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Biomedical subjects

R W Mitchell

Publications and source records attributed to R W Mitchell.

At least 55 records · Page 3Linked to original sources
PubMed1991

Effect of maturation on topographic distribution of bronchoconstrictor responses in large diameter airways of young swine.

We studied the effect of maturation on the topographic distribution of airway constriction in Generations 0 (trachea) through 6 in fourteen 2-wk-old swine (2ws) and sixteen 10-wk-old swine (10ws) in vivo and in excised airways from seven 2ws and seven 10ws in vitro. Animals were anesthetized with chloralose-urethane and received beta-adrenergic blockade and vagotomy prior to generation of random-order, dose-response curves with i.v. methacholine (MCh) and histamine (His) or serotonin (5HT) given intravenously. Lung resistance (RL) was measured, and airway diameter was assessed by tantalum bronchograms obtained at functional residual capacity for each dose of agonist. Baseline RL was substantially greater in 2ws (48 to 62 cm H2O/L/s) than in 10ws (9 to 11 cm H2O/L/s; p less than 0.001 for all groups). Intravenous infusion of 10(-6) mol/kg MCh caused a 416 +/- 110% increase in RL in 2 ws and a 314 +/- 32% increase in RL in 10 ws (p = NS); airway diameter (Daw) decreased by 10 +/- 1% (Generation 2) to 27 +/- 4% (Generation 6) in 2ws and from 8 +/- 2 (Generation 2) to 17 +/- 4% in 10ws. Intravenous infusion of 10(-6) mol/kg His caused a 513 +/- 85% increase in RL in 2ws and a 276 +/- 17% increase in RL in 10 ws (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1991

Reduced activity of acetylcholinesterase in canine tracheal smooth muscle homogenates after active immune-sensitization.

Previous investigations have suggested that immune-sensitization increases airway smooth muscle responsiveness to cholinomimetic stimulation by reducing the rate of degradation of acetylcholine. To examine the hypothesis that increased cholinomimetic responsiveness of tracheal smooth muscle (TSM) caused by immune-sensitization results from inhibition of acetylcholinesterase (AChase) activity, we developed a method for direct measurement of AChase activity in homogenates of TSM obtained from mongrel dogs actively sensitized in vivo to ragweed pollen extract (n = 7) and sham-sensitized littermate controls (n = 7). For both sensitized and control specimens, saturation of AChase was obtained at approximately 3.12 mM substrate (acetylthiocholine); however, maximal enzyme activity in homogenates of ragweed-sensitized tissues was significantly less (0.862 +/- 0.088 absorbance units/min/mg protein [AU/min/mg]) compared to control homogenates (1.590 +/- 0.129 AU/min/mg; P less than 0.001). Kinetic analysis (Eadie-Hofstee plot) indicated similar Michaelis constants (Km) for AChase from ragweed-sensitized (0.360 +/- 0.063) and control (0.336 +/- 0.062) homogenates (P = NS). The concentration of physostigmine eliciting half-maximal inhibition (Ki) of AChase activity also was similar for tissues from sensitized (-7.92 +/- 0.032 log M) and control animals (-7.86 +/- 0.012 log M; P = NS). Pretreatment with selected mediators of anaphylaxis (10(-4) M histamine, 10(-6) M serotonin, 10(-5) M prostaglandin E2, 10(-6) M prostaglandin F2 alpha, and 10(-7) M leukotriene D4) did not affect AChase activity. Our data demonstrate reduced AChase activity in homogenates of canine TSM after active immune-sensitization in vivo. This corresponds to functional augmentation of cholinomimetic contraction in actively sensitized tissues.

Acetylcholinesterase↗
PubMed1990

Maturation of acetylcholinesterase expression in tracheal smooth muscle contraction.

We examined postganglionic development of acetylcholinesterase (AChase) activity and tracheal smooth muscle (TSM) contraction elicited by cholinomimetic activation and electrical field depolarization in vitro. Epithelium-intact tracheal strips excised from 21 2-wk-old swine (2ws) and 19 10-wk-old swine (10ws) were tethered isometrically at optimal resting length, and responses were expressed as percent of the maximum to 63 mM potassium-chloride (%KCl). Cumulative concentration-response curves to KCl were equivalent for TSM from 2 and 10ws. However, maximal contraction to ACh in 2ws (168 +/- 8.4 %KCl) was greater than for 10ws (142 +/- 2.3 %KCl; P less than 0.02). Stimulus-response curves (field electrodes; AC source) demonstrated greater sensitivity for TSM in 10ws (stimulus causing 50% of the maximal response = 3.32 +/- 0.13 V in 2ws vs. 2.25 +/- 0.12 V in 10ws; P less than 0.001), indicating that the greater cholinomimetic responsiveness of 2ws did not result from augmented presynaptic nerve conduction. The AChase inhibitor, physostigmine, caused 1) greater sensitivity of responses elicited by electrical field stimulation in 2ws (P less than 0.05) but not in 10ws (P = NS), 2) augmentation of maximal responses to exogenous ACh in 10ws (27% increase; P less than 0.01) but not 2ws (2% increase; P = NS), and 3) a greater increase in sensitivity to cholinomimetic activation in 2ws compared with 10ws (P less than 0.02). These data demonstrate increased cholinergic contraction of TSM in 2 vs. 10ws that results at least in part from reduced AChase activity in the trachea of immature animals.

Acetylcholine↗
PubMed1990

Endotoxin in vivo impairs endothelium-dependent relaxation of canine arteries in vitro.

We studied the effect of endotoxin administration in vivo on arterial smooth muscle responses in vitro, testing the hypotheses that endotoxin augments adrenergic vasoconstriction and impairs endothelium-dependent vascular relaxation. Ten mongrel dogs were anesthetized and mechanically ventilated. Five received a bolus infusion of Escherichia coli endotoxin (5 mg/kg), and the remainder received a sham infusion. After 4 to 5 h, the anesthetized dogs were rapidly exsanguinated, and femoral, renal, and superior mesenteric arteries were removed. Arterial rings were mounted on force transducers in organ baths; contraction to phenylephrine or potassium-substituted Krebs-Henseleit solution (KCl), and relaxation to nitroprusside or acetylcholine were studied. Smooth muscle contractions to phenylephrine or KCl were similar between sham and endotoxin for each agonist. Also, nitroprusside-elicited relaxation from half-maximal phenylephrine-elicited contraction was similar. However, relaxation elicited by acetylcholine was markedly impaired in vessels from endotoxin-treated dogs. The negative log molar concentration of acetylcholine producing 50% relaxation for femoral arteries was 7.38 +/- 0.11 (endotoxin) versus 8.09 +/- 0.12 (control, p = 0.002), for renal arteries it was 6.71 +/- 0.33 (endotoxin) versus 7.81 +/- 0.18 (control, p = 0.019), and for mesenteric arteries it was 7.27 +/- 0.03 (endotoxin) versus 7.95 +/- 0.15 (control, p = 0.002). These results demonstrate that endotoxin treatment impairs endothelium-dependent relaxation of canine arteries in vitro. The data suggest that vascular changes in endotoxemia are accompanied by alteration in endothelial cell function, perhaps through altered endothelial production of vasodilatory mediators.

Acetylcholine↗
PubMed1989

Effects on the lower oesophageal sphincter of cisapride given before the combined administration of atropine and neostigmine.

Twenty healthy female patients undergoing laparoscopy were allocated randomly to receive either cisapride 10 mg i.v. in 5% dextrose 20 ml or placebo 15 min before antagonism of residual neuromuscular blockade with atropine 1.2 mg and neostigmine 2.5 mg. Barrier pressure (BrP = lower oesophageal sphincter (LOS) pressure minus gastric pressure) increased significantly (by 25%) following cisapride, but not placebo, within 10 min of injection; following the combined administration of atropine and neostigmine, there was an abrupt decrease in mean BrP in the cisapride group from 37.0 (SEM 4.5) cm H2O to 24.1 (3.2) cm H2O (P less than 0.01) and in the control group from 26.6 (4.8) cm H2O to 19.9 (3.1) cm H2O (P less than 0.05) 2 min after injection. Subsequently, there was a small increase in BrP to values not significantly lower than control measurements. Thus the administration of cisapride before antagonism of neuromuscular blockade with atropine and neostigmine failed to block the adverse effect of atropine on the LOS.

Adult↗
PubMed1989

Ca2+-dependent facilitated shortening in isotonic contraction of trachealis muscle.

We compared isotonic shortening with isometric force generation as a function of external Ca2+ in 166 tracheal smooth muscle (TSM) strips from 27 mongrel dogs in vitro. Concentration-response curves were generated with muscarinic stimulation (acetylcholine, ACh), alpha-adrenergic receptor activation (norepinephrine after beta-adrenoceptor blockade, NE), serotonin (5-HT), and KCl-substituted Krebs-Henseleit solution. The concentrations of 5-HT causing half-maximal shortening (ECS50, 1.54 +/- 0.14 X 10(-7) M) and half-maximal active isometric tension (ECT50, 1.72 +/- 0.30 X 10(-7) M) were similar (P = NS). Likewise, ECS50 (21.9 +/- 0.7 mM) and ECT50, (22.0 +/- 0.9 mM) were similar for KCl. In contrast, facilitated isotonic shortening (i.e., greater isotonic shortening for comparable degrees of force generation) was elicited with ACh and NE for all levels of force generation between 15 and 85% of maximum and for all concentrations of ACh from 3 X 10(-8) to 3 X 10(-5) M (P less than 0.05 for all points). Facilitated isotonic shortening also was elicited for all concentrations of NE from 10(-8) to 10(-6) M (P less than 0.05 for all points). Removal of Ca2+ from the perfusate substantially reduced the potency of ACh (P less than 0.001) and abolished differences between ECS50 (2.23 +/- 0.28 X 10(-5) M) and ECT50 (2.50 +/- 0.46 X 10(-5) M, P = NS). We demonstrate that for comparable degrees of force generation, muscarinic and alpha-adrenergic receptor activation cause greater isotonic shortening than KCl or 5-HT and that this facilitated shortening is associated with the concentration of external Ca2+.

Acetylcholine↗
PubMed1989

Expression of airway contractile properties and acetylcholinesterase activity in swine.

We studied the effect of maturation on contractile properties of tracheal smooth muscle from seventeen 2-wk-old swine (2ws) and fifteen 10-wk-old swine (10ws) in situ and in vitro. The response to parasympathetic stimulation was studied in situ in isometrically fixed segments. Contraction was elicited at lower frequencies [half-maximal response to electrical stimulation (ES50) = 6.7 +/- 0.05 Hz] in 2ws than in 10ws (ES50 = 9.1 +/- 0.4 Hz; P less than 0.01). Despite substantial differences in morphometrically normalized cross-sectional area in 2ws (0.012 +/- 0.003 cm2) and 10ws (0.028 +/- 0.001 cm2; P less than 0.01), maximal active tension elicited by parasympathetic stimulation was similar (12.4 +/- 3.2 g/cm in 2ws vs. 13.3 +/- 2.3 g/cm in 10ws; P = NS). In separate in vitro studies in 25 tracheal smooth muscle strips from 10 swine, concentration-response curves generated with potassium-substituted Krebs solution (KCl) were similar in 2ws and 10ws. In 58 other strips (10 swine), maximal active force elicited with acetylcholine (ACh) in 2ws was significantly greater than for 10ws (P less than 0.001). Removal of the epithelium had no effect. However, cholinesterase inhibition with 10(-7) M physostigmine augmented the response to ACh in 10ws (P less than 0.02) but not 2ws. We demonstrate increased force generation and sensitivity to vagal stimulation in 2ws vs. 10ws, which corresponds to increased reactivity to ACh in vitro. The relative hyperresponsiveness in 2ws is specific for cholinergic response and is attenuated at least in part by maturation of the activity of acetylcholinesterase enzyme.

Acetylcholinesterase↗
PubMed1989

Beta-adrenergic relaxation of dog trachealis: contractile agonist-specific interaction.

The phenomenon of contractile agonist-dependent relaxation by isoproterenol (ISO) of active tension elicited by acetylcholine (ACh), histamine (HIS), serotonin (5-HT), and potassium chloride-substituted Krebs-Henseleit solution (KCl) was studied in 210 tracheal smooth muscle (TSM) strips from 28 mongrel dogs in vitro. All TSM strips were contracted to similar active tensions [target tension (TT) = 50% of the maximal active tension elicited by 127 mM KCl] with ACh, HIS, 5-HT, or KCl and relaxed with either ISO, forskolin (FSK), N6,2'-O-dibutyryladenosine 3',5'-cyclic monophosphate (db-cAMP), or 3-isobutyl-1-methylxanthine (IMX). The concentrations of ISO causing 50% relaxation from TT (RC50) were ACh (2.9 +/- 1.1 x 10(-6) M) greater than 5-HT (8.4 +/- 1.5 x 10(-8) M) approximately KCl (8.1 +/- 2.1 x 10(-8) M) greater than HIS (1.6 +/- 0.2 x 10(-8) M). FSK and IMX relaxed TSM in the same rank order of potency as ISO. In contrast to the contractile agonist-dependent relaxation elicited by ISO, FSK, and IMX, db-cAMP was nearly equipotent in relaxing similarly contracted strips. These results are consistent with contractile agonist-specific interaction with cAMP production by ISO and FSK. These data demonstrate that the phenomenon of contractile agonist-dependent relaxation by ISO is not related specifically to the beta-adrenoceptor.

1-Methyl-3-isobutylxanthine↗
PubMed1988

Maternal serum alpha-fetoprotein levels in ectopic pregnancy. A prospective study.

Serum alpha-fetoprotein estimations were performed in 38 cases of ruptured or leaking ectopic pregnancy and 7 cases of ruptured, haemorrhagic corpus luteum cyst. A wide range of values was obtained, but in ectopic pregnancies, 65% of values were above the median range for each respective week of pregnancy. In 11 patients (29%), serum alpha-fetoprotein values were 2.5 times the median. In 13 patients values were within or below the normal range. The study demonstrated that in most cases of ruptured or leaking ectopic pregnancies serum alpha-fetoprotein values were significantly raised. A smaller subgroup of patients may show very low alpha-fetoprotein values in maternal serum.

Female↗
PubMed1988

Continuous extradural infusion of 0.125% bupivacaine for pain relief after lower abdominal surgery.

Twenty women, undergoing lower abdominal surgery, were allocated randomly to receive a continuous extradural infusion of either 0.125% bupivacaine or placebo at a rate of 15 ml h-1. All had received an intra-operative extradural block. Pain scores were recorded at 30, 60, 90, 120, 150, 180, 240 and 360 min after surgery. From 150 min onwards there was a significant benefit for those receiving the active drug. Six of nine patients in this group had adequate analgesia over the 6-h study period, while all patients in the placebo group required further pain relief.

Abdomen↗
PubMed1988

Effects of posture and baricity on spinal anaesthesia with 0.5% bupivacaine 5 ml. A double-blind study.

In four groups of 10 patients, 0.5% bupivacaine 5 ml was used in spinal anaesthesia for gynaecological surgery. Group 1 received plain solution in the sitting position, group 2 plain solution in the lateral position, group 3 hyperbaric solution in the sitting position and group 4 hyperbaric solution in the lateral position. All patients were returned to the horizontal supine position, the sitting subjects 2 min after, and the lateral subjects immediately after, spinal injection. In each group the mean height of block was to the mid-thoracic segments, but there was no significant difference between the groups. There was, however, considerable scatter within each group. Posture had some effect on the speed of onset of the analgesia, but no significant effect on the final outcome. The use of 0.5% bupivacaine as a test dose in extradural blockade is discussed.

Adult↗
PubMed1988

The lower oesophageal sphincter in the first trimester of pregnancy: comparison of supine with lithotomy positions.

Measurement were made of gastric pressure (GP), lower oesophageal sphincter pressure (LOSP) and barrier pressure (BrP) in the supine and lithotomy positions in 17 healthy women undergoing termination of pregnancy in the first trimester. Values in the supine position were similar to those seen in non-pregnant subjects, but there was a significant reduction in LOSP and BrP in the lithotomy position unrelated to any change in intragastric pressure. It is concluded that the lithotomy position is associated with increased risk of regurgitation in early pregnancy.

Adolescent↗
PubMed1988

Effects of beta-adrenoceptor antagonism on the cardiovascular and catecholamine responses to tracheal intubation.

The catecholamine and cardiovascular responses to laryngoscopy and tracheal intubation were studied in 20 patients who underwent elective gynaecological surgery and who were allocated randomly to receive either practolol 10 mg or saline intravenously prior to induction of anaesthesia. Anaesthesia was induced with fentanyl and thiopentone; atracurium was administered and the lungs were ventilated artificially with 67% nitrous oxide in oxygen. Tracheal intubation was performed when muscle relaxation was adequate. Arterial pressure, heart rate, plasma noradrenaline and adrenaline concentrations were measured before and after tracheal intubation. A significant increase in catecholamine concentrations occurred in both groups in response to tracheal intubation but the magnitude of the increase in adrenaline was greater in the practolol group. There were no significant differences in arterial pressure or heart rate changes between the groups. We conclude that pretreatment with practolol is of no value in the attenuation of the hypertensive response to direct laryngoscopy and tracheal intubation in previously normotensive patients.

Adult↗
PubMed1988

Antagonism of relaxation to isoproterenol caused by agonist interactions.

The interaction of contractile agonists on the relaxation elicited with isoproterenol (ISO) was studied in 112 tracheal smooth muscle (TSM) strips from 20 dogs in vitro. Strips were contracted to the same active target tension (TT) with acetylcholine (ACh), histamine (HIS), serotonin (5-hydroxytryptamine, 5-HT), potassium chloride (KCl), or the combinations of ACh + HIS, ACh + 5-HT, HIS + KCl, HIS + 5-HT (50% TT from each agonist). Although a less potent agonist, adding HIS to cause 50% of the TT reduced the concentration of ACh to elicit the remaining 50% TT and substantially altered relaxation by ISO compared with HIS alone [concentration required to achieve 50% relaxation (RC50) = 9.2 +/- 2.4 X 10(-8) vs. 9.0 +/- 4.4 X 10(-9) M to HIS alone; P less than 0.003]. Relaxation for TSM strips contracted with ACh + HIS was comparable to that elicited from the same TT with ACh alone, although concentrations required in combination were lower than for either agonist alone. Trachealis strips contracted equivalently with KCl + HIS also had augmented contraction and attenuated relaxation (RC50 = 3.7 +/- 0.8 X 10(-8) M; P less than 0.015 vs. HIS alone). However, combinations of 5-HT + ACh and 5-HT + HIS did not alter relaxation to ISO from that elicited by the weaker agonist alone. We demonstrate that TSM relaxation depends on the combination of agonists eliciting contraction and may be inhibited substantially by interactions among contractile agonists.

Acetylcholine↗
PubMed1987

Local parasympathetic mechanisms for ragweed-sensitized canine trachealis hyperresponsiveness.

Previous studies from our laboratory showed an atropine-sensitive component in the hyperresponsiveness of ragweed-sensitized canine tracheal smooth muscle (TSM) in vitro to histamine and potassium. The present studies were undertaken to elucidate the nature of the parasympathetic element in this hyperresponsiveness. TSM strips were dissected from ragweed-sensitized and littermate control dogs and their isometric force generation was measured in vitro. Mechanical responses of sensitized TSM were characterized by hyperreactivity (upward shift of the dose-response relationship) to acetylcholine (ACh), atropine-sensitive spontaneous base line activity and prolonged isometric force plateaus. Control TSM did not contract spontaneously and basal tone was maintained passively. However, eserine could produce spontaneous base-line activity and prolonged isometric force plateau in control TSM that mimicked that observed naturally in sensitized TSM. Sensitized TSM was supersensitive (leftward shift of the dose-response relationship) to ACh and electrical field stimulation, and showed a significant leftward shift of the threshold dose to carbamylcholine (carbachol). However, sensitized and control TSMs were equally reactive to carbachol at doses of 10(-8) M and greater. Also, ACh dose-response curves of sensitized and control TSMs in the presence of the cholinesterase inhibitor eserine (10(-8) M) showed no significant differences in sensitivity or reactivity. These results were consistent with a role for local parasympathetic mechanisms such as altered ACh release and/or breakdown in the hyperresponsiveness of ragweed-sensitized canine TSM.

Acetylcholine↗