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Biomedical subjects

S W Graves

Publications and source records attributed to S W Graves.

At least 55 records · Page 3Linked to original sources
PubMed1994

Unexplained increase in serum digoxin: a case report.

We describe a patient with unexpectedly high serum digoxin after cardiac surgery. To control atrial fibrillation in the immediate postoperative period, she was given a brief trial of digoxin (four 0.25-mg doses) over 12 h. Serum digoxin 6 h later was 2.5 micrograms/L. Two days later, the patient developed ventricular fibrillation, which progressed to cardiac arrest. During or immediately after resuscitation, blood was drawn for a digoxin measurement, and the concentration reported was 9.3 micrograms/L; this result was verified by repeated analysis. Digoxin decreased rapidly and progressively to near 4.0 micrograms/L over the next several hours and thereafter decreased slowly to 1.0 microgram/L over the next 11 days, despite no digoxin being administered. The unexpectedly high digoxin raised questions about the accuracy of the digoxin measurement, particularly about the possible influence of the digoxin-like immunoreactive factor. Analytical approaches to distinguishing true digoxin from this factor and other artifacts of digoxin measurement were applied to this patient, with unanticipated results.

Aged↗
PubMed1993

Impact of diabetes on sodium-lithium countertransport in pregnancy-induced hypertension.

The purpose of this study was to assess the impact of type I diabetes on sodium-lithium countertransport (CTT) in normotensive third trimester women and those with pregnancy-induced hypertension (PIH). CTT was measured in the following groups: nonpregnant diabetic and nondiabetic women, pregnant nondiabetics with and without PIH, and pregnant diabetics with and without PIH. CTT was determined as external sodium-stimulated lithium efflux from lithium loaded red cells [mmoles/liter of cells x hours = units (U)]. In the nonpregnant state, nondiabetics and diabetics demonstrated similar CTT activity (0.20 +/- 0.02 U, n = 22, v 0.26 +/- 0.03 U, n = 18). In pregnancy, normotensive nondiabetics and diabetics had CTT activity similar to each other, the values of both being significantly higher than those in nonpregnant women (0.39 +/- 0.03 U, n = 26, v 0.46 +/- 0.05 U, n = 17). Nondiabetics with PIH demonstrated higher CTT (0.53 +/- 0.03 U, n = 30) than normotensive pregnant nondiabetics (P = .002). However, diabetics with PIH and CTT activity (0.48 +/- 0.04 U) indistinguishable from normotensive pregnant diabetics (0.46 +/- 0.05 U). There were no differences in gestational age, renal function, or glycohemoglobin that could explain these observations. Therefore, we conclude that PIH in type I diabetic women, in contrast to PIH in nondiabetic pregnant women, is not associated with a further elevation in CTT.

Adult↗
PubMed1993

Volume expansion in renal failure patients: a paradigm for a clinically relevant [Na,K]ATPase inhibitor.

A volume-sensitive inhibitor of [Na,K]ATPase, termed the digitalis-like factor (DLF), is postulated to participate in hypertension. To test this hypothesis, end-stage renal failure patients on peritoneal dialysis were placed on a clinical protocol that brought about a gradual, sustained volume expansion. This was accompanied by significant increases in body weight (4.1 +/- 1.2 kg, p < 0.05), mean arterial pressure (18.2 +/- 6.4 mm Hg, p < 0.05), and serum DLF activity (4.7 +/- 1.9% inhibition, p < 0.05). Processing these patients' daily dialysates by ultrafiltration and high-performance liquid chromatography allowed for the identification of a single elution fraction having volume-sensitive [Na,K]ATPase inhibitory activity. This factor in turn was correlated with serum DLF activity (R = 0.60, p = 0.002), weight gain (R = 0.67, p = 0.0003), and mean arterial pressure (R = 0.59, p = 0.003). This factor was readily distinguished from ouabain and digoxin but was similar to the DLF isolated from amniotic fluid. These results suggest that volume expansion in renal failure patients on peritoneal dialysis gives rise to a unique volume-sensitive DLF that may contribute to these patients' increase in blood pressure.

Blood Pressure↗
PubMed1992

Increased platelet angiotensin II receptor number in pregnancy-induced hypertension.

Women with pregnancy-induced hypertension (PIH) are characterized by relatively greater blood pressure sensitivity to exogenous angiotensin II (Ang II) than normotensive pregnant women. Evidence suggests that this is due to an alteration in Ang II receptor sites. However, the question of whether this represents an increase in receptor number or affinity remains unanswered. To answer this question Ang II receptors on platelets from normotensive women during each trimester of pregnancy and the postpartum period were studied and compared with platelet Ang II binding in third trimester women with PIH and in postpartum women who had had a recent pregnancy complicated by PIH. We also measured plasma renin activity, Ang II, and aldosterone in blood samples from these women and sodium and creatinine in 24-hour urine collections. Normotensive pregnant women had significantly less platelet Ang II binding than nonpregnant, postpartum women (0.85 +/- 0.19 versus 2.87 +/- 0.83%, p = 0.003), reflecting a reduction in receptor number but not affinity. This probably reflects the significant increase in Ang II during pregnancy. Urinary sodium excretion was equivalent and could not explain these changes. Comparisons of third trimester women with PIH against those without PIH documented a significantly higher Ang II binding in the women with PIH (2.23 +/- 0.42 versus 0.85 +/- 0.19%) that was caused by an increase in receptor number (6.0 +/- 1.3 versus 3.0 +/- 0.8 fmol Ang II per 5.6 x 10(8) platelets, p = 0.047) but similar Ang II binding affinity. This reflected significantly lower Ang II levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
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

Lower serum ionized calcium and abnormal calciotropic hormone levels in preeclampsia.

Relative hypocalciuria has been reported in women with preeclampsia. However, there has been no systematic explanation for this finding. We measured serum and urinary calcium and serum calciotropic hormones in third trimester women with preeclampsia (n = 12, gestational hypertension and proteinuria) and with normotensive pregnancies (n = 24) to try to explain these changes. We confirmed that the women with preeclampsia have a relative hypocalciuria (2.9 +/- 0.7 vs. 6.5 +/- 0.2 mmol/day, P less than 0.01). Preeclamptic women also had lower serum ionized calcium than normotensive third trimester pregnant women (1.20 +/- 0.01 vs. 1.26 +/- 0.01 mmol/L, P less than 0.02). Intact PTH levels were significantly higher in preeclamptic women (29.9 +/- 4.3 vs. 15.4 +/- 1.3 ng/L, P less than 0.01) and a significant inverse relationship was observed between PTH and both urine calcium (r = -0.60, P less than 0.0001) and serum ionized calcium (r = -0.36, P less than 0.05). We measured vitamin D metabolites in a subgroup of both normotensive and preeclamptics. Preeclamptic and normotensive pregnant women had equivalent levels of 25-hydroxyvitamin D [25(OH)D]; however, preeclamptics had significantly lower 1,25-dihydroxyvitamin D [1,25-(OH)2D] levels (172.1 +/- 18.5 vs. 219.6 +/- 12.7 pmol/L, P less than 0.05). Lower 1,25-(OH)2D may contribute to suboptimal intestinal absorption of calcium during a time of increased calcium demand resulting in lower ionized calcium, increased PTH, and hypocalciuria in preeclampsia. Abnormalities in calcium homeostasis may contribute to the increased vascular sensitivity documented in preeclampsia.

Adult↗
PubMed1989

Endogenous digoxin-like immunoreactive factor and digitalis-like factor associated with the hypertension of patients receiving multiple alkylating agents as part of autologous bone marrow transplantation.

1. Hypertension is a complication of autologous bone marrow transplantation when therapy includes multiple alkylating agents. We have sought to identify the factors underlying this hypertension. We measured weight, serum creatinine, plasma renin activity, aldosterone and digoxin-like immunoreactive factor (DLIF), by digoxin radioimmunoassay, in 18 patients. Plasma catecholamines were also measured in five patients. 2. Of the 18 patients studied, 15 became hypertensive. The variable most consistently associated with these individuals' hypertension was DLIF activity which was increased in 14 of the 15 hypertensive patients (P = 0.055, Fisher exact test). Serum creatinine was increased at some point in seven of the 15 hypertensive patients, weight was increased in five and plasma renin activity and aldosterone were increased in one. Catecholamines were not increased in any of the five patients in which they were measured. 3. The association between changes in mean arterial pressure (MAP) and changes in DLIF for the group as a whole was assessed by analysing one data pair per patient, representing the maximal MAP. This correlation was significant (r = 0.75, P = 0.001). 4. Within individual patients, changes in MAP and changes in serum DLIF concentrations were significantly correlated (r greater than 0.50, P less than 0.05) in six of 15 hypertensive patients. 5. Digitalis-like factor (DLF) was measured by inhibition of (Na+,K+)-adenosine 5'-triphosphatase in five patients and DLF and DLIF were significantly correlated (r = 0.081, P = 0.0001). DLF and MAP were also significantly correlated (r = 0.59, P = 0.002). 6. This represents the first longitudinal study of the relationship between DLIF and blood pressure in hypertensive individuals, and the results suggest that DLIF may contribute to the increased blood pressure in some of these subjects.

Adult↗
PubMed1989

Increases in plasma digitalis-like factor activity during insulin-induced hypoglycemia.

Digitalis-like factor (DLF) appears to be widely distributed throughout the body, and has been specifically localized to the mammalian hypothalamus. In this study we monitored the DLF response to insulin-induced hypoglycemia in 11 normal males. Hypoglycemia was associated with a significant increase in serum DLF activity over basal values (40 +/- 5 pg digoxin Eq/ml, mean +/- SEM) at 60 min (83 +/- 8 pg digoxin Eq/ml) and 90 min (86 +/- 10 pg digoxin Eq/ml) following insulin administration (p less than 0.01). We measured the DLF response to insulin-induced hypoglycemia in other men after infusion of hypertonic saline (n = 8) or after oral water-loading (n = 8). Saline infusion (0.06 ml 5% saline/kg BW/min for 120 min prior to insulin infusion) or water loading (20 ml/kg BW over 60 min completed 30 min before insulin infusion) alone significantly increased serum DLF (saline: 21 +/- 5 to 60 +/- 18 pg digoxin Eq/ml, p less than 0.05; water: 18 +/- 11 to 49 +/- 15 digoxin Eq/ml, p less than 0.05). DLF activity was further significantly increased within each group 60 and 90 min after administration of insulin. In the group infused with hypertonic saline, insulin caused increases of serum DLF from 60 +/- 18 at time 0 to 170 +/- 17 pg digoxin Eq/ml at peak (p less than 0.01). Similarly, in the oral water-loaded group serum DLF increased from 49 +/- 15 at time 0 to 127 +/- 24 pg digoxin Eq/ml at peak (p less than 0.01) after they received insulin.2=

Adult↗
PubMed1987

Endogenous digitalis-like natriuretic factors.

There is increasing evidence for endogenous, circulating compounds that interact with the digitalis receptor of [Na,K]ATPase and with antidigoxin antisera. Circulating levels of these digitalis-like compounds increase in response to fluid or salt loading and appear to play a role in diseases characterized by fluid and salt retention, e.g. renal failure, liver disease, acromegaly, experimental and human hypertension, and preeclampsia. Because of assay nonspecificity, many diverse substances are being measured. Of the few compounds currently identified as having "digitalis-like" activity, none appears to be the natural ligand of the digitalis receptor and none appears linked with hypertension. Nevertheless, research still suggests that digitalis-like factors may have a central role in essential hypertension and related disorders.

Animals↗
PubMed1987

The possible role of digitalislike factors in pregnancy-induced hypertension.

A group of small, digitalislike compounds has been implicated in some forms of essential hypertension. Because of similarities between these forms of essential hypertension and pregnancy-induced hypertension, the presence of digitalislike factors in pregnancy-related fluids has been investigated. The factors are found in maternal sera with significantly higher levels of digitalislike activity, as monitored by digoxin radioimmunoassay, in the sera of third-trimester women with pregnancy-induced hypertension as compared to normotensive third-trimester controls (315 vs 195 pg digoxin equivalents/ml; p less than 0.001). Similarly, they are found in amniotic fluid, and significantly higher levels, as measured by radioimmunoassay (760 vs 540 pg digoxin equivalents/ml; p less than 0.0008) and by inhibition of ouabain-sensitive Na+,K+-adenosine triphosphatase (ATPase) (12.8 vs 2.7% inhibition; p less than 0.002), are found in those women whose pregnancies are complicated with hypertension. With purification, several digoxinlike immunoactive compounds are detected. Of these, some have a marked ability to inhibit ouabain-sensitive Na+,K+-ATPase. While as yet unidentified, these compounds have properties suggesting that they are not peptides, steroids, or fatty acids and lipids.

Amniotic Fluid↗
PubMed1986

Endogenous digitalis-like factors.

Recent research has demonstrated the presence of endogenous compounds in blood and urine that crossreact with antibodies raised against digoxin. Given the widespread therapeutic use of digoxin and its being monitored clinically by immunoassay, such digoxin-like immunoreactive compounds pose significant diagnostic and interpretive problems. Serum levels of this factor(s) approaching therapeutic digoxin levels have been found in digoxin-free patients in renal failure, pregnant women, and newborns. The compound is incompletely characterized; however, existing data suggest that it is a small, neutral, nonpeptidic compound. In serum it is highly protein bound, and alterations in this binding appear to give rise to the false-positive assay results. The urinary form is probably conjugated. Digoxin-like immunoreactive substances may play a role in volume homeostasis and appear associated with essential and pregnancy-induced hypertension. If such roles are primary, measurement of digoxin-like immunoreactive substances may prove to be of value in and of itself.

Animals↗
PubMed1986

Methods for eliminating interferences in digoxin immunoassays caused by digoxin-like factors.

Endogenous, circulating digoxin-like immunoreactive factors (DLIF) are known to cross react with many antisera used in digoxin assays, complicating the quantification of serum digoxin. We have explored ways to decrease or remove the interference from DLIF in such assays. Prolonging the assay incubation from 30 to 60 min decreased apparent digoxin concentrations (attributable to DLIF) by an average of 68% in the digoxin radioimmunoassays studied. The serum protein-binding of DLIF was also exploited to remove them from serum. Ultrafiltration, performed as part of a simple centrifugation step, removed approximately 90% of the DLIF. Analytical-recovery studies with true digoxin also demonstrated ultrafiltration to be an adequate method (greater than 95% of digoxin was recovered) for routine clinical use. Heat- or acid-precipitation of protein removed DLIF less effectively. Appropriate incubation times and ultrafiltration can dramatically minimize or eliminate DLIF interference in digoxin immunoassays.

Blood Proteins↗
PubMed1985

Protein binding of endogenous digoxin-immunoactive factors in human serum and its variation with clinical condition.

We previously identified endogenous digoxin-like immunoactivity in serum from pregnant women, newborn infants, and patients in renal failure. This activity is due to an endogenous factor(s) that cross-reacts with antibodies raised against digoxin. Using serum from the above sources as well as serum and urine from normal individuals, we further characterized these immunoreactive factors. The factors are water soluble, heat stable, and neutral in molecular charge. That isolated from serum has an apparent mol wt of 200 daltons, as estimated by membrane partitioning. The factor from urine has twice this apparent mol wt, an apparent higher affinity for the digoxin antisera, and is less resistant to acid hydrolysis. It may represent a conjugated metabolite of the factor from serum. The immunoactive factor in serum is noncovalently bound to serum protein, and we describe methods for estimating total, weakly protein-bound (i.e. heat-dissociable), tightly protein-bound (i.e. not heat-dissociable), and unbound (free) activity. Levels measured directly in serum by RIA represent the unbound and weakly protein-bound serum components. In normal subjects, over 90% of the total endogenous immunoactivity in serum is tightly but reversibly bound to protein and not detectable by direct measurement with conventional RIAs. Concentrations determined by direct measurement in serum from patients with renal failure [128 +/- 38 pg digoxin equivalents/ml (mean +/- SE)], pregnant women (141 +/- 12), and neonates (230 +/- 7) consistently exceeded those in normal subjects (61 +/- 3). Chromatography and ultrafiltration studies suggest that these differences are due to increased amounts of weakly protein-bound factor in these subjects rather than to a greater amount of total immunoactive factor. Altered protein binding of this endogenous factor seems to play a predominant role in the detection of digoxin-like immunoactivity in human serum. Our data also suggest that carrier proteins may play a prominent role in the transport of this endogenous immunoactive factor in blood.

Adult↗
PubMed1985

Endogenous digoxin immunoactivity is elevated in hypertensive pregnancy.

We have detected an endogenous digoxin-immunoreactive substance in the blood of third trimester pregnant women, of newborn infants and in amniotic fluids. In this report we present data showing an increase in blood levels of this endogenous substance in pregnant women with time of gestation (45 +/- 12, 125 +/- 32, and 195 +/- 27 pg/ml digoxin-equivalent for the 1st, 2nd, and 3rd trimesters, respectively, mean +/- SE). Preliminary evidence suggests the blood level of this substance is elevated in third-trimester hypertensive pregnant women (315 +/- 29 pg/ml). The immunoactive substance isolated from pregnant subjects is water soluble and reversibly bound to serum proteins. Heating the serum increases the measured immunoactivity. Exploration of the physiologic relevance of this endogenous substance or family of substances is in progress.

Digoxin↗
PubMed1984

Variable cross-reactivity of digoxin metabolites in digoxin immunoassays.

The authors investigated the cross-reactivity of the major known digoxin metabolites--digoxigenin, digoxigenin monodigitoxoside, digoxigenin bisdigitoxoside, and dihydrodigoxin--and of digitoxin in three 125I-radioimmunoassays and one enzyme immunoassay for digoxin. Digitoxin and dihydrodigoxin exhibit low cross-reactivity and nonparallel dilution responses for these assays. The cross-reactivities of the other three substances are significant for all assays studied with digoxigenin and monodigitoxoside having nonparallel and enhanced tracer displacement compared with digoxin itself. The authors demonstrate that because of nonparallel tracer displacement estimates of cross-reactivity calculated by the 50% displacement method fail to adequately predict the error induced in digoxin assays by digitoxin. They conclude that digoxin metabolites in serum are measured to various extents as the parent digoxin compound by all of the immunoassays they studied. In view of the varying biologic activity of digoxin metabolites and the large patient to patient variations in digoxin metabolism, the cross-reactivities the authors observe may help to explain the discrepancies in correlation of clinical response to measured serum digoxin values reported in other studies.

Cross Reactions↗
PubMed1984

Endogenous digoxin-immunoreactive substance in human pregnancies.

We report the presence of an immunoreactive digoxin-like substance in blood from third trimester pregnant women. The sera from 51 women in the third trimester of pregnancy were analyzed by 4 commercially available digoxin RIAs. None of these patients was receiving digoxin. Digoxin immunoreactivity was detected in all patients by 3 of 4 assays. The measured values, in nanograms per ml digoxin equivalent, were (mean +/- SD): method A, 0.27 +/- 0.05; method B, 0.28 +/- 0.07; method C, 0.01 +/- 0.01; and method D, 0.15 +/- 0.06. Method B measured values greater than 0.50 ng/ml in sera from 5 patients. Digoxin immunoactivity was not detectable 24 h postpartum, suggesting a half-life in serum of 6 h or less. Exogenous digoxin added to these serum samples resulted in quantitatively additive increments above the endogenous measured levels. Three of 4 digoxin RIAs did not distinguish between true digoxin and the endogenous substance present in the sera of third-trimester pregnant patients. Preliminary evidence suggests that the endogenous digoxin immunoactivity is not due to elevation of levels of major known steroids in the blood of these women. Clinical management of women requiring digoxin therapy during pregnancy, therefore, is complicated by the inability to assume the same therapeutic range of digoxin in serum during the third trimester of pregnancy as in adult nonpregnant individuals.

Adult↗