Molecular mechanism of doxorubicin-induced anticholinergic effect in guinea-pig atria

2000 ◽  
Vol 78 (6) ◽  
pp. 483-489 ◽  
Author(s):  
Yukio Hara ◽  
Kyosuke Temma ◽  
Zin Sekiya ◽  
Akihito Chugun ◽  
Hiroshi Kondo
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Acetylcholine Receptor ◽  
Action Potential Duration ◽  
Molecular Mechanisms ◽  
Muscarinic Acetylcholine Receptor ◽  
Anticholinergic Effect ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Muscarinic Acetylcholine

The molecular mechanisms of anticholinergic actions of doxorubicin were examined by electrophysiological methods in atria and myocytes isolated from guinea-pig heart. A direct anticholinergic action of doxorubicin was confirmed with antagonistic action on carbachol-induced negative inotropic effect in atria. Both carbachol and adenosine produced shortening of action potential duration in atria measured by a microelectrode method. Doxorubicin (10-100 µM) inhibited the carbachol-induced action potential shortening in a concentration-dependent manner. However, doxorubicin did not antagonize the shortening elicited by adenosine. The whole-cell voltage clamp technique was performed to induce the muscarinic acetylcholine-receptor-operated K+ current (IK.ACh) in atrial myocytes loaded with GTP or GTPgammaS, a nonhydrolysable analogue of GTP. Doxorubicin (1-100 µM) suppressed carbachol-induced IK.ACh in a concentration-dependent manner (IC50 = 5.6 µM). In contrast, doxorubicin (10 and 100 µM) suppressed neither adenosine-induced IK.ACh nor GTPgammaS-induced IK.ACh. These results indicate that doxorubicin produces a direct anticholinergic effect through the muscarinic receptors in atrial myocytes.Key words: action potential duration, anticholinergic action, atrial cell, doxorubicin, the muscarinic acetylcholine-receptor-operated K+ current.

scholarly journals Anticholinergic effect of 2-aminopyridine and its sulfonylcarbamide derivatives on electromechanical activity in guinea pig atrium

Medicina ◽  
2007 ◽  
Vol 43 (10) ◽  
pp. 808 ◽  
Author(s):  
Vida Gendvilienė ◽  
Danguolė Zablockaitė ◽  
Irma Martišienė ◽  
Herta Gurskaitė ◽  
Antanas Stankevičius
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Action Potential Duration ◽  
Pyridine Ring ◽  
Muscarinic Acetylcholine Receptor ◽  
New Drugs ◽  
Anticholinergic Effect ◽  
Contraction Force ◽  
Control Modification ◽  
Guinea Pig Atrium

The aim of the study was to investigate an action of 2-aminopyridine and its new sulfonylcarbamide derivatives 2-AP21, 2-AP22, 2-AP26, and 2-AP27 (10–5–10–3 M) on carbachol-induced shortening of action potential duration and reduction of contraction force in guinea pig atrial muscles. Experiments were carried out using a standard method of myocardium electromechanical activity registration. Under control conditions (perfusion of atrial strips with Tyrode solution), an average of action potential duration, measured at 90% (AP90) and 50% (AP50) of repolarization, were 112.32±6.07 ms and 50.21±3.25 ms, (n=19), respectively, and contraction force was of 1.42±0.28 mN (n=20). Carbachol (10–6M), an agonist of muscarinic acetylcholine receptor and activator of KAch channels, markedly decreased AP90 to 35.31±4.21%, AP50 – to 26.42±2.66% (n=19) (P<0.001), and contraction force – to 24.23±2.0% (n=20) (P<0.001) vs. control. Modification of 2-aminopyridine structure by replacing 2-amino group by 4-toluolsulfonylcarbamide fragment and quaternization of nitrogen in pyridine ring increased anticholinergic effect on action potential duration and contraction force. According to their maximal prolongation of AP at 90% of repolarization, all new drugs ranked as follows: 2-AP27>>2-AP26>2-AP22³2-AP>2-AP21. 2-aminopyridine derivative 2-AP27, containing 4-toluolsulfonylcarbamide fragment and 4-nitrobenzyl radical at quaternized nitrogen of the pyridine, had the most potent anticholinergic effect on AP90 (936.60±178.23%). 2-AP22 and 2-AP26 (containing methyl or allyl radicals at quaternized nitrogen of the pyridine, respectively) showed a much weaker anticholinergic effect (231.39±28.48% and 318.25±63.81%, respectively). The weakest anticholinergic effect (63.59±34.38%) was induced by 2-aminopyridine derivative 2-AP21, which had non-quaternized nitrogen of the pyridine.

Guinea pig visceral C-fiber neurons are diverse with respect to the K+ currents involved in action-potential repolarization

1994 ◽  
Vol 71 (2) ◽  
pp. 561-574 ◽  
Author(s):  
E. P. Christian ◽  
J. Togo ◽  
K. E. Naper
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Outward Current ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Whole Cell ◽  
C Fiber ◽  
K Current ◽  
Action Potential Repolarization

1. Intracellular recordings were made from C-fiber neurons identified by antidromic conduction velocity in intact guinea pig nodose ganglia maintained in vitro, and whole-cell patch clamp recordings were made from dissociated guinea pig nodose neurons to investigate the contribution of various K+ conductances to action-potential repolarization. 2. The repolarizing phase of the intracellularly recorded action potential was prolonged in a concentration-dependent manner by charybdotoxin (Chtx; EC50 = 39 nM) or iberiatoxin (Ibtx; EC50 = 48 nM) in a subpopulation of 16/36 C-fiber neurons. In a subset of these experiments, removal of extracellular Ca2+ reversibly prolonged action-potential duration (APD) in the same 4/9 intracellularly recorded C-fiber neurons affected by Chtx (> or = 100 nM). These convergent results support that a Ca(2+)-activated K+ current (IC) contributes to action-potential repolarization in a restricted subpopulation of C-fiber neurons. 3. Tetraethylammonium (TEA; 1-10 mM) increased APD considerably further in the presence of 100-250 nM Chtx or Ibtx, or in nominally Ca(2+)-free superfusate in 14/14 intracellularly recorded C-fiber neurons. TEA affected APD similarly in subpopulations of neurons with and without IC, suggesting that a voltage-dependent K+ current (IK) contributes significantly to action-potential repolarization in most nodose C-fiber neurons. 4. Substitution of Mn2+ for Ca2+ reduced outward whole-cell currents elicited by voltage command steps positive to -30 mV (2-25 ms) in a subpopulation of 21/36 dissociated nodose neurons, supporting the heterogeneous expression of IC. The kinetics of outward tail current relaxations (tau s of 1.5-2 ms) measured at the return of 2-3 ms depolarizing steps to -40 mV were indistinguishable in neurons with and without IC, precluding a separation of the nodose IC and IK by a difference in deactivation rates. 5. Chtx (10-250 nM) reduced in a subpopulation of 3/8 C-fiber neurons the total outward current elicited by voltage steps depolarized to -30 mV in single microelectrode voltage-clamp recordings. TEA (5-10 mM) further reduced outward current in the presence of 100-250 nM Chtx in all eight experiments. The Chtx-sensitive current was taken to represent IC, and the TEA-sensitive current, the IK component contributing to action-potential repolarization. 6. Rapidly inactivating current (IA) was implicated in action-potential repolarization in a subpopulation of intracellularly recorded C-fiber neurons. In 4/7 neurons, incremented hyperpolarizing prepulses negative to -50 mV progressively shortened APD.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Molecular Mechanisms of Action of M5 Muscarinic Acetylcholine Receptor Allosteric Modulators

2016 ◽  
Vol 90 (4) ◽  
pp. 427-436 ◽  
Author(s):  
Alice E. Berizzi ◽  
Patrick R. Gentry ◽  
Patricia Rueda ◽  
Sandra Den Hoedt ◽  
Patrick M. Sexton ◽  
...  
Keyword(s):  
Acetylcholine Receptor ◽  
Molecular Mechanisms ◽  
Muscarinic Acetylcholine Receptor ◽  
Mechanisms Of Action ◽  
Allosteric Modulators ◽  
Muscarinic Acetylcholine

Electrophysiological safety of sibutramine HCl

2008 ◽  
Vol 27 (7) ◽  
pp. 553-558 ◽  
Author(s):  
KS Kim ◽  
SJ Park ◽  
HA Lee ◽  
DK Kim ◽  
EJ Kim
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Papillary Muscle ◽  
Ventricular Myocytes ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Cardiovascular Side Effects ◽  
Blocking Effects ◽  
Inward Currents ◽  
Sibutramine Hcl

Sibutramine is known to induce cardiovascular side effects such as tachycardia, vasodilation, and hypertension. The present study was aimed to examine the effects of sibutramine on action potential of guinea pig papillary muscle, recombinant hERG currents (IhERG), and inward currents (INa and ICa) of rat ventricular myocytes. Sibutramine at 30 μg/mL induced a shortening of action potential duration (APD) of guinea pig papillary muscle; on average, APD30 and APD90 were shortened by 23% and 17% at a stimulation rate of 1 Hz, respectively. Sibutramine suppressed the following currents: IhERG (IC50:2.408 ± 0.5117 μg/mL), L-type Ca current (IC50:2.709 ± 0.4701 μg/mL), and Na current (IC50:7.718 ± 1.7368 μg/mL). Sibutramine blocked IhERG, ICa, and INa in a concentration-dependent manner. In conclusion, sibutramine exerted a shortening effect on APD in guinea pig papillary muscle through its more powerful blocking effects on ICa and INa rather than IhERG.

Blockade of Myocardial ATP-sensitive Potassium Channels by Ketamine 

1997 ◽  
Vol 87 (1) ◽  
pp. 68-74 ◽  
Author(s):  
Seong-Hoon Ko ◽  
Sang-Kyi Lee ◽  
Young-Jin Han ◽  
Huhn Choe ◽  
Yong-Geun Kwak ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Katp Channel ◽  
Ventricular Myocytes ◽  
Katp Channels ◽  
Dependent Manner ◽  
Channel Activity ◽  
Concentration Dependent Manner ◽  
Channel Currents ◽  
Inside Out

Background The adenosine triphosphate (ATP)-sensitive potassium (KATP) channel underlies the increase in potassium permeability during hypoxia and ischemia. The increased outward potassium current during ischemia may be an endogenous cardioprotective mechanism. This study was designed to determine the effects of ketamine on KATP channel in rat hearts. Methods Inside-out and cell-attached configurations of patch-clamp techniques and 3 M potassium chloride-filled conventional microelectrodes were used to investigate the effect of ketamine on KATP channel currents in single rat ventricular myocytes and on the action potential duration of rat papillary muscles, respectively. Results Ketamine inhibited KATP channel activity in rat ventricular myocytes in a concentration-dependent manner. In the inside-out patches, the concentration of ketamine for half-maximal inhibition and the Hill coefficient were 62.9 microM and 0.54, respectively. In a concentration-dependent manner, ketamine inhibited pinacidil- and 2,4-dinitrophenol-activated KATP channels in cell-attached patches. The application of ketamine to the intracellular side of membrane patches did not affect the conduction of single-channel currents of KATP channels. Ketamine increased the action potential duration, which was then shortened by pinacidil in a concentration-dependent manner. Conclusions Ketamine inhibited KATP channel activity in a concentration-dependent manner. These results suggest that ketamine may attenuate the cardioprotective effects of the KATP channel during ischemia and reperfusion in the rat myocardium.

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