Biomedical subjects

M A Murray

Publications and source records attributed to M A Murray.

At least 19 recordsLinked to original sources

PubMed1992

Guidepost cells.

Guidepost cells, as classically defined in the grasshopper embryo have only rarely been found in other systems. If the concept of guidepost cells is expanded, recognizing that any special role of specific cells in axon guidance is a function of the entire landscape in which axons are growing, and that growth cone--guidepost interactions may share mechanisms with many other cell--cell interactions, then numerous examples are found in both the peripheral and central nervous systems of many species.

Animals↗

PubMed1992

Potassium channel activators and bronchial asthma.

The cromakalim-like KCOs relax airways smooth muscle by an action that is associated with the opening of plasmalemmal K(+)-channels. The K(+)-channel involved may be analogous to the ATP-sensitive K(+)-channel identified in pancreatic beta-cells. It is unlikely to be open under normal circumstances and plays little role in determining the strong outward rectifying behaviour of the plasmalemma of the airways smooth muscle cell. K(+)-channel opening may cause relaxation of the airways smooth muscle cell by mechanisms additional to inhibition of Ca2+ influx through L-type VOCs. The cromakalim-like KCOs have bronchodilator activity in vivo and can depress NANC excitatory neuroeffector transmission in the lung at concentrations smaller than those required to relax airways smooth muscle. The mechanism of action of cromakalim in alleviating nocturnal asthma may not involve direct relaxation of airways smooth muscle. It is possible that cromakalim may instead act to inhibit the mechanisms underlying airway hyper-reactivity.

Animals↗

PubMed1992

Role of protein kinase C in constrictor responses of the rat basilar artery in vivo.

1. The goal of this study was to determine the effects of activation and inhibition of protein kinase C on the rat basilar artery in vivo. 2. The diameter of the basilar artery was measured through a craniotomy in rats anaesthetized with pentobarbitone sodium (50 mg kg-1, I.P., supplemented with 20 mg kg-1 h-1). Diameters were measured under control conditions and during topical application of various agonists, both alone and in the presence of antagonists. 3. Serotonin (5-HT) produced concentration-related constriction of the basilar artery (baseline diameter = 234 +/- 9 microns, mean +/- S.E.M.), which was inhibited by the 5-HT2 receptor antagonist LY53857. 4. Sphingosine (10(-6) M), a protein kinase C inhibitor which binds to the regulatory site of protein kinase C, inhibited the response to 10(-8) M-serotonin (-19 +/- 2% before vs. -3 +/- 2% during sphingosine, P less than 0.05). In contrast, constrictor responses to prostaglandin F2 alpha to (PGF2 alpha; 10(-6) M) were not inhibited by sphingosine (-16 +/- 2% before vs. -18 +/- 2% during sphingosine, P greater than 0.05). 5. H-7 (10(-9) M), another protein kinase C inhibitor, which binds to the catalytic site of protein kinase C, also inhibited constriction of the basilar artery in response to serotonin, but not prostaglandin F2 alpha. 6. Phorbol 12,13-dibutyrate (PDBu, 10(-8) M), which activates protein kinase C, produced slowly developing constriction of the basilar artery. PDBu-induced vasoconstriction (-33 +/- 2%) was attenuated by sphingosine (-11 +/- 4% during sphingosine, P less than 0.05) and H-7 (-1.5 +/- 5% during H-7, P less than 0.05). 7. In summary, activation of protein kinase C appears to mediate vasoconstrictor responses of the basilar artery to serotonin, but not PGF2 alpha.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1992

Effects of acute hypoxemia on insulin-like growth factors and their binding proteins in fetal sheep.

It has been proposed that insulin-like growth factor I (IGF-I) regulates fetal growth and differentiation. Plasma IGF-I concentrations correlate positively with fetal nutrient availability and newborn birth weights. To explore the hypothesis that hypoxemia decreases fetal growth by decreasing fetal IGF-I availability, we instrumented 14 fetal sheep with vascular catheters. At least 4 days after surgery, 10 fetuses were made acutely hypoxemic by infusing nitrogen into the maternal trachea for 3 h. Fetal blood oxyhemoglobin saturation decreased from 53 +/- 6 (SD) to 31 +/- 9%. Concomitantly, plasma IGF-I concentrations decreased from 91 +/- 11 to 67 +/- 10 ng/ml and IGF-I binding protein-1 concentration increased significantly, as assessed by ligand and Western blot analysis. Fetal IGF-I concentrations remained below control values throughout a subsequent recovery period (68 +/- 12 ng/ml at 6 h). In four control fetuses and in the ewes, plasma IGF-I concentrations were not significantly different from control values (97 +/- 18 and 181 +/- 18 ng/ml, respectively). These data support the hypothesis that decreases in fetal oxygen availability may decrease fetal growth by decreasing IGF-I production and availability.

Acute Disease↗

PubMed1992

Effect of protein kinase C inhibitors on endothelin- and vasopressin-induced constriction of the rat basilar artery.

The goal of this study was to determine whether inhibitors of protein kinase C (PKC) attenuate constrictor responses of the basilar artery in vivo to endothelin and arginine vasopressin. In anesthetized rats, the diameter of basilar arteries was measured through a cranial window [control diameter 218 +/- 3 (SE) microns]. Vessel diameter was measured during topical application of agonists and antagonists. Sphingosine (10(-6) M), a PKC inhibitor that binds to the regulatory site of PKC, attenuated vasoconstriction in response to endothelin (10(-9), 10(-8), and 10(-7) M) and vasopressin (10(-9) and 10(-8) M). H-7 (10(-9) M), a PKC inhibitor that binds to the catalytic site of PKC, also inhibited vasoconstriction in response to endothelin and vasopressin. Sphingosine and H-7 did not affect baseline diameter and did not attenuate vasoconstriction in response to prostaglandin (PG) F2 alpha. The V1 antagonist [d(CH2)5Tyr(Me)]arginine vasopressin (10(-8) M) significantly inhibited constriction in response to vasopressin (10(-9) and 10(-8) M) but not PGF2 alpha (10(-6) M). These observations suggest that activation of PKC may contribute to endothelin-induced constriction of the basilar artery in vivo and that PKC may also be a mediator of V1-receptor-mediated constriction of the basilar artery in response to vasopressin.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1992

Signal transduction pathways in constriction of the basilar artery in vivo.

We examined effects of a putative myosin light chain kinase inhibitor in the cerebral circulation in vivo. In anesthetized rats, diameter of basilar arteries was measured through a cranial window (control, 232 +/- 10 microns, mean +/- SEM). Vessel diameter was measured during topical application of agonists and antagonists. ML-7, which has been reported to compete with adenosine triphosphate for binding to the catalytic site on myosin light chain kinase, attenuated vasoconstriction in response to prostaglandin F2 alpha (10(-6) M; -22 +/- 1% before versus -14 +/- 1% and -3 +/- 2% during ML-7, 10(-7) and 10(-6) M, respectively; p less than 0.05). ML-7 (10(-6) M) did not affect baseline diameter. Responses to serotonin (10(-8) M) and phorbol 12,13-dibutyrate (10(-8) M) were not attenuated by ML-7. Thus, constriction of the basilar artery induced by prostaglandin F2 alpha in vivo is attenuated by an inhibitor of myosin light chain kinase.

Animals↗

PubMed1992

Relationship of self-efficacy and binging to adherence to diabetes regimen among adolescents.

OBJECTIVE: To test the hypothesis that poorer adherence to diabetes care is related to four variables associated with self-concept in adolescents with diabetes: self-esteem, self-efficacy, depression, and binging behavior. In addition, we expected adolescent females to be less adherent to diabetes care. RESEARCH DESIGN AND METHODS: We recruited 193 consecutive patients (aged 13-18 yr) with insulin-dependent diabetes mellitus during their regular quarterly visit to a diabetes clinic in a large urban hospital. Participants completed the Rosenberg Self-Esteem Scale, the Children's Depression Inventory, an assessment of the frequency of binging in the past 3 mo, and parallel forms of an adherence scale and a self-efficacy scale that were developed for use in this study. RESULTS: Adolescents who reported lower adherence tended to report lower self-esteem (r = 0.45, P less than 0.001) and self-efficacy (r = 0.57, P less than 0.001), more depressive symptoms (r = -0.50, P less than 0.001), more binging (r = -0.36, P less than 0.001), and had higher HbA1c (r = -0.24, P less than 0.001) than those with higher adherence scores. Together, the psychological variables accounted for 50% of the variance in adherence. There was no sex difference in reported binging, but, as expected, adolescent females reported less adherence overall (F[7,184] = 2.5, P = 0.018). CONCLUSIONS: Treatment adherence in adolescents with insulin-dependent diabetes mellitus is associated with behavioral and psychological variables. These findings suggest that specific behavioral and cognitive interventions could be used to improve adherence in those individuals who lack confidence in their ability to perform diabetes-related tasks.

Adolescent↗

PubMed1991

Mechanical, biochemical and electrophysiological studies of RP 49356 and cromakalim in guinea-pig and bovine trachealis muscle.

Experiments have been performed using guinea-pig and bovine trachealis in order to determine whether cromakalim and RP 49356 share the same relaxant action and to analyse the mechanisms underlying this action. RP 49356 was approximately 3 times less potent than cromakalim in suppressing the spontaneous tone of guinea-pig trachea and, like cromakalim, was antagonised by glibenclamide and by phentolamine. Biochemical studies showed that relaxant concentrations of cromakalim and RP 49356 did not alter the cAMP or cGMP content of guinea-pig trachealis muscle and did not inhibit cAMP or cGMP hydrolysis by tracheal homogenates. Like cromakalim, RP 49356 caused marked hyperpolarisation of guinea-pig trachealis cells. Patch clamp recording using inside-out membrane patches from bovine trachealis showed that cromakalim, RP 49356, glibenclamide and phentolamine were each without effect on the open state probability (Popen) of large conductance, Ca(2+)-activated K(+)-channels. We conclude that cromakalim and RP 49356 share a similar action in opening K(+)-channels in the trachealis cell membrane. This action probably does not involve the intracellular accumulation of cyclic nucleotides and the channel involved is not the large conductance, Ca(2+)-dependent K(+)-channel.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

PubMed1991

Guinea-pig isolated trachealis: the effects of charybdotoxin on mechanical activity, membrane potential changes and the activity of plasmalemmal K(+)-channels.

1. A study has been made, in guinea-pig isolated trachealis, of the effects of charybdotoxin in modulating (a) the activity of large conductance K(+)-channels, (b) the spontaneous electrical activity of intact cells and (c) the mechanical effects of some bronchodilator drugs. 2. Single smooth muscle cells were isolated from guinea-pig trachealis by enzymic digestion and were studied by the patch clamp recording technique. Recordings were made from outside-out plasmalemmal patches when the medium bathing the external surface of the patches contained 1.2 mM Ca2+ and 6 mM K+ while that bathing the cytosolic surface contained 0.1 microM Ca2+ and 140 mM K+. Charybdotoxin (100 nM), applied to the external surface of patches held at 0 mV, abolished the unitary currents associated with the opening of large conductance K(+)-channels. 3. Opened segments of guinea-pig trachea were used for the simultaneous recording of membrane potential and tension changes. In these experiments charybdotoxin (100 nM) caused the conversion of spontaneous electrical slow waves into spike-like action potentials. This effect was accompanied by a very small reduction in resting membrane potential. 4. Tissue bath recording showed that charybdotoxin (100 nM) increased the spontaneous mechanical tone of the tissue, antagonized (2.8 fold in each case) the relaxant actions of isoprenaline and theophylline but did not antagonize the relaxant actions of cromakalim or RP 49356. 5. It is concluded that charybdotoxin is an effective inhibitor of large conductance K(+)-channels in guinea-pig trachealis cells. The ability of charybdotoxin to convert spontaneous slow waves into spike-like action potentials suggests that the large, charybdotoxin-sensitive, K+-channels play an important role in determining the strong outward rectifying behaviour of the cells. The ability of charybdotoxin to antagonize isoprenaline and theophylline, but not to antagonize cromakalim and RP 49356, suggests that opening of the large conductance, charybdotoxin-sensitive K+-channel is implicated in the action of the former but not the latter pair of bronchodilator drugs.

Adrenergic beta-Agonists↗

PubMed1991

Role of protein kinase C in bradykinin-induced increases in microvascular permeability.

The goal of this study was to determine whether protein kinase C mediates bradykinin-induced increases in microvascular permeability. Permeability of the hamster cheek pouch was evaluated using intravital fluorescent microscopy and fluorescein isothiocyanate (FITC)-dextran (MW 70,000). We examined effects of sphingosine, a protein kinase C inhibitor, on bradykinin-induced increases in permeability. Increases in permeability were quantitated by counting the number of leaky sites and calculating the clearance of FITC-dextran. During bradykinin (10(-6) M), leaky sites increased from 0 to 40 +/- 4 (mean +/- SEM) sites/0.11 cm2, and clearance increased from 1.7 +/- 1.0 to 22 +/- 9 ml/sec x 10(-6). The bradykinin type-2 receptor antagonist D-Arg,[Hyp3,Thi5,8,D-Phe7]-bradykinin virtually abolished formation of leaky sites in response to bradykinin. To determine whether changes in microvascular pressure contribute to the increase in leaky sites, venular pressure was measured using a micropipette and survo-null device. Increases in cheek pouch venular pressure were similar during application of bradykinin and adenosine, which increased permeability, and isoproterenol, which did not increase permeability in the cheek pouch. Thus, increases in permeability were not linked to changes in microvascular pressure. The protein kinase C inhibitor, sphingosine (10(-6) M), markedly attenuated responses to bradykinin. Leaky sites increased from 0 to only 2 +/- 1 sites/0.11 cm2, and clearance increased from 3.9 +/- 1.4 to only 6.7 +/- 2.2 ml/sec x 10(-6). To test the specificity of sphingosine, we examined effects of adenosine (10(-6) M). Sphingosine did not significantly alter increases in microvascular permeability in responses to adenosine. We also examined effects of 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), another protein kinase C inhibitor, on responses to bradykinin and adenosine. H-7 greatly attenuated formation of leaky sites during stimulation with bradykinin and did not alter the number of leaky sites produced during adenosine. The findings suggest that protein kinase C may mediate increases in vascular permeability in response to bradykinin.

Adenosine↗

PubMed1990

Influence of functional impairment and social support on depressive symptoms in persons with diabetes.

Tested the buffering model of social support among 158 adults with diabetes. We predicted that, among patients with higher levels of illness-related impairment, adequate social support would act as a buffer against depression. Measures included the Beck Depression Inventory; the Sickness Impact Profile; and an assessment of the adequacy of social support to enable the patient to deal with illness-related tasks, domestic chores, financial responsibilities, and emotional needs. Depressive symptoms correlated positively with functional impairment (r = .58, p less than .001) and negatively with the adequacy of social support (r = -.31, p less than .001). In addition, social support moderated depression in the face of greater impairment such that, among patients who reported the most illness-related functional disabilities, adequate support provided a relative protection from depression. The findings suggest that individuals with inadequate support are most at risk to become depressed when disability related to illness increases.

Adaptation, Psychological↗

PubMed1990

Cerebral blood flow during fastigial pressor response in cats.

We tested the hypotheses that electrical stimulation of the fastigial nucleus increases cerebral blood flow by a dilator mechanism, impairs autoregulation during increases in arterial pressure, and attenuates increases in cerebral blood flow during acute hypertension by activation of sympathetic nerves. Cerebral blood flow was measured with microspheres in anesthetized cats during control and moderate or severe hypertension produced by stimulation of the rostral fastigial nucleus. Cervical sympathetic nerves to one cerebral hemisphere were cut to compare responses in the innervated and denervated hemispheres. Fastigial stimulation at a level that raised arterial pressure from 94 +/- 10 (mean +/- SE) to 133 +/- 6 mmHg had no significant effect on cerebral blood flow. Autoregulation was preserved because cerebral vascular resistance increased approximately 40% during the fastigial pressure response. When mean arterial pressure was raised to 189 +/- 9 mmHg by stimulation of the fastigial nucleus, cerebral blood flow increased similarly in the denervated hemisphere and the hemisphere with intact sympathetic nerves. We conclude that stimulation of the fastigial nucleus in cats does not have a direct dilator effect on cerebral vessels, does not impair autoregulation during moderate hypertension, and does not attenuate increases in cerebral blood flow during severe hypertension by activation of sympathetic pathways.

Animals↗

PubMed1990

Self-predictions of emotional response patterns: age, sex, and situational determinants.

A total of 407 males and females in 4 different age groups (M age = 8.0, 10.8, 15.2, and 20.3 years) completed questionnaires requiring self-ratings of 5 emotions (angry, happy, sad, fearful, and loving), on a 5-point scale, for 10 affect-laden sentences. Each of the 5 emotions was targeted as a key emotion by 2 sentences. The resulting patterns indicate that children as young as 8 can discriminate between affect-eliciting statements, differentially rate up to 5 concurrent emotional responses, and predict response patterns similar to those predicted by adults. Furthermore, sex differences occur during adolescence whereby males predict more varied but less intense secondary emotions, whereas females predict fewer but more intense secondary emotions.

Adolescent↗

PubMed1989

Differences in intrapartum obstetric care provided to women at low risk by family physicians and obstetricians.

To determine differences in practice style and to examine maternal and neonatal outcomes, we reviewed the hospital charts of 1115 women admitted by family physicians and 1250 women admitted by obstetricians who gave birth at one of three teaching hospitals in Toronto between April 1985 and March 1986. All the women in the two groups were categorized retrospectively as being at low risk at the onset of labour on the basis of their prenatal records and their admission histories and physical examination results. There were higher proportions of younger women and women of lower socioeconomic status in the family physician group than in the obstetrician group (p less than 0.001). The rates of interventions, including artificial rupture of the membranes, induction, augmentation, low forceps plus vacuum extraction, episiotomy and epidural anesthesia, were all higher in the obstetrician group. The mean birth weight and the cesarean section rate were the same in the two groups. Differences in labour and delivery outcomes between the two groups, including a higher rate of spontaneous vaginal delivery for the family physicians, reflected a more "expectant" practice style by family doctors. However, there were no significant differences in the rates of maternal or neonatal complications. A practice style characterized by a higher rate of interventions was not associated with improved maternal or newborn outcome in this low-risk setting.

Adult↗

PubMed1989

Cromakalim-induced relaxation of guinea-pig isolated trachealis: antagonism by glibenclamide and by phentolamine.

1. Tested against the spontaneous tone of guinea-pig isolated trachealis, cromakalim (0.1-100 microM), isoprenaline (1 nM-1 microM) and theophylline (1 microM-1 mM) each produced concentration-dependent relaxation. 2. Glibenclamide (0.1-10 microM) did not itself alter the spontaneous tone of the trachea nor did it modify the relaxant actions of isoprenaline or theophylline. In contrast, glibenclamide (0.1 and 1 microM) caused a concentration-dependent rightward shift of the log concentration-effect curve of cromakalim. Glibenclamide (10 microM) reduced the slope of the log concentration-effect curve of cromakalim and moved the foot of the curve back towards the control position. 3. Phentolamine (1, 10 and 100 microm) did not itself alter the spontaneous tone of the trachea nor did it modify the relaxant actions of isoprenaline or theophylline. In contrast phentolamine caused concentration-dependent depression of the log concentration-effect curve of cromakalim. 4. Neither prazosin (1 microM) nor yohimbine (10 microM) modified the spontaneous tone of the trachea. Prazosin and yohimbine each failed to antagonise the effects of cromakalim, isoprenaline and theophylline. 5. Intracellular electrophysiological recording showed that glibenclamide (1 microM) and phentolamine (100 microM) caused minor change in the resting membrane potential of trachealis cells. Slow wave activity was slightly depressed by these agents. In contrast tetraethylammonium (TEA; 8 mM) caused marked depolarisation, and promoted the conversion of slow waves into regenerative action potentials. These electrical changes were accompanied by tonic tension development. 6. Phentolamine (100 microM) and glibenclamide (1 microM) reduced and reversed both the relaxation and the hyperpolarisation induced by cromakalim (10 microM). 7. It is concluded that glibenclamide and phentolamine each provide selective antagonism of the relaxant action of cromakalim in guinea-pig trachealis. These agents also inhibit the plasmalemmal hyperpolarisation induced by cromakalim. The effect of phentolamine is unrelated to the blockade of alpha 1- or alpha 2-adrenoceptors. If either glibenclamide or phentolamine act to block the K+ channels opened by cromakalim, then such channels are not identical to those which endow the trachealis plasmalemma with its powerful rectifying behaviour.

Animals↗

PubMed1987

The guidance of axons from transplanted neurons through aneural Drosophila wings.

The sensory neurons of the wing of Drosophila arise during the first 24 hr of metamorphosis, and their axons converge to form a stereotyped set of nerves projecting proximally from the peripherally located cell bodies through the wing and towards the CNS. To better characterize the cues guiding this stereotyped axon outgrowth, we have performed a series of transplantation studies in which neurons from a variety of sources (wing, eye, antenna, and leg disks) were placed into mutant, aneural wings. Axons growing from such implants in effect assay the host wing for the presence and location of guidance cues. Our results show, first, that such axons prefer to grow in the normal, proximal direction and, second, that they prefer to grow along the approximate site of one of the normal nerves, that of the third longitudinal vein. It therefore appears that the aneural wing epithelium contains cues capable of directing both the polarity and the location of axonal outgrowth. These cues are relatively non-specific, in that a variety of neuronal types are capable of responding to them.

Animals↗

PubMed1986

Slow tight binding inhibitors of angiotensin converting enzyme.

We have found that apparent Ki values of some, but not all, carboxyalkyl-dipeptide inhibitors of angiotensin converting enzyme decrease as a function of incubation time. The most potent of the ACE inhibitors tested so far is RAC-X-65 (N-[1(S)-carboxy-3-carboxanilidiopropyl]-L-Ala-L-Pro). When RAC-X-65 is not preincubated with human serum ACE (2.4 X 10(-11) M), the apparent Ki value is 4.4 X 10(-10) M. Preincubation of RAC-X-65 with ACE for 15 min before addition of substrate yields an apparent Ki of 4.1 X 10(-11) M. a 90 min preincubation of the inhibitor with ACE yields an apparent Ki of 1.2 X 10(-11) M, i.e., the reaction of the inhibitor with enzyme is virtually stoichiometric. The enzyme:inhibitor complex is poorly separated by molecular sieve chromatography or by dilution. That such tightly bound complexes are formed in vivo is suggested by the following results: The intravenous ED50 (anesthetized rats) of RAC-X-65 is 9.43 nmol/kg, and the time for half recovery (t1/2) of responsiveness to i.v. angiotensin I, 120 ng/kg, following a cumulative dose of 240 nmol/kg of the inhibitor is 165 min. For comparison, the i.v. ED50 of captopril is 105 nmol/kg, and its t1/2 following a cumulative dose of 240 nmol/kg is 16 min. Implied is the possibility that slow tight binding inhibitors of ACE may be used in a 1 pill per day regimen for the treatment of hypertension.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1979

Plasma unconjugated oestriol and unconjugated oestradiol-17 beta in late pregnancy: individual fluctuation of concentrations from day to day and every 10 minutes.

Plasma unconjugated oestriol (E3) and unconjugated oestradiol-17 beta (E2) were determined by radioimmunoassay. In ten normal women in their last month of pregnancy the individual fluctuation of E3 concentrations (mean of the coefficients of variation, CV) from day to day (over 5 days) was 15.6% (range 6.4--26.2%). The individual fluctuation of E2 determined in eight of these women was 16.9 (10.4--25.5) %. In six of the same women who had blood samples collected every 10 min (for 3 h) the individual fluctuation of E3 concentrations was 13.8 (7.0--25.1) %, and of E2 was 16.1 (11.3--26.0) %. The degree of fluctuation of E3 in individuals was in proportion to the mean concentration, unlike E2, suggesting that in clinical practice individual changes in E3 values would be as easy to interpret at low levels as at high levels. The finding that concentrations of plasma unconjugated E3 fluctuate in individuals no more than for E2 or than reported for total E3, and less than reported for 24-h urinary oestrogens, lends practical support to the theoretical preference for the assay of plasma unconjugated E3 to assess fetoplacental function.

Adult↗