The Effect of beta Adrenergic Stimulation on QT and QTc Interval in Syncope Children with or without Coexisting Ventricular Arrhythmias

AbstractThe variant c.926C > T (p.T309I) in KCNQ1 gene was identified in 10 putatively unrelated Czech families with long QT syndrome (LQTS). Mutation carriers (24 heterozygous individuals) were more symptomatic compared to their non-affected relatives (17 individuals). The carriers showed a mild LQTS phenotype including a longer QTc interval at rest (466 ± 24 ms vs. 418 ± 20 ms) and after exercise (508 ± 32 ms vs. 417 ± 24 ms), 4 syncopes and 2 aborted cardiac arrests. The same haplotype associated with the c.926C > T variant was identified in all probands. Using the whole cell patch clamp technique and confocal microscopy, a complete loss of channel function was revealed in the homozygous setting, caused by an impaired channel trafficking. Dominant negativity with preserved reactivity to β-adrenergic stimulation was apparent in the heterozygous setting. In simulations on a human ventricular cell model, the dysfunction resulted in delayed afterdepolarizations (DADs) and premature action potentials under β-adrenergic stimulation that could be prevented by a slight inhibition of calcium current. We conclude that the KCNQ1 variant c.926C > T is the first identified LQTS-related founder mutation in Central Europe. The dominant negative channel dysfunction may lead to DADs under β-adrenergic stimulation. Inhibition of calcium current could be possible therapeutic strategy in LQTS1 patients refractory to β-blocker therapy.

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Compounds that increase cAMP prevent ischemia-reperfusion pulmonary capillary injury

Journal of Applied Physiology ◽

10.1152/jappl.1992.72.2.492 ◽

1992 ◽

Vol 72 (2) ◽

pp. 492-497 ◽

Cited By ~ 76

Author(s):

W. K. Adkins ◽

J. W. Barnard ◽

S. May ◽

A. F. Seibert ◽

J. Haynes ◽

...

Keyword(s):

Adenylate Cyclase ◽

Vascular Permeability ◽

Vascular Resistance ◽

Capillary Permeability ◽

Ischemia Reperfusion ◽

Receptor Activation ◽

Adrenergic Stimulation ◽

Beta Adrenergic ◽

Beta Receptor ◽

Pulmonary Capillary

This study evaluated the physiological effects of compounds that increase adenosine 3′,5′-cyclic monophosphate (cAMP) on changes in pulmonary capillary permeability and vascular resistance induced by ischemia-reperfusion (I-R) in isolated blood-perfused rabbit lungs. cAMP was elevated by 1) beta-adrenergic stimulation with isoproterenol (ISO, 10(-5) M), 2) post-beta-receptor stimulation of adenylate cyclase with forskolin (FSK, 10(-5) M), 3) and dibutyryl cAMP (DBcAMP, 1 mM), a cAMP analogue. Vascular permeability was assessed by determining the capillary filtration coefficient (Kf,c), and capillary pressure was measured using the double occlusion technique. The total, arterial, and venous vascular resistances were calculated from measured pulmonary arterial, venous, and capillary pressures and blood flow. Reperfusion after 2 h of ischemia significantly (P less than 0.05) increased Kf,c (from 0.115 +/- 0.028 to 0.224 +/- 0.040 ml.min-1.cmH2O-1.100 g-1). These I-R-induced changes in capillary permeability were prevented when ISO, FSK, or DBcAMP was added to the perfusate at reperfusion (0.110 +/- 0.022 and 0.103 +/- 0.021, 0.123 +/- 0.029 and 0.164 +/- 0.024, and 0.153 +/- 0.030 and 0.170 +/- 0.027 ml.min-1.cmH2O-1.100 g-1, respectively). I-R significantly increased total, arterial, and venous vascular resistances. These increases in vascular resistance were also blocked by ISO, FSK, and DBcAMP. These data suggest that beta-adrenergic stimulation, post-beta-receptor activation of adenylate cyclase, and DBcAMP prevent the changes in pulmonary vascular permeability and vascular resistances caused by I-R in isolated rabbit lungs through a mechanism involving an increase in intracellular levels of cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)

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Different effects of alpha- and beta-adrenergic stimulation on cytosolic pH and myofilament responsiveness to Ca2+ in cardiac myocytes.

Circulation Research ◽

10.1161/01.res.71.4.870 ◽

1992 ◽

Vol 71 (4) ◽

pp. 870-882 ◽

Cited By ~ 57

Author(s):

G Gambassi ◽

H A Spurgeon ◽

E G Lakatta ◽

P S Blank ◽

M C Capogrossi

Keyword(s):

Cardiac Myocytes ◽

Adrenergic Stimulation ◽

Cytosolic Ph ◽

Beta Adrenergic

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Relation between contractile function and regulatory cardiac proteins in hypertrophied hearts

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1996.270.6.h2021 ◽

1996 ◽

Vol 270 (6) ◽

pp. H2021-H2028 ◽

Cited By ~ 9

Author(s):

B. Stein ◽

S. Bartel ◽

U. Kirchhefer ◽

S. Kokott ◽

E. G. Krause ◽

...

Keyword(s):

Sarcoplasmic Reticulum ◽

Troponin I ◽

Contractile Function ◽

Papillary Muscles ◽

Camp Accumulation ◽

Adrenergic Stimulation ◽

Beta Adrenergic ◽

C Protein ◽

Camp Formation ◽

Phosphate Incorporation

The aim of this study was to examine the mechanism(s) underlying the reduced isoproterenol-induced positive inotropic and lusitropic effects in hypertrophied hearts. Chronic beta-adrenergic stimulation (2.4 mg isoproterenol.kg-1. day-1 for 4 days) induced cardiac hypertrophy by 33 +/- 2% in rats. A parallel downregulation of phospholamban (PLB) and sarcoplasmic reticulum Ca2(+)-ATPase (SERCA2) protein expression by 49 and 40%, respectively, was observed, whereas troponin I (TNI) and C protein remained unchanged. In papillary muscles from chronically beta-adrenergically stimulated rats, the isoproterenol-induced positive inotropic and lusitropic effects, as well as adenosine 3',5'-cyclic monophosphate (cAMP) accumulation, were attenuated compared with those in control animals. Acute exposure to isoproterenol induced phosphate incorporation into PLB, TNI, and C protein of 48 +/- 4.6, 55 +/- 5.0, and 27 +/- 4.9 pmol/mg homogenate protein, respectively, in control animals. In the hypertrophied hearts, phosphate incorporation into PLB was reduced by 76%, whereas phosphate incorporation into TNI or C protein remained unchanged. In conclusion, chronic beta-adrenergic stimulation reduced the isoproterenol-stimulated positive inotropic and lusitropic effects in papillary muscles, which were accompanied by 1) diminished cAMP formation, 2) attenuation of cAMP-mediated PLB phosphorylation, and 3) downregulation of PLB and SERCA2 protein.

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Changes in vascular responsiveness following chronic exposure to cold in the rat

Journal of Applied Physiology ◽

10.1152/jappl.1983.55.3.823 ◽

1983 ◽

Vol 55 (3) ◽

pp. 823-829 ◽

Cited By ~ 10

Author(s):

B. A. Bryar ◽

M. J. Fregly ◽

F. P. Field

Keyword(s):

Smooth Muscle ◽

Smooth Muscles ◽

Aortic Tissue ◽

Adrenergic Stimulation ◽

Beta Adrenergic ◽

Aortic Smooth Muscle ◽

Beta Adrenergic Agonists ◽

Adrenergic Antagonist ◽

Vascular Responsiveness ◽

High Concentrations

The responsiveness of smooth muscle from rings of aortic tissue of cold-acclimated (CA, 6 degrees C, 5-15 wk) rats to both alpha- and beta-adrenergic agonists and KCl was tested and compared with that of warm-adapted (25 degrees C) controls. alpha-Adrenergic stimulation, induced by low doses (10(-8)-10(-7) M) of phenylephrine and norepinephrine in the presence and absence of the beta-adrenergic antagonist, propranolol, resulted in the development of less active tension by aortic smooth muscle from CA rats than from controls. Similar results were observed with the weakly alpha 1-adrenergic agonistic activities of tyramine, clonidine, and high concentrations of isoproterenol (10(-6)-10(-4) M). There was also a significant reduction in the tension developed by smooth muscles of the aortas from CA rats when depolarized with KCl in concentrations ranging from 8 to 20 mM. In contrast, aortic smooth muscle, contracted to 75% of maximum with KCl, showed an enhanced relaxation to the beta-adrenergic agonist, isoproterenol, in CA rats. These studies suggest that acclimation of rats to cold results in both a decrease in alpha-adrenergic responsiveness and an increase in beta-adrenergic responsiveness in vascular smooth muscle as well as a change in the biochemical events that couple activation of adrenergic receptors to changes in vasomotor tone.

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Beta-Adrenergic Stimulation of Adenylate Cyclase and Alpha-Adrenergic Inhibition of Adenylate Cyclase: GTP-Binding Proteins as Macromolecular Messengers

Myocardial Injury - Advances in Experimental Medicine and Biology ◽

10.1007/978-1-4684-4472-8_6 ◽

1983 ◽

pp. 91-111 ◽

Cited By ~ 1

Author(s):

Lee E. Limbird

Keyword(s):

Adenylate Cyclase ◽

Binding Proteins ◽

Adrenergic Stimulation ◽

Beta Adrenergic ◽

Gtp Binding Proteins ◽

Gtp Binding ◽

Stimulation Of

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Effects of epinephrine on insulin-stimulated glucose uptake and GLUT-4 phosphorylation in muscle

AJP Cell Physiology ◽

10.1152/ajpcell.1997.273.3.c1082 ◽

1997 ◽

Vol 273 (3) ◽

pp. C1082-C1087 ◽

Cited By ~ 46

Author(s):

A. D. Lee ◽

P. A. Hansen ◽

J. Schluter ◽

E. A. Gulve ◽

J. Gao ◽

...

Keyword(s):

Skeletal Muscle ◽

Glucose Uptake ◽

Glucose Transport ◽

Glucose Transporter ◽

Inhibitory Effect ◽

Phosphate Concentration ◽

Intrinsic Activity ◽

Adrenergic Stimulation ◽

Beta Adrenergic ◽

Glut 4

beta-Adrenergic stimulation has been reported to inhibit insulin-stimulated glucose transport in adipocytes. This effect has been attributed to a decrease in the intrinsic activity of the GLUT-4 isoform of the glucose transporter that is mediated by phosphorylation of GLUT-4. Early studies showed no inhibition of insulin-stimulated glucose transport by epinephrine in skeletal muscle. The purpose of this study was to determine the effect of epinephrine on GLUT-4 phosphorylation, and reevaluate the effect of beta-adrenergic stimulation on insulin-activated glucose transport, in skeletal muscle. We found that 1 microM epinephrine, which raised adenosine 3',5'-cyclic monophosphate approximately ninefold, resulted in GLUT-4 phosphorylation in rat skeletal muscle but had no inhibitory effect on insulin-stimulated 3-O-methyl-D-glucose (3-MG) transport. In contrast to 3-MG transport, the uptakes of 2-deoxyglucose and glucose were markedly inhibited by epinephrine treatment. This inhibitory effect was presumably mediated by stimulation of glycogenolysis, which resulted in an increase in glucose 6-phosphate concentration to levels known to severely inhibit hexokinase. We conclude that 1) beta-adrenergic stimulation decreases glucose uptake by raising glucose 6-phosphate concentration, thus inhibiting hexokinase, but does not inhibit insulin-stimulated glucose transport and 2) phosphorylation of GLUT-4 has no effect on glucose transport in skeletal muscle.

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Inotropic sensitivity to beta-adrenergic stimulation in early sepsis

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1988.255.4.h699 ◽

1988 ◽

Vol 255 (4) ◽

pp. H699-H703 ◽

Cited By ~ 4

Author(s):

L. W. Smith ◽

K. H. McDonough

Keyword(s):

Contractile Function ◽

Plasma Catecholamines ◽

Left Ventricular ◽

Adrenergic Stimulation ◽

Maximal Increase ◽

Beta Adrenergic ◽

Arterial Blood ◽

Myocardial Contractile ◽

Early Sepsis

In early sepsis, maintenance of in vivo cardiovascular performance is at least partly dependent on sympathetic support to hearts with intrinsic contractile defects. Yet prolonged sympathetic stimulation, as occurs in sepsis, would be expected to alter the heart's ability to respond to this stimulation. We have investigated myocardial inotropic sensitivity to beta-adrenergic stimulation in a model of sepsis in which animals, at the time studied, exhibited bacteremia, normal arterial blood pressure and cardiac output, elevated heart rate, and elevated plasma catecholamines. Intrinsic myocardial contractile function, as assessed by the maximal rate of left ventricular pressure development (LV dP/dtmax) in an isovolumically contracting heart preparation, was significantly depressed in septic animals. To determine whether hearts from septic animals could respond normally to beta-adrenergic stimulation, we studied inotropic response to a bolus of isoproterenol in these isolated hearts. With maximal isoproterenol stimulation, hearts from septic animals were able to attain the same dP/dtmax as were hearts from control animals. With lower levels of isoproterenol, there was also no difference in inotropic indexes between the two groups when response was expressed as a percent of the maximal increase in dP/dtmax achieved with isoproterenol. These results suggest that in early sepsis, despite intrinsic myocardial contractile dysfunction, the ability of the heart to modulate its inotropic state in response in beta-adrenergic stimulation is intact.

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