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Biomedical subjects

A O Davies

Publications and source records attributed to A O Davies.

At least 19 recordsLinked to original sources
PubMed1993

Transverse myelitis following general anaesthesia.

A 47-year-old woman developed a complete transverse myelitis 2 weeks after an uncomplicated general anaesthetic for total abdominal hysterectomy and bilateral salpingo-oophorectomy. If spinal or epidural anaesthesia had been used, a causal relationship might have been assumed. This case emphasises the danger of attributing all cases of transverse myelitis which have a close temporal relationship to spinal or epidural anaesthesia, to the anaesthetic technique itself.

Anesthesia, General↗
PubMed1991

Abnormal Gs function in mitral valve prolapse dysautonomia is not associated with abnormal alpha S cDNA sequence.

We have previously shown that a subset of patients with mitral valve prolapse and hyperadrenergic symptoms has enhanced isoprenaline-stimulated beta-adrenergic receptor high-affinity state formation (supercoupling) and increased adenylyl cyclase activity due to abnormal signal transduction by the stimulatory guanine nucleotide regulatory protein (Gs). In this study we looked for an alteration of the nucleotide coding sequence of the gene for alpha s, the subunit of Gs that is directly responsible for formation of the high affinity state and adenylyl cyclase activation, by cloning and sequencing the alpha s cDNA from neutrophils of 4 symptomatic patients and 1 control. No difference was observed between patients and control in the alpha s cDNA sequence. The splice variant concentrations in the fully expressed protein were also grossly unchanged in five patients and four controls. These data show that a primary alteration of the alpha s gene coding sequence is not responsible for defective Gs-associated signal transduction in dysautonomic MVP patients, and suggest that the molecular lesion could be an abnormal posttranslational modification of alpha s, a defect in the beta or gamma subunits of Gs, or an unusual interaction between the subunits in the Gs of these patients.

Adenylyl Cyclases↗
PubMed1991

Abnormal guanine nucleotide regulatory protein in MVP dysautonomia: evidence from reconstitution of Gs.

We and others have used the term MVP dysautonomia for a particular subset of hyperadrenergic dysautonomia patients. The role of the stimulatory guanine nucleotide regulatory protein (Gs) in this dysautonomia was studied by cholate extraction of Gs from erythrocytes from 11 normal subjects and 14 symptomatic dysautonomic patients and reconstitution into cyc-S49 lymphoma membranes, which have normal receptor and adenylyl cyclase but lack Gs. Isoproterenol-stimulated adenylyl cyclase activity in the dysautonomia group was increased compared to that in controls [3.66 +/- 0.20 (mean +/- SE; n = 14) vs. 2.87 +/- 0.14 (n = 11) U cyc- reconstituted activity/mg erythrocyte protein; P less than 0.05]. beta-Adrenergic receptor high affinity state formation was greatest in the severely symptomatic group [KL/KH: severe symptoms, 130 +/- 48 (n = 6); mild symptoms, 33 +/- 7 (n = 7); control, 27 +/- 6 (n = 11); severe dysautonomia distinct, P less than 0.017]. Sodium dodecyl sulfate-polyacrylamide gels of cholera toxin-dependent ADP-ribosylated G-proteins yielded no gross distinction between severely symptomatic and control groups. This subset of hyperadrenergic dysautonomia patients, thus, has supercoupled beta 2-adrenergic receptors (increase in both agonist binding and cyclase activation) conferred by an abnormal Gs, whose effects on agonist binding reflect the severity of illness.

Adenosine Diphosphate Ribose↗
PubMed1990

Diversity in supercoupling of beta 2-adrenergic receptors in orthostatic hypotension.

Orthostatic hypotension is a clinical condition that frequently involves abnormal adrenergic control of cardiovascular function. Adrenergic function was studied in six patients with symptomatic orthostatic hypotension and in 11 age-matched healthy subjects. The patients demonstrated higher supine mean arterial pressures (MAP; 103 +/- 8 versus 86 +/- 4 mm Hg) and orthostatic hypotension (delta MAP -70 +/- 5 versus +15 +/- 2 mm Hg, p less than 0.001) compared with normal subjects. The delta MAP in phase II of the Valsalva maneuver was significantly greater (-31 +/- 4 versus -7 +/- 4 mm Hg, p less than 0.002) and phase IV heart rate response was blunted (-5 +/- 3 versus -30 +/- 8 beats/min, p less than 0.02) in these patients. More isoproterenol was required to increase heart rate by 25 beats per minute in patients with hypotension (810 +/- 670 versus 3.1 +/- 1.3 micrograms, p less than 0.05), indicating marked chronotropic hyposensitivity. Leukocyte beta 2-adrenergic receptor densities were similar in patients and controls. beta 2-Adrenergic receptor coupling, however, was elevated in patients with hypotension when compared with control subjects (ratio of the low-affinity and high-affinity dissociation constants [KL/KH] 140 +/- 7.4 versus 66 +/- 4.3, p less than 0.001). There were negative correlations between the KL/KH value and the dose of isoproterenol required to decrease MAP by 20 torr (p less than 0.02) and between the KL/KH value and the product of the hormone receptor and MAP (p less than 0.01). However, the patients could be subdivided into a group who could mount a nearly normal hormone receptor times MAP response on standing (group 1A), and a group who could not (group 1B). The group 1A patients had elevated plasma norepinephrine responses associated with milder beta 2-adrenergic receptor supercoupling, whereas group 1B patients had essentially no orthostatic plasma norepinephrine response and had much higher KL/KH values. Thus, though a state of biochemical supersensitivity existed in both patient subgroups, diminished catecholamine exposure was associated, as expected, with beta 2-adrenergic hypersensitivity in group 1B, whereas there was no diminution of catecholamine exposure in the beta 2-adrenergic hypersensitivity observed in group 1A patients.

Aged↗
PubMed1989

Spectrum of dysautonomia in mitral valvular prolapse.

PURPOSE: Symptoms suggesting altered autonomic regulation of cardiovascular function have been noted in some patients with mitral valvular prolapse (MVP) but may also occur in patients with other disorders. We evaluated cardiovascular responses to autonomic stimuli in 118 patients with symptoms of dysautonomia, 78 of whom had MVP, and 40 of whom did not, to determine if unique patterns of these responses distinguished patients in one symptomatic subgroup from another. SUBJECTS AND METHODS: The responses of patients to standing, quantitated Valsalva maneuver, facial immersion in ice water, and administration of isoproterenol, phenylephrine, and tyramine were compared with those in 12 asymptomatic patients with MVP and 23 normal volunteers. RESULTS: Constitutional, cardiovascular, and neuropsychiatric symptoms occurred with similar frequency in the two symptomatic patient groups. The most common pattern of abnormal responses in symptomatic patients with or without MVP was (1) an increased heart rate and elevated plasma norepinephrine levels while supine and then while standing quietly for five minutes, (2) an exaggerated increase in heart rate during phase II of Valsalva, (3) a diminished bradycardic response during phase IV of Valsalva, and (4) an exaggerated heart rate response to administration of isoproterenol. The increased heart rate during Valsalva, but not the exaggerated sensitivity to isoproterenol, was correlated with the magnitude of the chronotropic response to standing only in symptomatic patients with MVP. Exaggerated hypertensive overshoot during phase IV of Valsalva was observed in only a few symptomatic patients. No consistent pattern of these abnormalities, however, was noted in any of the patient subgroups. Hemodynamic responses to autonomic stimuli in asymptomatic MVP patients were generally indistinguishable from those observed in normal subjects. CONCLUSION: These findings suggest that abnormal cardiovascular responses to autonomic stimuli may occur in any patient with symptoms of dysautonomia regardless of the presence or absence of MVP and that the pattern of these abnormal responses may be diverse. It is therefore important to characterize the pattern of altered autonomic regulation of cardiovascular function in each patient when considering mechanistic implications or making therapeutic decisions about these patients.

Adolescent↗
PubMed1989

Physiological response to isoproterenol and coupling of beta-adrenergic receptors in young and elderly human subjects.

Diminished adrenergic responsiveness occurs in aged humans. The purpose of this study was to evaluate the coupling of beta-adrenergic receptors from human neutrophil preparations, and to investigate the relationship of this biochemical parameter to heart rate response after isoproterenol administration in young and elderly individuals. Fifteen young (aged 23-39 years) and eleven elderly (aged 59-82 years) volunteers participated in the study. The ratio, KL/KH, representing the ratio of dissociation constants for the low and high affinity state receptors, was calculated to determine coupling in the beta-adrenergic receptor system. An inverse correlation was observed between KL/KH and age. I25HR, representing the amount of isoproterenol required to elevate heart rate by 25 beats per minute, was determined; this parameter increased with age. Multiple regression analysis revealed that I25HR was most dependent upon age, but the changes with age were accompanied by diminution of both beta-adrenergic receptor affinity for agonist and in KL/KH.

Adult↗
PubMed1988

Lymphocyte beta-adrenergic receptor modification in bulimia.

beta-Adrenergic receptor binding on circulating lymphocytes was evaluated in young female bulimic patients (n = 12) and age- and sex-matched normal control volunteers (n = 10). Using iodine 125-labeled cyanopindolol, antagonist binding was evaluated (number of receptors [Bmax] and dissociation constant [KD]), and using isoproterenol competition of cyanopindolol binding, the concentration required to inhibit binding by 50% (IC50) for isoproterenol and the agonist affinity measure of KL/KH (ratio of dissociation constants for the low- and high-affinity states of the receptor) were determined. Plasma norepinephrine (NE) level was also measured. There was a trend toward lower plasma NE levels in the bulimic patients. The KL/KH ratio in bulimic patients was significantly greater than that for the normal volunteers, indicating increased receptor coupling. The KL/KH ratio was not significantly correlated with plasma NE level. Neither Bmax nor KD was different between the two groups. These findings suggest that beta-adrenergic receptors in bulimic patients may be more responsive than in normal subjects, without alteration of the traditional measures of receptor responses, a difference that cannot be explained on the basis of plasma NE. These findings provide another line of evidence for altered regulation of the noradrenergic system in bulimic patients during a controlled phase of their illness.

Adult↗
PubMed1988

Coupling of human beta 2-adrenergic receptors: relationship to redox potential.

The purpose of this study was to examine the quantitative relationship between the redox potential of a redox couplet and the alterations it induces in coupling of receptor occupation with enzyme activation. Normal neutrophil membrane preparations containing beta 2-adrenergic receptors were exposed to equimolar mixtures of the following redox couplets: ferrocyanide-ferricyanide, hemoglobin-methemoglobin, ascorbate-dehydroascorbate, lactate-pyruvate, glutathione ox-red, beta-hydroxybutyrate-acetoacetate, and NAD-NADH. There was a linear relationship between the redox potential of the couplets and the degree of change in coupling (p less than 0.001). The apparent redox potential of the high affinity complex was +0.30 +/- 0.093 V. The effect of lactate to uncouple beta-adrenergic receptors was partially blocked by preexposure to isoproterenol. Thus, high affinity state formation is regulated by redox couplets in a manner dependent on their redox potential.

Acidosis↗
PubMed1988

Exercise-induced fall in coupling of human beta 2-adrenergic receptors.

The purpose of this study was to quantitatively examine to what extent acute exertion diminishes the activity of beta-adrenergic receptors through diminishing coupling. Normal neutrophil membrane preparations containing beta 2-adrenergic receptors were obtained from healthy human volunteers, then exposed to autologous venous plasma obtained before and after acute forearm exertion. There was an acute, dramatic diminution in coupling (P less than .003) after only a few minutes of exercise. Preexertion plasma had no significant effect upon coupling. Substantial diminution in beta-adrenergic receptor sensitivity is thus acutely demonstrable in this model which serves as a model for both metabolic acidosis and acute exertion.

Acidosis↗
PubMed1987

Mitral valve prolapse with symptoms of beta-adrenergic hypersensitivity. Beta 2-adrenergic receptor supercoupling with desensitization on isoproterenol exposure.

Autonomic nervous system dysfunction has recently been identified in a subset of patients with mitral valve prolapse. These autonomic nervous system abnormalities may correspond, in part, to biochemical alterations in beta-adrenergic receptors. Nine women with mitral valve prolapse and symptoms and signs of beta-adrenergic hypersensitivity and seven normal volunteer women were studied. Quiet standing (five minutes) increased both heart rate and plasma norepinephrine (p less than 0.05) in symptomatic patients with mitral valve prolapse compared with normal subjects. The dose of isoproterenol required either to increase heart rate 25 beats/minute (0.5 +/- 0.3 microgram versus 1.0 +/- 0.3 microgram) or to decrease mean arterial pressure 20 mm Hg (11.1 +/- 4.8 versus 78.2 +/- 25.2 micrograms) was significantly less in the patients with mitral valve prolapse than in the volunteers. Symptomatic patients with mitral valve prolapse were desensitized by a four-hour isoproterenol infusion, whereas sensitivity in normal control subjects did not change. In the patients with mitral valve prolapse, baseline beta-adrenergic receptor coupling was elevated compared with that in control subjects (220 +/- 7 versus 81 +/- 2; p less than 0.001). Isoproterenol infusion induced uncoupling in these patients (KL/KH = 35 +/- 3, p less than 0.05) but did not alter coupling in normal volunteers. This study demonstrates physiologic and pharmacologic beta-adrenergic hypersensitivity in vivo directly corresponding to biochemical supercoupling in a subset of patients with mitral valve prolapse.

Adult↗
PubMed1986

Effects of endogenous redox-active compounds on coupling of human beta 2-adrenergic receptors.

Altered redox states such as metabolic acidosis may impair beta-adrenergic receptor responsiveness. Beta-adrenergic receptor function requires formation of a high affinity, "coupled" state of the receptor. The degree of coupling is reflected in the ratio of dissociation constants, KL/KH, for the low and high affinity states of the receptor. It has previously been demonstrated that 16 mM lactate and pH 7.1 induce independent defects in beta-adrenergic receptor function. The purpose of this study was to examine further how endogenous redox agents might alter high affinity state formation. Normal neutrophil membrane preparations containing beta-adrenergic receptors were exposed to several concentrations of three redox couplets native to plasma: lactate (L)-pyruvate (P), beta-hydroxybutyrate (BOHB)-acetoacetate (AcAc), and glutathione (GSH-GSSG). BOHB, AcAc, and P had no isolated effect on high affinity state formation while 10 mM lactate diminished KL/KH by 30% (p less than 0.001). Dropping the pH from 7.4 to 7.1 resulted in a 50% to 70% reduction in KL/KH (p less than 0.001), independent of metabolite present. GSH or GSSG exposure resulted in a concentration-dependent fall in KL/KH value. Thus, high affinity state formation is regulated by redox couplets and pH independently. The reduced responsiveness of beta-adrenergic receptors observed in such states as metabolic acidosis could result from direct effects of redox couplets in addition to those of low pH.

3-Hydroxybutyric Acid↗
PubMed1986

Nonequilibrium of two redox couplets in human plasma: lactate-pyruvate and beta-hydroxybutyrate-acetoacetate.

We examined the extracellular equilibrium status of two redox couplets normally found in plasma (lactate-pyruvate [L-P], beta-hydroxybutyrate, and acetoacetate) during acute metabolic acidosis produced by muscle exertion. Both pre- and postexertion plasma spontaneously underwent loss of acetoacetate and gain of L when compared to the baseline values. Exercise further induced a 332% rise in L (p less than .001) and a 102% rise in P (p less than .001). The empirically derived ratio of equilibrium constants, KLP/KBA, fell 50% (p less than .001), and the calculated change in free energy (delta F) fell from 3.6 to 3.1 kcal/mol (p less than .001) after exercise. The changes induced by exertion were simulated closely by an in vitro model of a reduced state. Thus, the triad of inconstant metabolite concentrations, inconstant KLP/KBA, and delta F both inconstant and non-zero, indicates that there is no state of equilibrium for these metabolite couplets in human plasma. The KLP/KBA ratio appeared to reflect the degree of deviation from equilibrium and may therefore be useful when investigating altered redox states such as metabolic acidosis.

3-Hydroxybutyric Acid↗
PubMed1986

Assessing redox status in human plasma: experience in critically ill patients.

Clinical evaluation of metabolic acidosis has involved measurement of lactate (L), pyruvate (P), beta-hydroxybutyrate (BOHB), and acetoacetate (AcAc). We previously demonstrated that these metabolites are not at equilibrium in plasma. Their degree of disequilibrium is reflected in the ratio of apparent equilibrium constants (KLP/KBA) for the two redox couplets, L-P and BOHB-AcAc. The purpose of the study was to examine how well this ratio reflects disequilibrium in patients with metabolic acidosis. Measurements of the four metabolites were obtained in 23 critically ill patients. Disequilibrium was again observed, as manifested in an inconstant ratio (p less than .01). The ratio increased with clinical improvement. Patients were more likely to die during their ICU stay if the estimated ratio was low, particularly if metabolic acidosis was present. Patients with respiratory acidosis had both intermediate probabilities of death and intermediate ratios when compared to inpatient controls (ICU patients without acidosis). Our data indicate that changes in the L-P-BOHB-AcAc cycle reflect the degree of metabolic derangement in critically ill patients.

3-Hydroxybutyric Acid↗
PubMed1984

Hydrocortisone-induced reversal of beta-adrenergic receptor uncoupling.

Prolonged exposure to adrenal-steroid hormones or adrenergic agonists results in opposing physiologic effects on beta-adrenergic receptors. These physiologic events have biochemical correlates that can be evaluated in the laboratory setting. The ability of hydrocortisone in vitro to reverse prior uncoupling of the receptor induced by terbutaline in vivo was examined. Healthy human volunteers received terbutaline sulfate, 2.5 mg orally every 8 h for 3 days, for a total of 9 doses. Neutrophils obtained from these volunteers were then incubated for 3 h in vitro in the presence of either hydrocortisone or saline placebo. Two types of receptor alterations were observed. Receptor density was reduced by 28% in terbutaline-treated subjects as compared with that in untreated control subjects (p less than 0.016). The receptors also appeared to be relatively uncoupled. This was assessed by examining the ability of the agonist isoproterenol to stabilize a high affinity form of the receptor detected by computer modeling of competition curves for [125I]cyanopindolol binding. The reduction in receptor density was not affected by incubation in hydrocortisone. The ability of isoproterenol to stabilize the high affinity form of the receptor in cells incubated with hydrocortisone was statistically indistinguishable from that of the control state. We conclude that hydrocortisone can reverse prior agonist-induced uncoupling in vitro without affecting prior homologous down regulation.

Adolescent↗
PubMed1984

Impaired formation of beta-adrenergic receptor-nucleotide regulatory protein complexes in pseudohypoparathyroidism.

Decreased activity of the guanine nucleotide regulatory protein (N) of the adenylate cyclase system is present in cell membranes of some patients with pseudohypoparathyrodism (PHP-Ia) whereas others have normal activity of N (PHP-Ib). Low N activity in PHP-Ia results in a decrease in hormone (H)-stimulatable adenylate cyclase in various tissues, which might be due to decreased ability to form an agonist-specific high affinity complex composed of H, receptor (R), and N. To test this hypothesis, we compared beta-adrenergic agonist-specific binding properties in erythrocyte membranes from five patients with PHP-Ia (N = 45% of control), five patients with PHP-Ib (N = 97%), and five control subjects. Competition curves that were generated by increasing concentrations of the beta-agonist isoproterenol competing with [125I]pindolol were shallow (slope factors less than 1) and were computer fit to a two-state model with corresponding high and low affinity for the agonist. The agonist competition curves from the PHP-Ia patients were shifted significantly (P less than 0.02) to the right as a result of a significant (P less than 0.01) decrease in the percent of beta-adrenergic receptors in the high affinity state from 64 +/- 22% in PHP-Ib and 56 +/- 5% in controls to 10 +/- 8% in PHP-Ia. The agonist competition curves were computer fit to a "ternary complex" model for the two-step reaction: H + R + N in equilibrium HR + N in equilibrium HRN. The modeling was consistent with a 60% decrease in the functional concentration of N, and was in good agreement with the biochemically determined decrease in erythrocyte N protein activity. These in vitro findings in erythrocytes taken together with the recent observations that in vivo isoproterenol-stimulated adenylate cyclase activity is decreased in patients with PHP (Carlson, H. E., and A. S. Brickman, 1983, J. Clin. Endocrinol. Metab. 56:1323-1326) are consistent with the notion that N is a bifunctional protein interacting with both R and the adenylate cyclase. It may be that in patients with PHP-Ia a single molecular and genetic defect accounts for both decreased HRN formation and decreased adenylate cyclase activity, whereas in PHP-Ib the biochemical lesion(s) appear not to affect HRN complex formation.

Adenylyl Cyclases↗