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Biomedical subjects

G H Williams

Publications and source records attributed to G H Williams.

At least 19 recordsLinked to original sources
PubMed1992

Effects on platelet aggregation and fibrinolytic activity during upright posture and exercise in healthy men.

The circadian variation of acute myocardial infarction suggests that daily activities such as assuming the upright posture and performing different daily activities may trigger the onset of coronary thrombosis. Such triggering may result from unfavorable alterations in the balance between the prothrombotic and antithrombotic properties of the blood. The present study compares the effects of 2 common daily activities, assuming the upright posture and exercise, on platelet aggregation and fibrinolytic activity. In healthy male subjects, assuming the upright posture in the morning significantly increased platelet aggregation and produced only a moderate increase in fibrinolytic activity within 10 minutes. These changes were still present after 90 minutes in the upright posture. Supine posture for 45 minutes resulted in levels of fibrinolytic activity and platelet aggregation comparable to that observed before initially assuming the upright posture in the morning. Return to the supine posture for 45 minutes resulted in levels of fibrinolytic activity and platelet aggregation comparable to that observed before the initial assumption of upright posture. The changes recurred when upright posture was taken later in the day. Exercise did not increase platelet aggregation to levels beyond that produced by the upright posture, but was associated with a marked increase in fibrinolytic activity. Thus, exercise and upright posture produce distinctive alterations in the thrombogenic potential of the blood that may influence the timing of clinical vascular events.

Adult↗
PubMed1992

Rapidity and duration of platelet suppression by enteric-coated aspirin in healthy young men.

The recent demonstration of aspirin's ability to prevent and reduce the severity of myocardial infarction has led to a marked increase in its use and to a need for information regarding the time-course of onset and offset of its antiplatelet effect. A study of healthy men was conducted to determine (1) the rapidity of onset of inhibition of platelet aggregation in response to adenosine diphosphate, and thromboxane A2 production after chewed enteric-coated aspirin (325 mg, n = 10); and (2) the duration of platelet inhibition after cessation of enteric-coated aspirin (325 mg) every other day for 14 days (n = 10). When chewed, enteric-coated aspirin greatly inhibited platelet aggregation response to adenosine diphosphate and thromboxane A2 production within 15 minutes. Complete recovery of platelet aggregation occurred in half of the subjects by day 3, and in 80% of the subjects by day 4; the platelet response was not affected by exercise. This study demonstrates a rapid onset of aspirin's antiplatelet effect and provides information relevant for optimal timing of initiation of aspirin for acute conditions such as myocardial infarction and unstable angina, and cessation of aspirin before surgery.

Adenosine Diphosphate↗
PubMed1992

Renal and adrenal responsiveness to angiotensin II: influence of beta adrenergic blockade.

The increase in aldosterone secretion that occurs in response to Angiotensin II (AII) is enhanced when normal humans are in external balance on a low salt diet. The responsible mechanism has not been identified. Angiotensin converting enzyme inhibition reduces blood levels of AII and aldosterone, but does not decrease PRA or AI and does not modify adrenal responsiveness to AII in the sodium-depleted state. This study was designed to assess the possibility that the enhanced adrenal response reflects plasma renin activity (PRA), plasma AI concentration, or catecholamines acting via a beta adrenergic receptor. Nine healthy males were studied when in balance on a high sodium intake (200 mmol Na/day), a low sodium diet (10 mmol Na) and after 4 days of beta adrenergic blockade with either nadolol or propranolol. The adequacy of beta adrenergic blockade was assessed with a postural stimulus and significant blockade was achieved, somewhat more with nadolol (40 mg/day) than with propranolol (Inderal LA, 80 mg every 12 hrs). Beta blockade enhanced the renal vascular and pressor response to AII but did not modify the adrenal response to posture or to AII. This study confirms the role for AII levels in the modulation of renal vascular and pressor responses to AII and rules out a role for PRA, AI, or catecholamines acting via a beta adrenergic receptor in the modulation of adrenal responsiveness to AII.

Adrenal Glands↗
PubMed1992

Back to front? Examining research priorities in rheumatology.

Arthrosis and back troubles together account for at least a third of all rheumatic suffering, and they are much the commonest rheumatological causes of impairment and disability. In contrast to the inflammatory arthropathies, one cannot help but be struck by the fact that research endeavour has not been commensurate with the burden that has to be endured.

Back Pain↗
PubMed1992

Regulation of intracellular pH in single rat zona glomerulosa cells.

The cytosolic pH (pHi) regulation of rat adrenal zona glomerulosa (ZG) cells was studied using single-cell spectrofluorimetry. Basal pHi was similar for cells incubated in the absence or presence of the HCO3(-)-CO2 buffering system. In the absence of HCO3-, inhibition of the Na(+)-H+ exchanger by dimethylamiloride (DMA) or removal of extracellular Na+ produced substantial acidification of basal pHi. In the presence of HCO3-, neither maneuver affected basal pHi. However, removing extracellular Cl- produced a prompt alkalinization not observed in the absence of HCO3-. Alkalinizing mechanisms were examined by monitoring pHi recovery from an acid load imposed by the NH4Cl pulse technique. In the absence of HCO3-, Na+ removal or DMA addition blocked greater than 80% of pHi recovery. In the presence of HCO3-, 34% of the pHi recovery rate was inhibited by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), 34% by DMA, and 72% by Na+ removal plus DIDS. Therefore both Na(+)-H+ and anion exchangers are active in these cells, working independently to maintain basal pHi. In the absence of HCO3-, Na(+)-H+ exchange is principally responsible for pHi recovery from an acid load. In HCO(3-)-containing medium, such recovery is shared by Na(+)-H+ and Cl(-)-HCO3- exchange.

Acids↗
PubMed1992

Calcium channels and control of cytosolic calcium in rat and bovine zona glomerulosa cells.

Rat and bovine adrenal zona glomerulosa (ZG) cells possess a low-threshold, voltage-dependent Ca2+ current that was characterized using whole cell voltage clamp techniques. Activation of this current is observed at membrane potentials above -80 mV with maximal peak Ca2+ current elicited near -30 mV. Inactivation of the Ca2+ current was half-maximal between -74 and -58 mV, depending on the external Ca2+ concentration and was nearly complete at -40 mV. The voltage dependency of the current indicates that a calcium current could be sustained at membrane potentials between -80 and -40 mV and thereby elevates cytosolic calcium (Cai) levels. Under basal conditions, Cai is stable in single rat ZG cells, whereas more than half of the bovine ZG cells produce repeated Cai transients. These Cai transients, which are blocked by removal of external Ca2+ or addition of Ni2+, are likely due to repetitive electrical activity in bovine ZG cells. Cai responses can be elicited by small increases in external K+ concentration (5-10 mM) in both rat and bovine ZG cells, indicating the opening of low-threshold Ca2+ channels. However, these Cai changes remain robust at high external K+ concentrations (20-40 mM). In experiments combining Cai measurements and whole cell voltage clamp, a steep dependence of Cai on membrane potential was revealed beginning at depolarizing voltages near a holding membrane potential of -80 mV. A maximal increase in Cai occurred near -30 mV (equivalent to an external K+ concentration of 40 mM), a membrane voltage at which sustained current through low-threshold Ca2+ channels should be negligible. These data raise the possibility of additional voltage-dependent pathways for Ca2+ influx.

4-Aminopyridine↗
PubMed1992

K+ channels in adrenal zona glomerulosa cells. I. Characterization of distinct channel types.

Four distinct types of K+ channels were identified in rat and bovine adrenal zona glomerulosa (ZG) cells and characterized using single-channel recording techniques. Inward rectifier channels were the most frequently observed K+ channel types in the membrane patches of both rat and bovine ZG cells. The slope conductance of the inward current was 42 pS with an extracellular K+ concentration of 150 mM. The probability of the open state of these channels increased with depolarization. With the use of inside-out membrane patches with symmetric 150 mM K+ solutions, the rectifying behavior was found to require Mg2+ on the intracellular side of the membrane. Delayed rectifier K+ channels with conductances of 27 and 48 pS were found with rat ZG cells. These channels persisted with prolonged positive voltage steps and showed long mean open times with increasing depolarization. Transient outward currents with a conductance of 28 pS were observed only in bovine ZG cells. These channels showed substantial inactivation during positive voltage steps of 250 ms duration. Ca(2+)-activated K+ channels with a large conductance (228 pS) were identified in rat and bovine ZG cells. These different classes of K+ channels may be important for the control of resting membrane potential and the generation of action potentials, thus participating in the regulation of Ca2+ influx and aldosterone secretion in ZG cells.

Animals↗
PubMed1992

Single K+ channels in adrenal zona glomerulosa cells. II. Inhibition by angiotensin II.

The effects of angiotensin II (ANG II) on single K+ channels were studied in rat and bovine adrenal zona glomerulosa (ZG) cells, using the patch-clamp technique. ANG II (0.1-10 nM) induced substantial inhibition of inward rectifier and delayed rectifier K+ channel activities in rat and bovine ZG cells. Analysis of single-channel activities showed that the ANG II-induced channel-blocking effect involved reductions in the probability of the open state (Po) and the mean open time. The changes in these channel parameters occurred at all test voltages, indicating that the effect of ANG II was voltage independent. ANG II could not interact directly with the extracellular sides of the membranes in these experiments using cell-attached patches. Therefore, the effect of ANG II on K+ channels must occur through an indirect cytosolic transduction pathway. The ANG II-induced block of K+ channels will result in membrane depolarization, which may activate voltage-dependent Ca2+ channels, thereby increasing cytosolic free Ca2+ and stimulating aldosterone secretion. These channel-modulating actions of ANG II may be an important step in the initial sequence of events underlying its transduction mechanism.

Angiotensin II↗
PubMed1992

Non-modulation as an intermediate phenotype in essential hypertension.

Non-modulation is a trait characterized by abnormal angiotensin-mediated control of aldosterone release and the renal blood supply. To determine whether non-modulation defines a specific subgroup of the hypertensive population and its utility as an intermediate phenotype, we have studied the distribution of this quantitative trait, whether its features are reproducible on repeated testing, and whether there is concordance of its multiple features. Essential hypertensive patients (224) and normotensive subjects (119) received an infusion of angiotensin II (Ang II) at 3 ng.kg-1.min-1 for 30-45 minutes. p-Aminohippurate (PAH) clearance was assessed as an index of renal plasma flow while the subjects were on a 200 meq sodium diet; plasma aldosterone levels were measured while the subjects were on a 10 meq sodium diet. In 54 subjects, diuretic-induced volume depletion superimposed on a low salt diet was substituted for the Ang II infusion. The results of each study were submitted to maximum likelihood analysis to assess bimodality. In response to both diuretic-induced volume depletion (p < 0.000023) and Ang II infusion (p < 0.0009), aldosterone responses were bimodally distributed in the essential hypertensive but not in the normotensive subjects, suggesting that this trait identifies a discrete subgroup. In the 59 subjects who had both an adrenal and renal study, 50 (85%) were concordant. Finally, in 27 subjects studied two to six times over a span of 1-60 months, the intraclass correlations of the adrenal, PAH, or both responses were highly significant (p values between 0.001 and 0.00007), indicating high reproducibility of results on repeated testing.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1992

Cochlear implants in children: reliability of computed tomography.

Preoperative temporal bone computed tomography (CT) can demonstrate anatomic details relevant to surgical management and is therefore essential in the presurgical evaluation of patients receiving cochlear implants. The purpose of this study was to evaluate preoperative CT studies and compare them to surgical findings in 34 children who received the Nucleus multichannel cochlear implant. The focus of this report is to discuss the dependability of CT scans in predicting surgical findings at the time of cochlear implantation. Results indicate that agreement of CT interpretations with surgical findings is partially related to the etiology of hearing loss and the experience of the surgeon and neuroradiologist. Advantages and limitations of the CT scans in predicting surgical findings are discussed.

Adolescent↗
PubMed1992

Dose effect of adrenocorticotropin on aldosterone and cortisol biosynthesis in cultured bovine adrenal glomerulosa cells: in vitro correlate of hyperreninemic hypoaldosteronism.

In some critically ill patients, aldosterone secretion is diminished despite hyperreninemia. These same patients demonstrate appropriately elevated plasma ACTH and cortisol levels. In addition, infusion of ACTH or angiotensin-II (AII) fails to elicit the normal aldosterone response, implying that the defect is at the level of the zona glomerulosa (ZG) cell. To test the hypothesis that elevated ACTH levels induce this defect, Percoll-purified bovine ZG cells were plated in serum-free defined medium and cultured for 5 days. On days 1-4, cells were exposed to various concentrations of ACTH for 1 h. On the fifth day of culture, half of the wells pretreated with ACTH were treated for 1 h with AII (10(-7) M); the other half of the wells received another dose of ACTH for 1 h. Additionally, cells were exposed to daily 1-h pulses of AII (10(-7) M) alone or in combination with ACTH (10(-8) M) for 5 days. Acutely dispersed bovine ZG cells showed dose-dependent increases in aldosterone when incubated with ACTH, potassium, or AII, with minimal cortisol production. Acutely dispersed bovine fasciculata cells produced no aldosterone, but demonstrated a dose-dependent cortisol response to ACTH and AII, but not potassium. On day 1 of culture, the ZG cells demonstrated a significant (P less than 0.001 in all cases) dose-related increase in aldosterone secretion in response to ACTH. However, continued daily pulsation with ACTH resulted in a dose-dependent decrease in aldosterone secretion, with a concomitant dose- and time-related rise in cortisol production. Indeed, ACTH-induced cortisol production in ZG became similar to ACTH-induced cortisol production in zona fasciculata cells. The addition of AII to the daily ACTH pulse did not significantly alter the aldosterone or cortisol response patterns to ACTH alone. In contrast, ZG cells treated with AII alone for 5 days showed a minimal change in cortisol production and no reduction in aldosterone production until day 4. Northern blot analysis of total RNA isolated from ZG cells pulsed with ACTH for 5 days demonstrated a parallel dose-dependent increase in 17 alpha-hydroxylase mRNA, which did not occur in cells pulsed with AII alone. These in vitro results suggest that elevated ACTH levels over time induce 17 alpha-hydroxylase activity in ZG cells, thereby shifting steroid biosynthesis from an aldosterone-producing to a cortisol-producing pathway. It is likely that the chronically elevated ACTH levels in critically ill patients induce a similar change in ZG cell biosynthesis, resulting in their hyperreninemic hypoaldosterone state.

Adrenocorticotropic Hormone↗
PubMed1992

Markers of sodium and volume homeostasis in pregnancy-induced hypertension.

Normal pregnancy is associated with increased levels of digitalis-like factor (DLF) and erythrocyte sodium-lithium countertransport (RBC CTT), which return to normal levels postpartum. Patients with pregnancy-induced hypertension (PIH) have greater increases in both factors than women with normotensive pregnancies. This study was designed to determine if both abnormalities are observed concomitantly in PIH, if they correlate with blood pressure, if they correlate negatively with a hormonal index of volume status (PRA), and if they differ in women with and without proteinuria. Twenty-six normotensive women and 26 women with PIH were studied in the third trimester. Thirteen of these patients were also studied 6 months postpartum. Women with PIH, compared to those who were normotensive, had higher RBC CTT (0.49 +/- 0.04 vs. 0.36 +/- 0.03 mmol Li/L cells.h; P = 0.004) and DLF (0.30 +/- 0.3 vs. 0.20 +/- 0.03 microgram digoxin equiv./L; P = 0.01) and lower PRA [4.58 +/- 0.76 vs. 7.34 +/- 0.86 ng/mL.h (1.27 +/- 0.21 vs. 2.04 +/- 0.24 ng/L.s); P = 0.001]. All three parameters correlated significantly with diastolic blood pressures (RBC CTT and DLF positively (P less than or equal to 0.02) and PRA negatively (P = 0.03). Comparisons of DLF, RBC CTT, and PRA demonstrated a significant correlation of RBC CTT and DLF for normotensive pregnant women only (r = 0.38; P = 0.05). Patients with PIH were further analyzed according to whether proteinuria (24-h urinary protein, greater than 0.30 g; urine dipstick, greater than or equal to 2+) was present or absent. There was no significant difference in diastolic blood pressure or PRA between the hypertensive subpopulations, although there was a tendency for those without proteinuria to have lower PRAs [3.85 +/- 0.80 ng/mL.h (1.07 +/- 0.02 ng/L.s)] than those with proteinuria [5.31 +/- 1.30 ng/mL.h (1.48 +/- 0.36 ng/L.s)]. RBC CTT was significantly higher (P less than 0.05) in women with PIH without proteinuria, whereas serum DLF was significantly higher in women with PIH with proteinuria (P less than 0.05). In 13 women studied 6 months postpartum, there was a significant reduction in serum DLF, RBC CTT, and PRA for all women and in blood pressure for women who had had PIH (P less than 0.01). Thus, women with PIH, compared to normotensive pregnant women, had abnormalities in a variety of factors known to be volume sensitive or indicative of salt- and volume-sensitive forms of hypertension.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1992

Abnormal norepinephrine and aldosterone responses to upright posture in nonmodulating hypertension.

The subgroup of patients with nonmodulating hypertension demonstrates a number of abnormalities of the renin-angiotensin-aldosterone axis. We previously identified abnormalities in plasma and urinary dopamine in nonmodulators and posited that this may be in part due to a generalized defect in sympathetic nervous system activity. In the present study we assessed the state of activation of the renin-angiotensin system and the sympathetic nervous system in normal subjects and patients with modulating, nonmodulating, and low renin essential hypertension during sodium depletion and change from supine to upright posture. Levels of plasma norepinephrine were higher in non-modulators during the posture study (P < 0.05). PRA rose with upright posture in all groups, but low renin subjects had a blunted response. Nonmodulators and low renin subjects had lower aldosterone levels both supine (P< 0.05) and upright (P< 0.01). However, the aldosterone/PRA increment ratio was increased in low renin subjects (P< 0.01), whereas it was decreased in nonmodulators. Twenty-four-hour urine collections for catecholamine determinations were obtained in a subgroup of the subjects, with nonmodulators showing higher levels of norepinephrine excretion which approached significance (P = 0.08). In vitro experiments using rat and human adrenal glomerulosa cells showed that norepinephrine does not affect aldosterone secretion per se. These observations extend the series of abnormalities observed in nonmodulating hypertension. However, it is likely that the alterations in norepinephrine levels during sodium depetion and upright posture are a secondary event and not linked to the altered aldosterone production in these patients.

Adult↗
PubMed1992

Interrelationships between the renin-angiotensin-aldosterone and calcium homeostatic systems.

Blood pressure is affected by both sodium and calcium intake. To determine if there is an interaction between the regulatory mechanisms for these two cations, eight normal male volunteers received the following 1-h infusions on three different days: 1) angiotensin II (AII), 2) the synthetic 1-34 amino terminal fragment of human PTH [hPTH(1-34)], and 3) AII and hPTH(1-34) together. Blood samples were obtained at t = 0 and every 20 min during each infusion and urine was collected for 3 h both before and after the start of each infusion. Infusion of AII produced an increase in intact PTH from 18 +/- 2 to 31 +/- 4 ng/L (P < 0.05), most likely in response to a small decrease in serum ionized calcium (1.25 +/- 0.01 to 1.23 +/- 0.01 mmol/L, P < 0.05). Urinary excretion of calcium was unchanged. Infusion of hPTH(1-34) at 200 U/h increased N-terminal PTH levels (18 +/- 3 to 268 +/- 42 ng/L, P < 0.05), decreased tubular reabsorption of phosphate (0.92 +/- 0.03 to 0.82 +/- 0.11, P < 0.05), and increased urinary cAMP (0.18 +/- 0.02 to 0.53 +/- 0.05 nmol/L of glomerular filtrate, P = 0.0001). hPTH(1-34) infusion suppressed endogenous intact PTH (18 +/- 3 to 14 +/- 2 ng/L, P < 0.005) and increased PRA from 0.14 +/- 0.02 to 0.32 +/- 0.05 ng/(L.s) (P < 0.05) without a change in serum ionized calcium which suggests direct effects of hPTH(1-34) on the parathyroid glands and the juxtaglomerular apparatus. The effects of AII and hPTH(1-34) were antagonistic with little change in serum ionized calcium, intact PTH, or PRA when both were infused together. These interrelationships between the major hormonal systems controlling sodium and calcium homeostasis suggest a mechanism underlying the close association of calcium and sodium in the regulation of blood pressure.

Adult↗
PubMed1991

The effect of enteric-coated aspirin on the morning increase in platelet activity.

In vitro platelet aggregability to adenosine diphosphate (ADP) and epinephrine increases in the morning, as does the frequency of myocardial infarction. A single-blind, randomized, cross-over study of 15 healthy males was conducted to determine: (1) if other measures of platelet activity show a morning increases and (2) if aspirin eliminates any increases in platelet activity detected. Subjects received 325 mg of enteric-coated aspirin (ECA) or placebo. During placebo therapy,platelet thromboxane A2 production (following collagen stimulation) increased significantly after the subjects got up, as did platelet aggregability to ADP, epinephrine, and collagen. ECA markedly reduced baseline platelet thromboxane A2 production and eliminated the increase after the subjects got up. It also abolished biphasic aggregation in response to epinephrine and ADP (thereby eliminating the morning increase in aggregability to these agents), lengthened collagen lag time, reduced synergistic aggregation to combined agonists, was effective on day 2, and did not alter increases of tissue plasminogen activator that occurred following the subjects' arising. If aspirin prevents myocardial infarction by its antiplatelet action, as seems likely, the preferential reduction of morning infarction observed in the Physicians' Health Study, and the demonstration that aspirin eliminates the morning increase in platelet activity, suggest that the morning increase in myocardial infarction is due in part to a concurrent relatively modest increase in platelet activity.

Adult↗
PubMed1991

Disablement and the ideological crisis in health care.

Disablement from chronic illness presents medicine with a constant reminder of the limits to its therapeutic effectiveness, and challenges the political legitimacy of Welfare States. In this regard, chronic illness forms a crucial component of the 'crisis' in health care. In this paper I look at the different ways in which disablement stimulates this crisis--for medicine, for political economy, and for disabled people themselves. In looking at responses to the crisis I detect a certain reluctance, or inability, to move away from an atomistic perspective which underpins much of our thinking on health and social policy, and much else besides. I conclude by arguing, against post-modern cynics, that a reasoned defence of the Welfare State requires a broader concept of self-sufficiency and a perspective which both acknowledges the need for help, and recognizes the extent to which the provision of help may further disempower the disadvantaged.

Chronic Disease↗