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Biomedical subjects

G M Briggs

Publications and source records attributed to G M Briggs.

At least 19 recordsLinked to original sources
PubMed2000

Uterine artery embolisation for symptomatic fibroids.

Traditional operative treatments for symptomatic fibroids--hysterectomy and myomectomy--involve considerable morbidity. Although morbidity is reduced with endoscopic surgery, this technique is not widely available, and has limitations. Embolisation of the pelvic vasculature is not a new procedure, having been used to treat postpartum and postsurgical bleeding for 20 years. It has only recently been used to treat symptomatic fibroids. Uterine artery embolisation can produce a mean reduction of 29%-51% in uterine volume at the time of the three-month review, with longer follow-up showing continued shrinkage and no regrowth. The range of shrinkage is highly variable, which needs to be explained to all potential candidates. Symptomatic relief is a more certain outcome, with relief of pelvic pressure symptoms in 91%-96% of women. There is a small risk of complications requiring hysterectomy, and the long-term effect on ovarian function is unknown.

Arteries↗
PubMed1997

Technetium-99m-sestamibi scanning in recurrent medullary thyroid carcinoma.

UNLABELLED: The presence of recurrent medullary thyroid carcinoma (MTC) can be detected early by measurement of serum calcitonin levels, but the localization of recurrent tumors is often difficult. METHODS: We compared 99mTc-sestamibi scans with computed tomographic (CT) scans in 10 patients with recurrent MTC, who had basal serum calcitonin values ranging from 220-61800 ng/liter. Two patients additionally had bone scans performed because of the clinical suspicion of bone metastases. RESULTS: Seven of the 10 patients had at least one site of abnormal 99mTc-sestamibi uptake, and all of these patients had basal serum calcitonin values > 6000 ng/liter. Only five of the 10 patients had abnormal CT scans. Technetium-99m-sestamibi scans detected 22 abnormal sites in the soft tissues of the neck and chest, while CT scans detected only 11 lesions in the neck and chest. Five of these sestamibi positive sites (in the neck and mediastinum of one patient) were confirmed histologically to represent MTC. When imaging the liver, CT scans detected 47 lesions in three patients while 99mTc-sestamibi scans detected none. One of these liver lesions was confirmed as MTC histologically. When imaging bone in two of the patients, the bone scans detected 17 abnormal sites, while 99mTc-sestamibi scans detected six abnormal sites. CONCLUSION: Technetium-99m-sestamibi scans complement CT and bone scans in the localization of recurrent MTC in patients with extremely high calcitonin levels. Technetium-99m-sestamibi scans are more sensitive than CT scans in the assessment of the soft tissues of the neck and chest, but CT is more appropriate for imaging hepatic lesions and bone scans are better for imaging bone lesions. Technetium-99m-sestamibi scans are unlikely to be abnormal in patients with only mild elevation of calcitonin.

Adult↗
PubMed1996

In vitro characterization of a novel series of platelet-derived growth factor receptor tyrosine kinase inhibitors.

In this report, we describe the discovery and characterization of a novel biarylhydrazone series of platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitors typified by the prototype WIN 41662 (3-phenyl-N1-[1-(4-pytidyl)pyrimidine]hydrazone). WIN 41662 inhibited PDGF-stimulated autophosphorylation of PDGF receptors from human vascular smooth muscle cells (hVSMC) with an IC50 value of 60 nM. The inhibitor appeared to be competitive with respect to substrate (Mn(2+)-ATP), having a calculated Ki of 15 +/- 5 nM. WIN 41662 was approximately 500-fold more potent in inhibiting the PDGF receptor tyrosine kinase than the p56lck tyrosine kinase. It was inactive against other serine/threonine and tyrosine kinases tested. WIN 41662 produced concentration-dependent inhibition of PDGF-stimulated receptor autophosphorylation in intact hVSMC with an IC50 < 100 nM. Intracellular Ca2+ mobilization and cell proliferation were events that occurred in hVSMC subsequent to PDGF receptor activation. WIN 41662 inhibited PDGF-stimulated Ca2+ mobilization and cell proliferation ([3H]TdR incorporation) with IC50 values of 430 nM and 2.3 microM, respectively. These effects appeared to be specifically related to PDGF receptor tyrosine kinase inhibition since WIN 41662 was not cytotoxic (in vitro) and since WIN 72039, a close structural analog that does not inhibit PDGF receptor tyrosine kinase, also did not inhibit PDGF-stimulated receptor autophosphorylation, Ca2+ mobilization, or hVSMC proliferation. Thus, WIN 41662 is representative of a novel class of selective PDGF receptor tyrosine kinase inhibitors that inhibit PDGF-regulated secondary events in intact cells.

Adenosine Triphosphate↗
PubMed1995

4,5-Dihydro-3-(methanesulfonamidophenyl)-1-phenyl-1H-2,4-benzodiazepines: a novel class III antiarrhythmic agents.

A series of 4,5-dihydro-3-[2-(methanesulfonamidophenyl)ethyl]-1-phenyl- 1H-2,4-benzodiazepines has been identified as potential antiarrhythmic agents that interact at the delayed rectifier myocardial potassium channels (IKr) and prolong the ventricular effective refractory period (ERP) in rabbit isolated Langendorff heart preparations. Structure-activity relationship (SAR) studies based upon prolongation of ERP indicate that placement of the sulfonamido group is important for potent activity in this model. Furthermore, methanesulfonamido has enhanced activity over its ethyl or trifluoromethyl analogs. Slightly greater activity was observed in compounds that had a heteroatom in the ethyl bridge that connects the methanesulfonamidophenyl to the benzodiazepine. Further incremental improvements in activity were noted when the 1-phenyl ring was substituted with a variety of substituents. Chirality of the compounds of interest in this series does not appear to influence activity in this model. Several of these compounds were chosen for advanced evaluation, and all possess high selectivity for blockade of potassium current in hearts relative to other ion channels. In addition, these compounds prolong cardiac refractoriness in dogs following oral dosing. Thus, these agents may represent potential new class III agents, but with the potential liability of myocardial IKr blockers.

Animals↗
PubMed1993

Identification of a specific radioligand for the cardiac rapidly activating delayed rectifier K+ channel.

Class III antiarrhythmic drugs show promise as effective treatments for the suppression of potentially lethal cardiac arrhythmias. Dofetilide (UK-68,798), is a potent class III antiarrhythmic agent that is presently under clinical investigation. The objective of this study was to determine whether [3H]dofetilide could be used as a specific radioligand for the rapidly activating delayed rectifier K+ channel of the heart. We find that [3H]dofetilide binds to high-affinity sites on guinea pig cardiac myocytes. Competition studies using unlabeled dofetilide indicate that binding is characterized by an IC50 of 100 +/- 30 nM (mean +/- SD, n = 13). Scatchard analyses of binding indicate a Kd of 70 +/- 6 nM and a maximal binding capacity of 0.30 +/- 0.02 pmol/mg protein. [3H]Dofetilide is displaced from guinea pig myocytes by dofetilide, clofilium, quinidine, sotalol, and sematilide with a rank order of potency that correlates with functional blockade of the rapidly activating delayed rectifier K+ current (correlation coefficient, 0.951; slope, 0.99 +/- 0.19; p = 0.014). High-affinity [3H]dofetilide binding is not detected in rat myocytes, which are devoid of delayed rectifier K+ current. We conclude that [3H]dofetilide specifically binds to sites associated with the rapidly activating delayed rectifier K+ channel of guinea pig myocardium.

Animals↗
PubMed1991

Diastolic dysfunction in hypertrophic cardiomyopathy. Effect on active force generation during systole.

We tested the hypothesis that intracellular Ca++ [( Ca++]i) overload underlies the diastolic dysfunction of patients with hypertrophic cardiomyopathy. Myocardial tissue was obtained at the time of surgery or transplantation from patients with hypertrophic cardiomyopathy and was compared with control myocardium obtained from patients without heart disease. The isometric contractions and electrophysiologic properties of all myocardial specimens were recorded by standard techniques and [Ca++]i was measured with the bioluminescent calcium indicator aequorin. In contrast to the controls, action potentials, Ca++ transients, and isometric contraction and relaxation were markedly prolonged in the hypertrophic myocardium, and the Ca++ transients consisted of two distinct components. At 38 degrees C and 1 Hz pacing frequency, a state of relative Ca++ overload appeared develop, which produced a rise in end-diastolic [Ca++]i, incomplete relaxation, and fusion of twitches with a resultant decrease in active tension development. We also found that drugs with increase [Ca++]i, such as digitalis, exacerbated these abnormalities, whereas drugs that lower [Ca++]i, such as verapamil, or agents that increase cyclic AMP, such as forskolin, prevented them. These results may explain why patients with hypertrophic cardiomyopathy tolerate tachycardia poorly, and may have important implications with regard to the pharmacologic treatment of patients with hypertrophic cardiomyopathy.

Adult↗
PubMed1990

Duplex ultrasound diagnosis of lower limb deep venous thrombosis.

To compare a non-invasive technique with contrast venography in the diagnosis of lower limb deep venous thrombosis (DVT), 355 patients (380 limbs) were examined over 15 months, using Duplex ultrasound. During this period, ascending venograms were performed in 53 of these patients (56 limbs) and the results were compared. Duplex detection of intraluminal thrombus was based on venous compressibility, Doppler-derived flow spectra, and visualization of thrombus within the lumen. Venography was designated the 'gold standard'. Duplex scanning had a sensitivity of 90.9%, and specificity of 91.3% in diagnosing DVT anywhere in the lower limb. Sensitivity, specificity, and accuracy were best in the femoral segment (95.2%, 100%, 98.2%, respectively), and fell slightly in the more distal limb: popliteal segment (90.4%, 97.1% and 94.6%), and calf veins (88.8%, 92.0% and 90.4%). These results indicate that duplex scanning produces sufficiently accurate data in the diagnosis of lower limb DVT to warrant its clinical use. It provides both the facility for diagnosis without the risks of contrast venography, and permits repeated imaging to follow the immediate progression of disease and efficacy of treatment.

Humans↗
PubMed1990

Effect of exercise conditioning on excitation-contraction coupling in aged rats.

We studied aged (24-26 mo) Fischer 344 rats after they underwent 8 wk of moderate exercise conditioning. Right ventricular papillary muscles were loaded with the calcium indicator aequorin. Electrophysiological recordings were also performed. Time to peak isometric tension in muscles from exercised aged rats (EAR) was shorter than in those from unexercised aged rats (UAR) (126 +/- 7 vs. 167 +/- 7 ms; P less than 0.01). Time to 50% relaxation from peak isometric tension was also shorter in EAR than in UAR (88 +/- 3 vs. 119 +/- 12 ms; P less than 0.05). There was a trend toward decrease in time to peak light and a significant decrease in time to 50% decline from peak light (33 +/- 4 ms in EAR vs. 59 +/- 17 ms in UAR; P = 0.001). Action potential amplitude was smaller in EAR than in UAR (67 +/- 4 vs. 82 +/- 3 mV; P = 0.003); however, action potential duration was longer (137 +/- 6 ms in EAR vs. 100 +/- 10 ms in UAR; P = 0.005). Right ventricular-to-body weight ratios revealed no evidence of hypertrophy in EAR compared with UAR. Cardiac tissue norepinephrine content was significantly greater in EAR than in UAR (1,212 +/- 25 vs. 630 +/- 105 ng/tissue; P = 0.02). In summary, exercise reversed the age-related prolongation of isometric contraction and associated intracellular calcium transient in the aged rat while it prolonged the transmembrane action potential. In addition, exercise in aged rats resulted in an increase in cardiac norepinephrine content.

Aequorin↗
PubMed1990

Role of intracellular calcium handling in force-interval relationships of human ventricular myocardium.

Experiments were performed in human working myocardium to investigate the relationship of intracellular calcium handling and availability to alterations in the strength of contraction produced by changes in stimulation rate and pattern. Both control and myopathic muscles exhibited potentiation of peak isometric force during the postextrasystolic contraction which was associated with an increase in the peak intracellular calcium transient. Frequency-related force potentiation was attenuated in myopathic muscles compared to controls. This occurred despite an increase in resting intracellular calcium and in the peak amplitude of the calcium transient as detected with aequorin. Therefore, abnormalities in contractile function of myopathic muscles during frequency-related force potentiation are not due to decreased availability of intracellular calcium, but more likely reflect differences in myofibrillar calcium responsiveness. Sarcolemmal calcium influx may also contribute to frequency-related changes in contractile force in myopathic muscles as suggested by a decrease in action potential duration with increasing stimulation frequency which is associated with fluctuations in peak calcium transient amplitude.

Action Potentials↗
PubMed1990

Properties of adult rat ventricular cells in long-term culture.

Adult mammalian cardiac myocytes in long-term culture offer advantages over intact heart tissue and freshly isolated ventricular cell preparations for a variety of experimental studies. To characterize this preparation in detail, we have examined the physiological properties of isolated adult rat ventricular cells maintained in culture for 10-14 days. Adult rat myocytes in longterm culture contracted spontaneously, with electrical coupling of adjacent cells, at 1-3 Hz. Most myocytes showed myofibrils with well-developed mitochondria and transverse tubular systems. They showed predominantly the V1 type myosin heavy chain isoform. In standard physiological superfusion media (pH 7.35), the intracellular pH of cultured cells measured with 2',7'-bis-carboxyethyl-carboxyfluorescein (BCECF) was 7.26 +/- 0.03, and was regulated by an amiloride-sensitive Na-H exchanger. The time-averaged free intracellular Ca2+ level of cultured adult rat myocytes measured with fura-2 at an extracellular Ca2+ level of 1 mM was 99.0 +/- 16.8 nM. Ouabain, Bay k 8644 or isoproterenol caused a significant rise in time-averaged intracellular [Ca2+], while the dihydropyridine Ca channel blocker nifedipine induced a decrease in intracellular [Ca2+]. Measurements of contractile state with an optical-video system demonstrated that ouabain. Bay k 8644, isoproterenol, or elevated extracellular [Ca2+] increased the amplitude of cell motion and the rates of both shortening and relaxation, while nifedipine lowered them. Microelectrode impalements indicated a resting potential of -75 +/- 1 mV and an action potential amplitude of 100 +/- 2 mV. Exposure of cultured adult rat cardiocytes to the thyroid hormone triiodothyronine (10 nM) for 48 hours resulted in a 2-fold increase in NaK-ATPase alpha-1 catalytic subunit mRNA accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Inhibition of aftercontractions and phasic calcium release by yohimbine in ferret papillary muscle.

Phasic release of calcium from the sarcoplasmic reticulum occurs in all mammalian cardiac preparations when the intracellular calcium concentration is sufficiently high. The phasic calcium release is often sufficient to trigger electrophysiological responses and aftercontractions. These can be detrimental to normal cardiac function. We induced phasic calcium release in ferret papillary muscles loaded with the calcium indicator aequorin. Development of phasic calcium release was associated with an increase in resting and peak [Ca2+]i. Inhibiting sodium channels with yohimbine reduced resting [Ca2+]i and prevented phasic calcium release. We propose a mechanism where by reduced [Na+]i, and the subsequent increased efflux of calcium via sodium/calcium exchange reduced [Ca2+]i.

Aequorin↗
PubMed1989

Dietary CHO and stimulation of carbohydrases along villus column of fasted rat jejunum.

Adult rats when fed a high carbohydrate diet of 70% sucrose or glucose for 24 h following a 4-day fast showed increased concentrations of intestinal sucrase-isomaltase (EC 3.2.1.48, EC 3.2.1.10) and maltase-glucoamylase (EC 3.2.1.20) but not lactase-phlorizin hydrolase (EC 3.2.1.23, EC 3.2.1.62). The concentration increases of these enzymes were accompanied by corresponding acceleration of their synthesis rates. Contrary to earlier studies by others, suggesting that upper villus cells in the fasted intestine are unresponsive to stimulation of sucrase activity by refeeding a high-sucrose diet, the concentration increases of both sucrase-isomaltase and maltase-glucoamylase were seen to occur in cells all along the length of the villus column. The earlier studies differed from the present study by basing enzyme assays relative to protein rather than the DNA content of villus cell fractions. We have shown that villus cells increase their protein content severalfold while migrating to villus tip, providing the basis for the difference between earlier and the present findings. Further evidence that stimulation of sucrase-isomaltase and maltase-glucoamylase by high carbohydrate is not restricted to the crypt and lower villus region was obtained by the finding that their synthesis rates appeared to be equally stimulated along the length of the villus column.

Animals↗
PubMed1988

Modulation by the thyroid state of intracellular calcium and contractility in ferret ventricular muscle.

The purpose of this study was to determine whether the cardiac contractile abnormalities induced by hyperthyroidism or hypothyroidism are caused by changes in intracellular Ca2+ handling or by alterations in the distribution of isoenzymes of ventricular myosin. Right ventricular papillary muscles obtained from euthyroid ferrets and ferrets treated with L-thyroxine (hyperthyroid) or methimazole (hypothyroid) were loaded with the calcium indicator aequorin for recording intracellular Ca2+ levels during isometric contraction. In muscles from the hypothyroid ferrets, peak tension was reduced and the duration of contraction prolonged compared to the controls; these changes were associated with a Ca2+ transient of decreased amplitude and prolonged duration. Hyperthyroidism produced opposite changes in the time course of the Ca2+ transient and the associated isometric contraction. Native polyacrylamide gel electrophoresis was performed on myosin extracted from the right ventricular free wall of control and treated ferrets. The hyperthyroid state was associated with new myosin formation as indicated by the appearance of three myosin bands on the pyrophosphate gel. Gels of myosin from hypothyroid and euthyroid ferrets showed a single band that migrated with the slowest of the three bands from the hyperthyroid ferrets. These results suggest that changes in both Ca2+ handling and myosin isoenzymes may contribute to the contractile abnormalities observed in hyperthyroidism. Alterations in intracellular Ca2+ handling alone may account for the contractile changes induced by hypothyroidism.

Animals↗
PubMed1988

Differential effect of DPI 201-106 on the sensitivity of the myofilaments to Ca2+ in intact and skinned trabeculae from control and myopathic human hearts.

The effects of DPI, a new inotropic agent, were compared in trabeculae carneae from control and myopathic human hearts loaded with aequorin, a bioluminescent calcium indicator that emits light when it combines with calcium, and in saponin-skinned trabeculae carneae from the same hearts. The force-pCa curves in saponin-skinned fibers and the peak force-peak Ca2+ curves in aequorin-loaded preparations were not significantly different between the control and myopathic tissues. The force-pCa curve in the skinned and aequorin-loaded preparations from the same control hearts displayed no significant shifts with the addition of DPI. In contrast, a leftward shift was present in the force-calcium relationship in the presence of DPI in aequorin-loaded and skinned muscles from myopathic hearts, indicating an increase in the sensitivity of the myofilaments to calcium. These differences in the modulation of calcium activation between myopathic and control tissues indicate that pharmacological agents may produce differential effects in normal and diseased hearts.

Actin Cytoskeleton↗
PubMed1988

Role of intracellular sodium in the regulation of intracellular calcium and contractility. Effects of DPI 201-106 on excitation-contraction coupling in human ventricular myocardium.

Experiments were performed to investigate the mechanism of action of DPI 201-106 on human heart muscle. In both control and myopathic muscles, DPI produced concentration-dependent increases in action potential duration, resting muscle tension, peak isometric tension, and duration of isometric tension. These changes were associated with increases in resting intracellular calcium and peak calcium transients as measured by aequorin. At higher concentrations of DPI, a second delayed Ca2+ transient (L') appeared. L' was inhibited by tetrodotoxin and ryanodine, suggesting that DPI acts at both the sarcolemma and the sarcoplasmic reticulum. DPI toxicity was manifested by after-glimmers and after-contractions reflecting a Ca2+-overload state: DPI effects were mimicked by veratridine, a Na+ channel agonist, and reversed by tetrodotoxin, yohimbine, and cadmium, Na+ channel antagonists. These results suggest that DPI acts primarily as a Na+ channel agonist. DPI may produce an increase in intracellular Ca2+ by increasing intracellular Na+ and altering Na+-Ca2+ exchange across the sarcolemma. DPI may also increase intracellular Ca2+ by directly altering sarcoplasmic reticulum Ca2+ handling.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1987

Ca2+ signals obtained with multiple indicators in mammalian vascular muscle cells.

Enzymatically isolated single cells from ferret portal vein were loaded with the fluorescent dyes fura-2 and chlortetracycline. Ferret portal vein intact strips were loaded with the luminescent indicator aequorin. At short loading times, fura-2 loading resulted in relatively homogeneous images of labeled cells. At longer loading times, extremely heterogeneous images were obtained that were similar to those produced by chlortetracycline, an indicator recognized to enter calcium-storage organelles. A significant effect of fura-2 on contractile function was detected at the long but not at the short loading time. Caffeine, which is known to deplete calcium from sarcoplasmic reticulum, decreased the fura-2 fluorescent intensity when cells were incubated for a long loading time but caused no statistically significant change at the short loading time. Caffeine caused no drop in the aequorin signal but did cause a drop in the chlortetracycline fluorescence. These results are consistent with the idea that aequorin reports cytoplasmic intracellular calcium concentration ([Ca2+]i), chlortetracycline reports stored calcium, and fura-2 reports a mixed signal from the cytoplasm and calcium-storage organelles depending on incubation time.

Aequorin↗
PubMed1986

Effect of yohimbine on action potentials recorded from isolated canine ventricular myocytes.

Yohimbine is used extensively as an alpha 2-adrenoceptor antagonist. This drug also inhibits sodium channels in the squid axon. In this study we investigated the electrophysiological effects of yohimbine in isolated canine ventricular myocytes. Yohimbine produced a reversible and concentration-dependent decrease in the maximum upstroke velocity and a slight increase in the action potential duration. The maximum upstroke velocity was reduced by over 90% by 10(-4) M yohimbine. It did not effect the resting or plateau potentials in control or isoproterenol-treated cells. Delayed after-depolarizations were also inhibited. These data suggest that yohimbine can produce a local anesthetic effect which is primarily due to inhibition of sodium channels.

Action Potentials↗