diphosphonate, as [99mTc]EHDP, a substance used in bone scanning and for management of certain metabolic bone diseases, has been examined. The maximum instantaneous extraction for [99mTc]EHDP was 0.27 +/- 0.05 (mean +/- SD, N = 10) and the net extraction at 5 min was 0.18 +/- 0.05 (N = 10). The permeability ratio of [99mTc]EHDP to the freely diffusible compound, sucrose, using the formula PS = -Fs loge (1 - Emax), was 0.71. This is similar to the ratio of diffusion coefficients of EHDP to sucrose, which is estimated to be 0.78. These results suggest that the mechanism by which [99mTc]EHDP passes through the capillaries in bone is passive diffusion. Tissue level estimations of EHDP confirm a rapid blood clearance associated with an increase in the rate of urinary excretion; the level of [99mTc]EHDP in bone, however, remains constant. The fractional excretion of [99mTc]EHDP was 27.3 +/- 2.0% in control dogs and was unchanged by thyroparathyroidectomy and subsequent infusion of parathyroid hormone.
A new method for internal calibration of left ventricular cineangiography
Authors: Laks M. M. , Garner D. , Beazell J. , Piscatelli J.
Published: December 2017

Previous methods of internal calibration for cineangiography have made use of reference objects such as catheters or wires of known length or diameter. Such devices have either insufficient X-ray resolution, or require a specific orientation within the ventricle which is difficult to confirm. External calibration methods, while eliminating these errors, can only estimate actual position of the left ventricle. The use of a Swan-Ganz balloon catheter as a calibration object diminishes these problems. When positioned within the left ventrical and filled with a radiopaque medium, the balloon is of sufficient size and density to avoid errors induced by previously employed objects. The inflated balloon geometry is simple and reproducible. The use of this internal calibration catheter markedly diminishes major sources of errors in the determination of ventriculograms for both dogs and humans.
Myocardial mechanics and energetics in experimental iron-deficiency anemia
Authors: Levine H. J. , Wolk M. J. , Keefe J. F. , Bing O. H. , Snow J. A. , Messer J. V.
Published: December 2017

The effect of iron-deficiency anemia on myocardial mechanics and energetics was studied in 10 anesthetized bealge puppies. Nine littermates served as controls. Left ventricular/body weight ratio was increased 14.2% (P less than 0.05) and cardiac index 36.5% (P less than 0.02) in the anemic puppies. Heart rate, mean systolic pressure, myocardial lactate extraction coefficient, and lactic dehydrogenase isozymes were similar in both groups. Contractile state measured in vivo (pressure-velocity curves) and in isolated muscles (isotonic force-velocity curves) was virtually identical in the littermate groups. Despite markedly increased coronary blood flow in the anemia animals, oxygen consumption per unit weight of myocardium was the same in both groups. Contractile element efficiency averaged 18.3% in 10 adult mongrel dogs studied in a similar fashion and was 27.1% and 39.8% in the normal puppies and anemic puppies, respectively. The oxygen cost of internal or force-generating work was similar among the three groups of dogs. It is concluded that the volume load produced by iron-deficiency anemia was associated with a normal contractile state, normal unit myocardial oxygen consumption, no evidence of chronic anaerobiosis, and a high contractile element efficiency, perhaps as a consequence of increased diastolic fiber stretch.
Fibrinogen synthesis stimulation by prostaglandin E1 and some other vasodilators
Authors: Carlson T. H. , Fradl D. C. , Leonard B. D. , Wentland S. H. , Reeve E. B.
Published: December 2017

Three-hour constant-rate intravenous infusion into rabbits of 1-3 mg prostaglandin E1 (PGE1) per kilogram markedly increased plasma fibrinogen 24 h later. 131I-labeled fibrinogen and model studies showed increased synthesis underlay this. Similar PGE1 doses lowered systolic blood pressure. Maintaining systolic blood pressure by infusing noradrenaline with the PGE1 did not alter plasma fibrinogen response to PGE1; plasma fibrinogen was unchanged by noradrenaline infusion. Regression equations relating plasma fibrinogen increment to PGE1 dose, plasma fibrinogen increment to dose and systolic blood pressure change, and systolic blood pressure change to dose are given as well as the constants relating plasma fibrinogen increment to dose using the Michaelis-Menten equation. Infusions of cyclic AMP, dibutyryl cyclic AMP, and cyclic GMP intravenously led to only small plasma fibrinogen increases. Daily intravenous infusions of PGE1 led to loss of both plasma fibrinogen and systolic blood pressure responses in two animals; a third animal showed only loss of the former and a fourth only loss of the latter response. PGE1 slightly enhanced the small plasma fibrinogen increase following intravenous bradykinin. Approximate arterial blood PGE1 concentrations resulting from the intravenous infusion of 1 mg mg PGE1 kg-1 3 h-1 are calculated. These are compared with measured values.
Action of adenosine and adenine nucleotides on dogs' isolated veins
Authors: Verhaeghe R. H.
Published: December 2017

Adenosine depressed norepinephrine contractions of dogs' saphenous vein strips in both the presence and the absence of Ca2+ and after inhibition of calcium influx by verapamil. It antagonized noncompetitively contractions induced by Ca2+ in depolarized strips after alpha-adrenergic blockade. Contractions obtained with acetylcholine were also depressed by adenosine. This depression was not accompanied by an increase in cAMP or a decrease in the elevated cGMP level. Thus the depression of the smooth muscle cell reactivity still occurs in the absence of calcium influx and is not mediated by the cyclic 3',5'-nucleotide system. Adenosine diphosphate and triphosphate, but not adenosine (10(-6) to 10(-4) M), increased the basal tension of resting saphenous strips. This was prevented by removal of calcium from the bath. In contracted strips, lower concentrations of both nucleotides (10(-6) to 10(-5) M) caused relaxation whereas with high concentrations (10(-4) to 10(-3) M) further contraction occurred. Thus, unlike adenosine, the adenine nucleotides facilitate calcium influx.
Capillary lengths, anastomoses, and estimated capillary transit times in skeletal muscle
Authors: Honig C. R. , Feldstein M. L. , Frierson J. L.
Published: December 2017

Total capillary length, capillary segment length, and number of anastomoses per capillary were measured in rat gracilis muscle at rest and after 2 min of phasic contraction. Mean values of the foregoing variables at rest (+/-SD) were, respectively, 1,012 micronm +/- 484, 409 micron +/- 274, and 0.83 +/- 1.09. Total capillary lengths are well described by the gamma distribution, number of anastomoses by the negative binomial distribution, and segment length by the Weibull distribution. Contraction has no significant effect on the means or the frequency distributions, indicating that: 1) pressure gradients between adjacent capillaries are small, and 2) intercapillary anastomoses do not improve flow distribution in exercise. Erythrocyte velocities observed in resting muscle (Burton, K. S., and P. C. Johnson. Am J. Physiol. 223: 517-524, 1972) were shown to be adequately characterized by the gamma distribution. From these velocities and the observed distribution of path lengths, we computed an estimated distribution of capillary transit times. Mean transit time was 4.29 s. The median was 2.45 s, and 11% of values exceeded 8 s. The range was 90 ms-43 s. This heterogeneity of transit times should profoundly affect calculations of O2 transport and the shape of indicator dilution curves.
Zero offset in electromagnetic flowmeters
Authors: Montgomery G. D. , Scher A. M. , Corbin L. V.
Published: December 2017

In electromagnetic square-wave flowmeters, it should be theoretically possible to determine zero flow by turning off the magnet drive. In actuality, this is not possible. A major source of zero offset in many commercial flowmeters lies in the fact that the very large voltage transients, seen as the flowmeter drive switches polarity, are distorted by the input amplifiers. This can be corrected by improved amplifier design. A second source of zero offset when flow probes have been immersed in conducting fluids is resistive leakage between the drive voltage and the input electrodes. This can be minimized through the use of shielded coils, with shield grounded, and by the use of a magnet drive isolated from ground. If both of these sources of zero offset are corrected, offset is greatly reduced. Polarization of the flowmeter electrodes, which has previously been suggested as a cause of zero offset, was not detected.
Intraperitoneal pressure in formation and reabsorption of ascites in cats
Authors: Zink J. , Greenway C. V.
Published: December 2017

The rate of ascites formation or reabsorption was recorded in anesthetized cats using the technique of intraperitoneal plethysmography. Hepatic venous pressure was increased using an extracorporeal circuit to drain effluent blood from the liver. When the intraperitoneal pressure was set to zero, elevation of hepatic venous pressure increased portal pressure and produced a constant rate of ascites formation. However, equivalent increments of portal pressure without elevation of hepatic venous pressure did not cause ascites formation, indicating that the liver was the source of ascites when hepatic venous pressure was increased. The rate of ascites formation was proportional to hepatic venous pressure, but elevation of the intraperitoneal pressure reduced the transsinusoidal pressure gradient responsible for fluid filtration from the liver. Although this reduced the rate of ascites formation, a secondary effect partly opposed this reduction in filtration rate. From this study and from previous work, there are now quantitative data showing that the intraperitoneal pressure is an important factor which accelerates the rate of reabsorption and decreases the rate of formation of ascites to bring these processes into equilibrium.
Dependence of reactive hyperemia in skeletal muscle on oxygen tension
Authors: Tuma R. F. , Lindbom L. , Arfors K. E.
Published: December 2017

Red blood cell velocity was measured in capillaries of the rabbit tenuissimus muscle during exposure to a low-oxygen-tension (PO2 = 5 mmHg) and a high-oxygen-tension (room-air PO2 = 150 mmHg) suffusion solution. Control capillary red blood cell velocity was significantly reduced (44%) by elevating the suffusion solution PO2 from 5 to 150 mmHg. The reactive hyperemias that occurred after a 120-s aortic occlusion under these two conditions were compared. The mean RBC velocity during the hyperemia in the 1st min following the removal of occlusion was significantly reduced by increasing oxygen tension, as was the duration of the hyperemia. Peak capillary red blood cell velocities in the hyperemic phase during exposures to low and high PO2 were not significantly different. It can be concluded from this study that although oxygen tension does affect postocclusive reactive hyperemia, other factors such as myogenically induced vascular relaxation also contribute to the production of this phenomenon.
A microscope-television system for studying flow velocity in human skin capillaries
Authors: Fagrell B. , Fronek A. , Intaglietta M.
Published: December 2017

A noninvasive technique for studying blood flow dynamics in human skin capillaries is described. A light microscope combined with a closed-circuit TV system was used to monitor and record capillary blood flow velocity on video tape. Arterial pulsations were recorded plethysmographically and converted into video signals by modulating the position of a square, white area in the televised scene. Twelve healthy subjects were studied. The mean (+/- SD) resting capillary blood flow velocity was 0.65 +/- 0.3 mm/s at an average skin temperature of 30.4 +/- 2.3 degrees C. Spontaneous fluctuations at a frequency of 6-10 cycles/min were observed in most subjects. A well-pronounced flow pulsatile component could be demonstrated in all capillaries studied. The technique can be used in clinical practice for studying the physiology and pathophysiology of cutaneous microcirculation in man. It can be expected that the method may become an important diagnostic tool in diseases that involve disturbances of the microcirculation, such as diabetes, hypertension, and atherosclerosis.