SD‐3212, a new class I and IV antiarrhythmic drug: a potent inhibitor of the muscarinic acetylcholine‐receptor‐operated potassium current in guinea‐pig atrial cells

Hara, Yukio; Nakaya, Haruaki

doi:10.1111/j.1476-5381.1995.tb17237.x

Cited by 70 publications

(53 citation statements)

References 29 publications

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“…Using an experimental protocol similar to that used in studying the Na channel blockade by local anesthetics [8,11], effects of verapamil and ketamine on I Ca were evaluated. Organic Ca channel blockers are reported to produce a little tonic block and significant UDB of I Ca , due to higher affinity for open Ca channels [14,[19][20][21].…”

Section: Discussionmentioning

confidence: 99%

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Tonic Block of the Sodium and Calcium Currents by Ketamine in Isolated Guinea Pig Ventricular Myocytes.

Hara

Chugun

Nakaya

et al. 1998

The Journal of Veterinary Medical Science

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ABSTRACT. Effects of ketamine on the sodium (I Na ) and L-type calcium currents (I Ca ) were examined by using whole-cell patch clamp techniques in guinea pig single ventricular myocytes. The mode of action of ketamine was compared with those of quinidine, a sodium channel blocker, and verapamil, a calcium channel blocker. Ketamine (30-300 µM) inhibited both I Na and I Ca in a concentrationdependent manner. Quinidine (30 µM) and verapamil (0.1 µM) produced use-dependent depression of I Na and I Ca , respectively. The amplitude of I Na elicited by the first depolarizing pulse after a long quiescent period was slightly decreased by quinidine. During a train of depolarizing pulse the current amplitude decreased gradually, and reached a steady state level in the quinidine-treated cells (use-dependent block, UDB). Verapamil produced a similar mode of inhibition of I Ca , i.e., UDB. In contrast, ketamine produced significant decrease in I Na and I Ca elicited by the first depolarizing pulses and the decreases of both currents were not augmented during a train of depolarizing pulses. From these results, it can be concluded that ketamine produces tonic block of the cardiac sodium and calcium channels and the mode of inhibition is clearly different from UDB by quinidine and verapamil. -KEY WORDS: calcium current, cardiac myocyte, ketamine, sodium current, tonic block.J. Vet. Med. Sci. 60(4): 479-483, 1998 MATERIALS AND METHODSCell preparations: Guinea pigs, weighing 200-350 g, were used in this study. Single ventricular cells were isolated by an enzymatic dispersion, as previously described [11]. Briefly, the heart was removed from the open-chest guinea pig anesthetized with pentobarbital Na, and mounted on a modified Langendorff perfusion system for retrograde perfusion of the coronary circulation with a normal HEPESTyrode solution. The perfusion medium was then changed to a nominally Ca-free HEPES-Tyrode solution and then to a solution containing 0.02% w/v collagenase (Wako, Osaka, Japan). After digestion, the heart was perfused with a high K + and low Cl -solution (modified Kraftbrühe (KB) solution) [17,22]. Ventricular tissue was cut into small pieces in the modified KB solution and gently shaken to isolate cells. Dispersed cells were stored in the KB solution at 4°C and used over the next 7-10 hr.Recording techniques: Whole-cell membrane currents were recorded by patch clamp method [9]. Single ventricular cells were placed in a recording chamber (1-ml volume) attached to an inverted microscope (Olympus IMT-2, Tokyo, Japan) and superfused with the HEPES-Tyrode solution at a rate of 3 ml/min. The temperature of the external solution was kept constant at 36 ± 1°C. Glass patch pipettes with a diameter of 1.5 mm were filled with a pipette solution. The resistance of the patch pipette filled with the pipette solution was 2-3 MΩ. The tight-seal, whole cell voltage clamp technique was used. After the gigaohmseal between the tip of the electrode and the cell membrane was established, the membrane patch was disrupted by K...

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Section: Discussionmentioning

confidence: 99%

“…Single ventricular cells were isolated by an enzymatic dispersion, as previously described [11]. Briefly, the heart was removed from the open-chest guinea pig anesthetized with pentobarbital Na, and mounted on a modified Langendorff perfusion system for retrograde perfusion of the coronary circulation with a normal HEPESTyrode solution.…”

Section: Methodsmentioning

confidence: 99%

Tonic Block of the Sodium and Calcium Currents by Ketamine in Isolated Guinea Pig Ventricular Myocytes.

Hara

Chugun

Nakaya

et al. 1998

The Journal of Veterinary Medical Science

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“…Molecular mechanisms by which several drugs inhibit I K.ACh have been proposed; some drugs block the muscarinic receptors and others inhibit the muscarinic potassium channel itself and/or GTP-binding proteins [10,11,18,19,24]. These molecular mechanisms can be elucidated using data from the patch clamp method in atrial myocytes [3,11,24]. The I K.ACh is activated by an application of carbachol through binding to the muscarinic M 2 receptor in GTP-loaded cells.…”

Section: Discussionmentioning

confidence: 99%

“…Many drugs, including antiarrhythmic drugs, anticancer chemotherapeutic drugs and antimalarial drugs, that produce anticholinergic actions in the heart have been reported to inhibit I K.ACh [10,11,14,24,26]. Molecular mechanisms by which several drugs inhibit I K.ACh have been proposed; some drugs block the muscarinic receptors and others inhibit the muscarinic potassium channel itself and/or GTP-binding proteins [10,11,18,19,24]. These molecular mechanisms can be elucidated using data from the patch clamp method in atrial myocytes [3,11,24].…”

Section: Discussionmentioning

confidence: 99%

“…Interaction of acetylcholine receptor-operated potassium channel and Gβγ subunit of GTP binding proteins is important for activation of I K.ACh in cardiac myocytes [20,21]. Many drugs, including antiarrhythmic drugs, anticancer chemotherapeutic drugs and antimalarial drugs, that produce anticholinergic actions in the heart have been reported to inhibit I K.ACh [10,11,14,24,26]. Molecular mechanisms by which several drugs inhibit I K.ACh have been proposed; some drugs block the muscarinic receptors and others inhibit the muscarinic potassium channel itself and/or GTP-binding proteins [10,11,18,19,24].…”

Section: Discussionmentioning

confidence: 99%

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Benzodiazepines Inhibit the Acetylcholine Receptor-Operated Potassium Current (I<sub>K.ACh</sub>) by Different Mechanisms in Guinea-pig Atrial Myocytes

Okada

Mizuno

Nakarai

et al. 2012

The Journal of Veterinary Medical Science

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ABSTRACT. The anticholinergic effects of 7 benzodiazepines, bromazepam, camazepam, chlordiazepoxide, diazepam, lorazepam, medazepam and triazolam, were compared by examining their inhibitory effects on the acetylcholine receptor-operated potassium current (I K.ACh ) in guinea-pig atrial myocytes. All of these benzodiazepines (0.3-300 µM) inhibited carbachol (1 µM)-induced I K.ACh in a concentration-dependent manner. The ascending order of IC 50 values for carbachol-induced I K.ACh was as follows; medazepam, diazepam, camazepam, triazolam, bromazepam, lorazepam and chlordiazepoxide (>300 µM). The compounds, except for bromazepam, also inhibited I K.ACh activated by an intracellular loading of 100 µM guanosine 5'-[γ-thio]triphosphate (GTPγS) in a concentration-dependent manner. The ascending order of IC 50 values for GTPγS-activated I K.ACh was as follows; medazepam, diazepam, camazepam, lorazepam, triazolam chlordiazepoxide (>300 µM) and bromazepam (>300 µM). To clarify the molecular mechanism of the inhibition, IC 50 ratio, the ratio of IC 50 for GTPγS-activated I K.ACh to carbachol-induced I K.ACh , was calculated. The IC 50 ratio for camazepam, diazepam, lorazepam, medazepam and triazolam was close to unity, while it for chlordiazepoxide could not be calculated. These compounds would act on the GTP binding protein and/or potassium channel to achieve the anticholinergic effects in atrial myocytes. In contrast, since the IC 50 ratio for bromazepam is presumably much higher than unity judging from the IC 50 values (104.0 ± 30.0 µM for carbachol-induced I K.ACh and >300 µM for GTPγS-activated I K.ACh ), it would act on the muscarinic receptor. In summary, benzodiazepines had the anticholinergic effects on atrial myocytes through inhibiting I K.ACh by different molecular mechanisms. KEY WORDS: acetylcholine receptor-operated potassium current, atrial myocyte, benzodiazepines, bromazepam, patch clamp method.

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Binding Study of Semotiadil and Levosemotiadil with α1-Acid Glycoprotein Using High-Performance Frontal Analysis

Rosas

Shibukawa

Yoshikawa

et al. 1999

Analytical Biochemistry

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SD‐3212, a new class I and IV antiarrhythmic drug: a potent inhibitor of the muscarinic acetylcholine‐receptor‐operated potassium current in guinea‐pig atrial cells

Cited by 70 publications

References 29 publications

Tonic Block of the Sodium and Calcium Currents by Ketamine in Isolated Guinea Pig Ventricular Myocytes.

Tonic Block of the Sodium and Calcium Currents by Ketamine in Isolated Guinea Pig Ventricular Myocytes.

Benzodiazepines Inhibit the Acetylcholine Receptor-Operated Potassium Current (I<sub>K.ACh</sub>) by Different Mechanisms in Guinea-pig Atrial Myocytes

Binding Study of Semotiadil and Levosemotiadil with α1-Acid Glycoprotein Using High-Performance Frontal Analysis

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