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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
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↗
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↗
PubMed1986

Electrophysiological properties of cultured adult rat ventricular cardiac muscle cells.

Action and resting potential characteristics of isolated adult rat myocardial cells maintained in culture for 10-28 days are described. Resting potentials averaged -76.3 +/- 2 mV in 5 mM extracellular [K+] ([K+]o). Resting potentials changed by 54.3 mV/decade change in [K+]o for concentrations greater than 5 mM. The average maximum rate of rise of action potential (Vmax) was 117.7 +/- 10 V/s with overshoots of 34.6 +/- 2.5 mV. Action potential durations (APD) to 0 and -40 mV and full repolarization were 21.8 +/- 3.9, 36.3 +/- 6.0, and 206 +/- 16.9 ms respectively. Action potential configurations were qualitatively similar to those previously reported by others for rat myocardial tissue or freshly dissociated cells. Tetrodotoxin (4 micrograms/ml) decreased Vmax to less than 24 V/s and decreased overshoot and APD. Isoproterenol (10(-8) M) decreased APD with slight elevation of the overshoot. Verapamil (10(-5) to 10(-4) M) depressed overshoot and plateau while slowing the final phase of repolarization. Verapamil (10(-4) M) depressed upstroke velocity and blocked excitability. While APDs recorded from these cultured cells are apparently longer than those reported by others for rat myocardial APDs, the values of all other electrophysiological parameters recorded are within the limits previously reported for normal rat myocardial tissue. These data indicate that adult rat myocardial cells maintained in tissue culture for 10-28 days possess electrophysiological properties and responses to pharmacological agents similar to adult rat myocardial tissue or undamaged freshly isolated cells.

Action Potentials↗
PubMed1984

Decrease in bone density in young male guinea pigs fed high levels of ascorbic acid.

These experiments were conducted to investigate the effects of high oral intakes of ascorbic acid on bone metabolism in young guinea pigs and to inquire into the mechanism mediating these effects. Male guinea pigs 14 days old fed 8.7% of ascorbic acid for 6 weeks had decreased bone density and decreased urinary hydroxyproline compared to control animals fed 0.2% of ascorbic acid. To assess whether these changes were due to the acidity of the diet or to vitamin activity, salts of ascorbic acid, salts of erythorbic acid and free erythorbic acid were fed. There were no significant bone changes in any of these groups. The results strongly indicate that the acidity of ascorbic acid plays a part in the decrease in bone density but do not rule out that some other metabolic property specific to ascorbic acid may also be implicated.

Aging↗
PubMed1983

Contrast agent-induced thrombophlebitis following leg phlebography: meglumine loxaglate versus meglumine lothalamate.

A comparison was made of the incidence of venous thrombophlebitis resulting from the use of a high-osmolality contrast medium (Conray 60%, meglumine ioxaglate) and a low-osmolality contrast medium (Hexabrix 59%, meglumine iothalamate). In 30 patients with varicose veins, Conray was injected into one leg and Hexabrix into the other. The incidence of thrombophlebitis was then determined using the iodine-125 fibrinogen uptake test in a prospective, randomized, double-blind study. There was significantly less thrombophlebitis with Hexabrix than with Conray and the authors conclude that Hexabrix is safer for phlebography. Hexabrix is also stable in solution, only slightly more expensive than Conray, and one fifth the cost of metrizamide.

Adult↗
PubMed1983

Iohexol and meglumine iothalamate in phlebography of the leg. Comparison of the tolerance.

Fifty patients were examined by ascending phlebography of both legs in a prospective, double blind, within-patient series. Each leg was randomly allocated to the examination using either iohexol 300 mg I/ml or meglumine iothalamate 280 mg I/ml as the contrast medium. Immediate side effects were recorded in all patients, and delayed effects in 45 patients. Statistical analysis using the chi-square test showed that iohexol produced significantly less immediate pain in the leg than meglumine iothalamate. Iohexol produced significantly less nausea, and vomiting during the injection than meglumine iothalamate. No significant difference was found in the incidence of delayed pain and swelling with either medium. The quality of the films produced by iohexol was significantly better than that obtained with meglumine iothalamate.

Adult↗