Mechanisms underlying early and delayed afterdepolarizations induced by catecholamines

1990 ◽  
Vol 258 (6) ◽  
pp. H1796-H1805 ◽  
Author(s):  
S. G. Priori ◽  
P. B. Corr
Keyword(s):  
Action Potential ◽  
Ventricular Myocytes ◽  
Receptor Activation ◽  
Adrenergic Stimulation ◽  
Adrenergic Agonist ◽  
Beta Adrenergic ◽  
Low Concentrations ◽  
Coupling Interval ◽  
Major Factors ◽  
Extracellular Sodium

The relative influence of alpha- and beta-adrenergic receptor activation in eliciting early (EADs) and delayed (DADs) after depolarizations was assessed using intracellular microelectrode recordings in isolated adult canine ventricular myocytes. Normoxic myocytes were exposed to the alpha-adrenergic agonist phenylephrine (10(-8)-10(-6) M) or the beta-adrenergic agonist isoproterenol (10(-9)-10(-6) M) during pacing at different frequencies (0.5-4 Hz). alpha-Adrenergic stimulation resulted in a dose-dependent prolongation of action potential duration but failed to induce either EADs or DADs. beta-Adrenergic stimulation with isoproterenol at low concentrations (10(-9)-10(-8) M) induced a prolongation of the action potential, whereas higher concentrations (10(-7) and 10(-6) M) resulted in a marked shortening. Isoproterenol elicited single or multiple (2-5) DADs at concentrations from 10(-8) to 10(-6) M, with a corresponding increase in the amplitude of the DADs and decrease in the coupling interval as cells were paced at increasing rates. DADs often initiated and maintained sustained triggered rhythms that spontaneously terminated. Isoproterenol (10(-8)-10(-6) M) also elicited EADs in 80% of cells at the highest concentration utilized (10(-6) M) and at intermediate pacing frequencies (1-2 Hz). EADs often occurred with a 2:1 or 3:1 pattern. EADs and DADs induced by isoproterenol were reversibly abolished by low extracellular sodium, ryanodine (10(-6) M), or benzamil (10(-4) M), thus indicating that Ca2+ release from the sarcoplasmic reticulum and extracellular Na+ concentration are two major factors in the development of both types of afterdepolarizations. The demonstration that EADs can be induced by isoproterenol in ventricular muscle suggest a novel pathway for beta-adrenergic receptors to mediate arrhythmogenesis in the intact heart.

Compounds that increase cAMP prevent ischemia-reperfusion pulmonary capillary injury

1992 ◽  
Vol 72 (2) ◽  
pp. 492-497 ◽  
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)

Altered beta-adrenergic and muscarinic response of CFTR Cl- current in dialyzed cardiac myocytes

1995 ◽  
Vol 268 (5) ◽  
pp. H1795-H1802
Author(s):  
S. I. Zakharov ◽  
R. D. Harvey
Keyword(s):  
Patch Clamp ◽  
Muscarinic Receptor ◽  
Ventricular Myocytes ◽  
Receptor Activation ◽  
Current Response ◽  
Patch Clamp Technique ◽  
Beta Adrenergic ◽  
Perforated Patch ◽  
Clamp Technique ◽  
Perforated Patch Clamp

Autonomic regulation of the cardiac cystic fibrosis transmembrane conductance regulator (CFTR) Cl- current was studied in isolated guinea pig ventricular myocytes using various configurations of the whole cell patch-clamp technique. When currents were recorded using the conventional patch-clamp technique, it was possible to continue to activate the Cl- current on repeated exposure to isoproterenol (Iso) for up to 60 min after initiating dialysis. However, there was significant rundown of the magnitude of the Cl- current response to the maximally stimulating concentrations of Iso. In addition, the concentration of Iso that produced half-maximal activation of the Cl- current (K1/2) increased with time. Conversely, the K1/2 for acetylcholine inhibition of the Iso-activated current decreased with time. When currents were recorded using the perforated patch-clamp technique, the sensitivity to both beta-adrenergic- and muscarinic-receptor stimulation was stable. Immediately after initiation of dialysis with the conventional patch-clamp technique, the sensitivity to Iso was nearly identical to that determined using the perforated patch-clamp technique. However, the initial sensitivity to muscarinic-receptor activation was significantly greater. These results indicate that cell dialysis associated with conventional patch-clamp techniques not only results in a time-dependent rundown of current amplitude, but it also significantly alters the concentration dependence of beta-adrenergic and muscarinic-receptor regulation of ion channel function.

Troponin I phosphorylation in spontaneously hypertensive rat heart: effect of beta-adrenergic stimulation

1997 ◽  
Vol 273 (3) ◽  
pp. H1440-H1451 ◽  
Author(s):  
B. K. McConnell ◽  
C. S. Moravec ◽  
I. Morano ◽  
M. Bond
Keyword(s):  
Troponin I ◽  
Ventricular Myocytes ◽  
Spontaneously Hypertensive Rat ◽  
Left Ventricular ◽  
Adrenergic Stimulation ◽  
Beta Adrenergic ◽  
Spontaneously Hypertensive ◽  
Myosin Light Chain 2 ◽  
Wistar Kyoto ◽  
Phospholamban Phosphorylation

We compared baseline and protein kinase A (PKA)-dependent troponin I (TnI) phosphorylation in 32Pi-labeled left ventricular myocytes from hearts of 26-wk spontaneously hypertensive rats (SHR) and Wistar-Kyoto controls (WKY). TnI phosphorylation was normalized to myosin light chain 2 phosphorylation, which was invariant. There was no difference in baseline TnI phosphorylation in SHR and WKY, but stimulation with isoproterenol, norepinephrine plus prazosin, forskolin, chloroadenosine 3',5'-cyclic monophosphate, or 3-isobutyl-1-methylxanthine caused a greater increase in TnI phosphorylation in the SHR than in the WKY. This was observed both in the presence and absence of the phosphatase inhibitor calyculin A; thus the differences in TnI phosphorylation between SHR and WKY are not due to decreased phosphatase activity in the SHR. After stimulation of the beta-adrenergic pathway, phospholamban phosphorylation was not different in SHR and WKY, indicating that the observed differences may be specific for PKA phosphorylation of TnI. The increased PKA-dependent TnI phosphorylation in the SHR resulted in decreased Ca2+ sensitivity of actomyosin adenosinetriphosphatase activity as compared with the WKY. We conclude that increased PKA-dependent TnI phosphorylation in the SHR may contribute to the impaired response to sympathetic stimulation.

Abstract 279: Loss Of Rad GTPase Produces A Sympathomimetic Cardiac Phenotype Leading To Calcium Overload And Arrhythmia.

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Janet R Manning ◽  
Guo Yin ◽  
John Penn ◽  
Catherine Kaminski ◽  
Gail Sievert ◽  
...  
Keyword(s):  
Calcium Current ◽  
Ventricular Myocytes ◽  
Isolated Heart ◽  
Small Gtpase ◽  
Calcium Transients ◽  
Calcium Handling ◽  
Adrenergic Stimulation ◽  
Biological Organization ◽  
Beta Adrenergic ◽  
Cardiac Phenotype

Background: Rad is a small GTPase that regulates inward calcium current in excitable cells. In human heart failure, calcium dysregulation is accompanied by lowered levels of Rad expression, and dampened responsiveness to beta-adrenergic stimulation. However, the effects of Rad ablation on calcium cycling in the heart have yet to be examined. Hypothesis: Loss of Rad emulates beta-adrenergic stimulation in cardiac myocytes, elevating calcium levels, and promoting after depolarizations. Methods: The role of Rad was evaluated using knockout mice (RadKO)at several levels of biological organization. Inward calcium current, action potentials, fractional shortening, and calcium transients were measured in isolated ventricular myocytes. Functional parameters were recorded in the isolated working heart, and telemetry was used to monitor ECGs in intact freely-roaming mice. Results: Isolated ventricular myoctyes from Rad null mice display increased ICaL density, greater inward current at low voltages, and after depolarizations at low frequencies. Isolated cells exhibit increased diastolic calcium levels and increased dynamic calcium changes in transient amplitude during pacing. Further, RadKO cardiomyocytes develop a significantly greater number of spontaneous calcium transients than wildtype cohorts. Ventricular myocytes and intact working hearts from RadKO mice fail to respond to beta-adrenergic stimulation at the level of channel activation, calcium transient kinetics, and exhibit a significantly dampened change in +dP/dt in the isolated heart. Consistent with these effects, PKA substrates are phosphorylated at baseline in RadKO cardiomyocytes, suggesting tonic PKA activation. Conclusion: These data suggest the new provocative hypothesis that beta-adrenergic-mediated changes in excitation, calcium handling, and heart contraction involve relief of Rad-dependent negative regulation of channel function.

Selective attenuation by adenosine of arrhythmogenic action of isoproterenol on ventricular myocytes

2001 ◽  
Vol 280 (6) ◽  
pp. H2789-H2795 ◽  
Author(s):  
Yejia Song ◽  
John C. Shryock ◽  
Harm J. Knot ◽  
Luiz Belardinelli
Keyword(s):  
Action Potential ◽  
Receptor Agonist ◽  
Ventricular Myocytes ◽  
Adrenergic Stimulation ◽  
Motion Detector ◽  
Adenosine Receptor Agonist ◽  
Action Potential Plateau ◽  
Delayed Afterdepolarizations ◽  
Isolated Ventricular Myocytes ◽  
Potential Plateau

We examined whether adenosine equally attenuated the stimulatory effects of isoproterenol on arrhythmic activity and twitch shortening of guinea pig isolated ventricular myocytes. Transmembrane voltages and whole cell currents were recorded with patch electrodes, and cell twitch shortening was measured using a video-motion detector. Isoproterenol increased the action potential duration at 50% repolarization (APD50), L-type Ca2+ current [ I Ca(L)], and cell twitch shortening and induced delayed afterdepolarizations (DAD), transient inward current ( I Ti), and aftercontractions. Adenosine attenuated the arrhythmogenic actions of isoproterenol more than it attenuated the effects of isoproterenol on APD50, I Ca(L), or twitch shortening. Adenosine (0.1–100 μmol/l) decreased the amplitude of DADs by 30 ± 6% to 92 ± 5% but attenuated isoproterenol-induced prolongation of the APD50 by only 14 ± 4% to 59 ± 4% and had no effect on the voltage of action potential plateau. Adenosine (30 μmol/l) inhibited I Ti by 91 ± 4% but decreased isoproterenol-stimulated I Ca(L) by only 30 ± 12%. Isoproterenol-induced aftercontractions were abolished by adenosine (10 μmol/l), whereas the amplitude of twitch shortening was not reduced. The effects of adenosine on twitch shortenings and aftercontractions were mimicked by the A1-adenosine receptor agonist CPA ( N 6-cyclopentyladenosine) and by ryanodine. In conclusion, adenosine antagonized the proarrhythmic effect of β-adrenergic stimulation on ventricular myocytes without reducing cell twitch shortening.

scholarly journals Beta-adrenergic stimulation reverses the I Kr–I Ks dominant pattern during cardiac action potential

2014 ◽  
Vol 466 (11) ◽  
pp. 2067-2076 ◽  
Author(s):  
Tamas Banyasz ◽  
Zhong Jian ◽  
Balazs Horvath ◽  
Shaden Khabbaz ◽  
Leighton T. Izu ◽  
...  
Keyword(s):  
Action Potential ◽  
Cardiac Action Potential ◽  
Adrenergic Stimulation ◽  
Beta Adrenergic ◽  
Cardiac Action ◽  
Dominant Pattern
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