Reduction in human fetal umbilical-placental vascular resistance by glyceryl trinitrate.
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Adult↗
Biomedical subjects
W Giles
Publications and source records attributed to W Giles.
Antenatal care of low risk obstetric patients by midwives. A randomised controlled trial.
OBJECTIVES: To assess the practicality, acceptability to patients and salary costs of the antenatal care of low risk obstetric patients by midwives. DESIGN: A randomised controlled trial. SETTING: The antenatal clinic at Westmead Hospital, a teaching hospital of the University of Sydney in western Sydney. PATIENTS: From January 1989 until November 1990, 89 women booking for full antenatal care at Westmead Hospital and classified as low risk were randomly allocated to one of two groups. Group 1 (43 patients) had their antenatal care provided by registered midwives. Group 2 (46 patients) had their antenatal care provided by an obstetrician (either Visiting Medical Officer or Staff Specialist) in a routine hospital antenatal clinic. INTERVENTIONS: Patients in the midwives' clinic were seen by an obstetrician at their first visit to the antenatal clinic and again at 30 weeks and at 40 weeks. MAIN OUTCOME MEASURES: These were the salary costs of each clinic and the patients' levels of satisfaction. Maternal and neonatal indicators, delivery details and analgesic requirements were also considered. These indicators were planned before data collection commenced. RESULTS: The major differences found were a 28% to 68% salary cost saving and that patients cared for by midwives showed appreciation of the continuity of care and information given at the midwives' clinic. CONCLUSIONS: The care of low risk obstetric patients by midwives in a midwives' clinic showed salary cost savings and high patient acceptance.
Continuity of Patient Care↗
Necrotizing enterocolitis in a perinatal centre.
Thirty-five neonates developed radiologically proven necrotizing enterocolitis (NEC) over a 40 month period. They were 28 +/- 2 weeks gestation, and weighted 1094 +/- 411 g at birth. Eighteen infants (51%) required surgery and three (8.5%) died. The incidence was 6.7% in the very low birthweight (VLBW) infants. A large proportion of NEC (60%) presented beyond 10 days of life. An inverse relationship between gestation and age of onset was observed. The age of presentation was 22 +/- 13 days (range 10-53 days) for the 18 infants less than or equal to 28 weeks compared with 7 +/- 5 days for those over 28 weeks (P less than 0.01). Five NEC infants had bacteraemia which occurred 2-7 days prior to gastrointestinal symptoms of NEC, and four were staphylococcal. Compared with infants controlled for gestation, there was no significant differences observed in perinatal events or feeding history. We concluded that an immature gastrointestinal system is vulnerable to NEC even beyond the early neonatal period.
Enterocolitis, Pseudomembranous↗
Inhibition of the muscarinic receptor-activated K+ current by N-ethylmaleimide in rabbit heart.
The effects of N-ethylmaleimide (NEM), a sulfhydryl alkylating agent, on the ACh-activated K+ current were examined in single cells from rabbit hearts using whole-cell and single channel patch clamp techniques. Bath application of NEM (50 microM) or the muscarinic antagonist, atropine (1 microM) completely inhibited the ACh-activated K+ current in whole-cell recordings. In cell-attached patch conditions, the inhibitory effect of NEM was still observed; in contrast, atropine was ineffective when the agents were bath applied, indicating that the site of action of NEM is different from that of atropine. Inside-out patch recordings confirmed that GTP was required on the internal side of the membrane for activation of this K+ channel when ACh was present in the pipette. NEM abolished this GTP-activated K+ channel activity. GTP gamma S, a non-hydrolysable GTP analogue, was able to activate this K+ channel in the absence of a muscarinic agonist, an effect thought to be due to the direct activation of GTP-binding proteins. Pretreatment with NEM almost completely prevented this effect of GTP gamma S. In contrast, after the activation of the K+ channel by GTP gamma S had reached a steady-state, NEM failed to show a significant inhibitory effect. These results demonstrate that NEM prevents the activation of muscarinic receptor-regulated K+ channel and suggest an involvement of alkylation of the GTP-binding proteins which are coupled to this type of K+ channel.
Acetylcholine↗
Methadone levels and neonatal withdrawal.
The purpose of this study was to observe the effects of methadone exposure in utero, with special reference to maternal and neonatal methadone concentrations and neonatal withdrawal. Two groups of mother-infant pairs were studied. In the first group, serum methadone concentrations were determined in infants at 1, 6 and 24 h after delivery. In the second group, blood was obtained at 24, 48, 72 and 96 h after birth. There was no correlation between neonatal serum levels and the intensity of withdrawal symptoms. There was no relationship between maternal methadone dose at delivery or maternal serum levels and neonatal methadone levels. The results of this study may be complicated by the prenatal exposure of the neonates to other drugs of abuse apart from methadone.
Adult↗
Regulation of spontaneous opening of muscarinic K+ channels in rabbit atrium.
1. Intracellular mechanism(s) for controlling the opening of muscarinic K+ channels in the absence of an applied muscarinic agonist were studied in rabbit atrium by applying the patch clamp technique to isolated single myocytes. 2. In the cell-attached patch configuration, currents due to the activity of both the muscarinic K+ channel and the inward rectifying K+ channel were recorded. However, while the inward rectifying K+ channel currents were observed in only ten patches of 211 examined, spontaneous opening (i.e. in the absence of a muscarinic agonist) of the muscarinic K+ channel currents was observed in all patches examined in these atrial cells. 3. The single-channel currents due to spontaneous opening of muscarinic K+ channels were identified on the basis of their very similar conductance and gating properties to the unitary events which have been recorded when 0.5 microM-acetylcholine is included in the pipette and 10 microM-GTP is present in the internal side of the patch membrane. 4. Although the spontaneous opening of the muscarinic K+ channels disappeared soon after excision of the patch membrane, this type of channel activity reappeared following application of ATP and MgCl2 to the internal side of the torn-off patch, as expected from previous publications. 5. The K+ channel activity induced by the ATP and Mg2+ (measured as the product of the number of channels, N, times the probability of opening, Po) was strongly dependent upon concentration of free Mg2+; it was half-maximal at 2.2 x 10(-4) M [Mg2+]i. However, after the muscarinic K+ channels had been activated by 100 microM-guanosine 5'-O-3-thiotriphosphate (GTP gamma S) together with ATP and Mg2+, an increase in the Mg2+ concentration from 5.5 x 10(-5) to 2 x 10(-3) M failed to enhance this channel activity. 6. Pertussis toxin, which is known to uncouple muscarinic receptors from associated G-proteins (G(i) or G(o)), failed to inhibit the ATP- and Mg(2+)-induced activation of this K+ channel in the absence agonists. 7. In experiments made to test whether the Mg(2+)-ATP requirement results from an obligatory phosphorylation reaction, ATP was replaced with adenylyl-imidodiphosphate (AMP-PNP), an analogue of ATP which is resistant to hydrolysis. This K+ channel activity was not present when ATP was replaced with AMP-PNP.(ABSTRACT TRUNCATED AT 400 WORDS)
Adenosine Triphosphate↗
Voltage clamp measurements of the hyperpolarization-activated inward current I(f) in single cells from rabbit sino-atrial node.
1. The kinetics and ion transfer characteristics of the hyperpolarization-activated inward current, I(f), have been studied in single cells obtained by enzymatic dispersion from the rabbit sino-atrial (S-A) node. These experiments were done to assess the role of I(f) in the generation of the pacemaker depolarization in the S-A node. 2. The activation and the deactivation of I(f) in these single cells are accompanied by significant conductance increases and decreases respectively, confirming earlier findings from multicellular man-made strips of rabbit S-A node, and from mammalian Purkinje fibres. 3. The steady-state activation of I(f) lies between -40 and -120 mV, and its voltage dependence can be described by a Boltzmann relation with the half-activation point at approximately -70 mV. 4. The delay or sigmoidicity in both the onset of I(f) and the deactivation of the tail currents can be accounted for semi-quantitatively by using a second-order Hodgkin-Huxley kinetic scheme. 5. The reversal potential for I(f) is -24 +/- 2 mV (mean +/- S.E.M., n = 6). It does not change significantly as a function of the amount of I(f) which is activated, indicating that ion accumulation or depletion phenomena are not important variables controlling the time course of I(f), or its selectivity. 6. The fully-activated current-voltage relationship for I(f) is approximately linear with a slope conductance of 12.0 +/- 0.88 nS per cell (mean +/- S.E.M., n = 6). 7. A simple mathematical model based on the measured values of maximum conductance, reversal potential, and kinetics of I(f) has been developed to simulate the size and time course of I(f) during typical spontaneous pacemaker activity in rabbit sino-atrial node cells. The calculations show that I(f) can change significantly during pacing and suggest that this current change is, at least in part, responsible for the pacemaker depolarization.
Action Potentials↗
Discrepancies in hemoglobin levels.
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Female↗
Mechanism of acetylcholine-induced inhibition of Ca current in bullfrog atrial myocytes.
The mechanism of the anti-beta-adrenergic action of acetylcholine (ACh) on Ca current, ICa, was examined using the tight-seal, whole-cell voltage clamp technique in single atrial myocytes from the bullfrog. Both isoproterenol (ISO) and forskolin increased ICa dose dependently. After ICa had been enhanced maximally by ISO (10(-6) M), subsequent application of forskolin (50 microM) did not further increase ICa, suggesting that ISO and forskolin increase ICa via a common biochemical pathway, possibly by stimulation of adenylate cyclase. ACh (10(-5) M) completely inhibited the effect of low doses of forskolin (2 x 10(-6) M), as well as ISO, but it failed to block the effects of high doses of forskolin (greater than 5 x 10(-5) M). Intracellular application of cyclic AMP (cAMP) also increased ICa. ACh (10(-5) M) failed to inhibit this cAMP effect, indicating that the inhibitory action of ACh occurs at a site proximal to the production of cAMP. ACh (10(-5) M) also activated an inwardly rectifying K+ current IK(ACh). Intracellular application of a nonhydrolyzable GTP analogue, GTP gamma S (5 X 10(-4) M), activated IK(ACh) within several minutes; subsequent application of ACh (10(-5) M) did not increase IK(ACh) further. These results demonstrate that a GTP-binding protein coupled to these K+ channels can be activated maximally by GTP gamma S even in the absence of ACh. Intracellular application of GTP gamma S also strongly inhibited the effect of ISO on ICa in the absence of ACh. Pertussis toxin (IAP) completely prevented both the inhibitory effect of ACh on ICa and the ACh-induced activation of IK(ACh). GTP gamma S (50 microM-1 mM) alone did not increase ICa significantly; however, when ISO was applied first, GTP gamma S (5 x 10(-4) M) gradually inhibited the ISO effect on ICa. These results indicate that ACh antagonizes the effect of ISO on ICa via a GTP-binding protein (Gi and/or Go). This effect may be mediated through a direct inhibition by the alpha-subunit of Gi which is coupled to the adenylate cyclase.
Acetylcholine↗
N-ethylmaleimide uncouples muscarinic receptors from acetylcholine-sensitive potassium channels in bullfrog atrium.
The effect of N-ethylmaleimide (NEM), a sulphydryl alkylating agent, on the acetylcholine-activated K+ current, IK(ACh), has been studied in single cells from bullfrog atrium using a tight-seal, whole-cell voltage clamp technique. Addition of NEM (5 x 10(-5) M) produced a time-dependent complete block of IK(ACh). Dialysis of guanosine-5'-O-(3-thiotriphosphate) (GTP gamma S, 5-10 x 10(-4) M), a nonhydrolyzable GTP analogue, into the myoplasm from the recording pipette gradually activated IK(ACh) even in the absence of acetylcholine. This effect is thought to be due to a GTP gamma S-induced dissociation of GTP-binding proteins (Gi and/or Go) into subunits that can directly activate these K+ channels. When NEM (5 x 10(-5) M) was applied after the GTP gamma S effect had fully developed, it failed to inhibit the GTP gamma S-induced K+ current, indicating that the NEM effect is unlikely to be on the dissociated subunits of the GTP-binding protein(s) or on the K+ channels. In contrast, pretreatment with NEM before GTP gamma S application markedly reduced the muscarinic K+ current, suggesting that NEM can block this K+ current by inhibition of the dissociation of the GTP-binding proteins into functional subunits. In NEM-treated cells the stimulatory effect of isoproterenol on ICa was present, but the inhibitory action of ACh on ICa was completely abolished. These results demonstrated that NEM can preferentially inhibit muscarinic receptor-effector interactions, probably by alkylating the GTP-binding proteins that are essential for these responses.
Acetylcholine↗
Down syndrome and low maternal serum alpha fetoprotein.
The early pregnancy maternal serum alpha-fetoprotein (MSAFP) results for 35 patients who delivered a baby with Down syndrome (DS) were analysed. These results were collected from 1981 to mid-1989. Eight of the 35 showed an MSAFP result less than 0.5 multiples of the median (MOM). These MSAFP results were corrected for maternal weight. The results support other workers' conclusions that mid-trimester hormonal analyses may be helpful in diagnosing the presence of DS in women otherwise not considered at risk.
Adult↗
Two distinct types of inwardly rectifying K+ channels in bull-frog atrial myocytes.
1. Single atrial myocytes were enzymatically isolated from the bull-frog as previously described (Hume & Giles, 1981), and patch-clamp techniques were used in an attempt to identify and separate two inwardly rectifying K+ channels in this tissue. 2. Single-channel measurements consistently demonstrated the existence of two different resting K+ channels, which both exhibited strong inward rectification. The unitary conductances of these K+ channels were 34 +/- 4 and 22 +/- 3 pS (mean +/- S.D., at 22-24 degrees C) when measured with 110 mM-K+ in the pipette solution, and their mean open times were 0.87 +/- 0.33 and 129.9 +/- 49.4 ms, respectively. 3. In the absence of acetylcholine (ACh) in the pipette, openings of the larger channels with the shorter open times occurred at a very low frequency. When ACh was present in the patch pipette, the activity of this channel increased significantly, although the single-channel conductance and gating behaviour were very similar either with or without ACh in the pipette. 4. The zero-current voltage (extrapolated from the inward currents through these types of channels) depended on the extracellular K+ concentration. [K+]o, in the fashion expected for a predominantly K(+)-selective channel: it shifted by 58 mV for a tenfold change in [K+]o. Very similar results were obtained from whole-cell voltage-clamp measurements (53 mV for a tenfold change in [K+]o). 5. The conductance of both types of K+ channels depended on [K+]o. The single-channel conductances were 25 +/- 3 and 13 +/- 2 pS with 50 mM [K+]o, and 19 +/- 4 and 9 +/- 2 pS with 20 mM [K+]o, respectively. 6. These results demonstrate that two types of resting inwardly rectifying K+ channels can be identified in single atrial myocytes. One of these is an inwardly rectifying K+ channel (IK1) previously identified in whole-cell voltage-clamp experiments (Hume & Giles, 1983). The second channel is the muscarinic receptor-regulated K+ channel (IK(ACh) which was first described in mammalian nodal and atrial cells. 7. N-Ethylmaleimide (NEM), a reagent which alkylates sulphydryl groups, affects these two types of K+ channels differentially. In the cell-attached patch configuration, bath application of NEM (50 microM) completely abolished the activity of IK(ACh), without affecting the IK1 channel activity. 8. To obtain further evidence that these two currents, IK1 and IK(ACh), were different, the inside-out patch-clamp technique was used.(ABSTRACT TRUNCATED AT 400 WORDS)
Acetylcholine↗
Ca2(+)-activated K+ currents in smooth muscle.
Calcium-activated potassium currents have been described in a wide variety of cell types. This report summarizes some important properties of these currents in smooth muscle and provides examples from our recent single channel recordings from human cystic artery.
Animals↗
Calcitonin gene-related peptide regulates calcium current in heart muscle.
The influx of Ca2+ due to the transmembrane calcium current, ICa, has a fundamental role in cardiac pacemaker activity, in the action potential plateau and in excitation-contraction coupling. Both sympathetic and parasympathetic neurotransmitters can modulate ICa. Recent studies indicate that in both the cardiovascular and the central nervous systems, nerve varicosities exist that contain a novel non-adrenergic, non-cholinergic peptide--calcitonin gene-related peptide (CGRP). Although CGRP is known to exert strong positive inotropic and chronotropic effects, as well as to cause vasodilation, very little is known about the ionic mechanisms of these effects. Here we report that CGRP dramatically increases ICa in single heart cells. Although this CGRP-induced increase in ICa resembles the effect of beta-adrenergic agonists, our results demonstrate some significant differences between the effects of CGRP and these agonists: (1) the increase due to CGRP cannot be blocked by beta-adrenergic antagonists; (2) the CGRP-induced effect is transient; and, (3) CGRP can inhibit isoproterenol-stimulated ICa. Our results provide the first electrophysiological evidence that CGRP can significantly modulate ICa in the heart, and suggest a new additional mechanism for the neurogenic control of cardiac function.
Action Potentials↗
Outpatient methadone programme for pregnant heroin using women.
A prospective study of pregnant narcotic users who attended the antenatal clinic at Westmead Hospital was undertaken to determine the practicality and safety of an outpatient methadone programme for these women. Forty-six women were commenced and managed on a methadone maintenance programme based at the Drug and Alcohol Clinic at Westmead Hospital (GROUP I), 12 women were maintained on long-term methadone therapy by outside prescribers (GROUP II), 12 women not on methadone continued to use heroin through the pregnancy (GROUP III), 14 women used heroin intermittently (GROUP IV). These were compared with a group of 52 women who were non-drug using (GROUP V). Women on the hospital based methadone programme had an earlier first antenatal clinic visit (p less than 0.001) than those women on outside methadone programmes or on heroin and had a longer pregnancy (p less than 0.001) than those women on heroin. The birth-weights on babies delivered to women on the Westmead Methadone Programme were significantly higher than those on babies born to women using heroin (p less than 0.05). A disappointing aspect of the study was a lower number of antenatal clinic visits (p less than 0.001) for all narcotic using women when compared with the comparison group. The outcome of the Westmead Methadone Programme women showed that better maternal and neonatal outcome followed entry into a hospital monitored methadone programme with attendant antenatal care.
Adult↗
Trauma during pregnancy--a review of management.
The assessment and management of 22 pregnant patients who were admitted after trauma to Westmead Hospital between July, 1987 and October, 1988 was reviewed. Thirteen of the 22 patients were victims of motor vehicle accidents. Despite the fact that an injury research unit, responsible for the clerking and review of all trauma patients, is well established at our institution, only 6 patients in this series had been assessed in this fashion. Although a number of important obstetric investigations (albeit uncommon in the accident and emergency room situation) are well described in the literature, these were not performed in a number of patients. A protocol for the management of such patients is recommended so that more standardized and appropriate care might be given to the injured pregnant patient.
Accidents, Home↗
Modulation of the delayed rectifier K+ current by isoprenaline in bull-frog atrial myocytes.
1. The effects of isoprenaline (ISO) on the calcium current (ICa) and delayed rectifier K+ current (IK) were examined using a tight-seal whole-cell voltage-clamp technique in single cells from bull-frog atrium to examine the ionic mechanism(s) of catecholamine-induced action potential shape changes. 2. The effects of ISO on the action potential were dose-dependent. Very low doses (5 x 10(-9) M) prolonged the action potential. Higher doses (10(-6) M) of ISO increased the plateau height, but shortened the action potential by accelerating the early repolarization phase. 3. ISO increased IK and ICa in a dose-dependent fashion. Both of these effects were blocked by a beta-receptor antagonist, propranolol (3 x 10(-7) M). In contrast IK1, the inwardly rectifying K+ current, was not changed significantly by ISO. 4. The ISO-induced increase in IK was observed in the presence of CdCl2 (3 x 10(-4) M), indicating that this effect is not due to a Ca2(+)-activated potassium current. 5. The reversal potential of IK in normal Ringer solution (-83 +/- 2 mV) was not significantly changed by ISO. Thus, stimulation of the Na(+)-K+ pump and a consequent hyperpolarizing shift in EK are not responsible for the increase in IK. 6. In the presence of ISO (10(-6) M) the steady-state activation curve (n infinity) for IK was consistently shifted to more negative values (by approximately 10 mV). The activation and deactivation kinetics of IK were also changed by ISO: activation was accelerated, deactivation was slowed. These ISO-induced changes in IK result in an increase in IK at voltages corresponding to the plateau of the action potential. 7. ISO (10(-6) M) increased ICa dramatically, approximately 6-fold at 0 mV. At the same time, the time constant of ICa inactivation decreased significantly (34 +/- 4 ms control; 23 +/- 4 ms ISO). 8. These results confirm that low doses of sympathetic agonists acting via beta-receptors increase ICa. Relatively high doses of beta-receptor agonists increase both ICa and IK, but these two effects appear to be generated by different biophysical mechanisms. 9. These dose-dependent changes in ICa and IK can explain the observed ISO-induced changes in action potential shape. At doses of approximately 10(-8) M ICa is increased, resulting in a more depolarized plateau and small lengthening of the action potential.(ABSTRACT TRUNCATED AT 400 WORDS)
Action Potentials↗
Slow inward tail currents in rabbit cardiac cells.
1. A whole-cell gigaseal suction microelectrode voltage-clamp technique has been used to study slow inward tail currents in single myocytes obtained by enzymatic dispersion of rabbit ventricle and atrium. A variety of stimulation protocols, Tyrode solutions and pharmacological agents have been used to test three hypotheses: (a) that the slow inward tail current is generated by an electrogenic Na(+)-Ca2+ exchanger; (b) that a rise in [Ca2+]i, due to release from the sarcoplasmic reticulum can modulate the activity of this exchanger; and (c) that the uptake of calcium by the sarcoplasmic reticulum is a major determinant of the time course of the tail current. 2. As shown previously in amphibian atrium and guinea-pig ventricle, slow inward tail currents can be observed consistently under conditions in which action potentials and ionic currents are recorded using microelectrode constituents which only minimally disturb the intracellular milieu. 3. In ventricular cells, the envelope of these tail currents obtained by varying the duration of the preceding depolarizations shows that (a) the tail currents are activated by pulses as short as 10 ms, and reach a maximum for pulse durations of 100-200 ms, (b) the rate of decay of the tail current gradually increases as the activating depolarizations are prolonged, and (c) the tails cannot be due to deactivation of calcium currents, in agreement with other studies in frog heart. 4. When the mean level of [Ca2+]i is raised following inhibition of the Na(+)-K+ pump by strophanthidin (10(-5) M) or reductions in [K+]o (0.5 mM), the slow inward tail grows in size prior to the onset of a contracture or other signs of calcium-induced toxicity. 5. In a number of different preparations, replacement of [Ca2+]o with BaCl2 markedly or completely inhibits the Na(+)-Ca2+ exchanger, whereas Sr2+ replacement does not have this effect. In myocytes from rabbit ventricle the slow inward tails are reduced significantly and decay more slowly in 0.5-2.2 mM-BaCl2 Tyrode solution, while in 2.2 mM SrCl2 these tails are not altered. 6. The slow inward tail also shows a dependence on [K+]o, corresponding to previous data on Na(+)-Ca2+ exchange in other tissues. Increasing [K+]o in the Tyrode solution to a final concentration of 10-15 mM results in a marked inhibition of the slow tails. This effect cannot be accounted for by changes in the inwardly rectifying potassium current, IK1. 7. The slow tail currents were changed significantly by increasing the temperature of the superfusing Tyrode solution.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗