Potassium Channel Blockade of Atrial Negative Inotropic Responses to P1Purinoceptor and Muscarinic Receptor Agonists and to Cromakalim

Urquhart, Robert A.; Ford, William R.; Broadley, Kenneth J.

doi:10.1097/00005344-199302000-00014

Cited by 10 publications

(3 citation statements)

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“…These findings rule out the involvement of voltage-dependent K v cannels on the inhibitory effects of A 1 and M 2 agonists and confirm data from interaction studies between 4-AP (0.3–3 mM) and R-PIA in the guinea-pig using spontaneously beating and electrically-driven atria (De Biasi et al, 1989 ). Concerning the lack of effect of glibenclamide in antagonizing the responses to M 2 and A 1 receptor agonists in rat atria, our results agree with previous reports in the guinea-pig indicating that cardiodepression by these agents are not operated by ATP-sensitive K ATP /K IR 6 channels (Urquhart et al, 1993 ; Ford and Broadley, 1999 ).…”

Section: Discussionsupporting

confidence: 92%

“…Due to different expression levels of A 1 and M 2 receptors, the maximal GIRK/K IR 3.1∕3.4 current that can be activated by endogenous adenosine is smaller than the current triggered by cholinergic agonists (Kurachi et al, 1986 ). Activation of GIRK/K IR 3.1/3.4 currents causes a reduction in the action potential duration, thereby decreasing the time available for Ca 2+ influx through Ca v 1 (L-type) channels and, hence, heart rate and the force of muscle contraction in atrial myocardium (Urquhart et al, 1993 ; Belardinelli et al, 1995 ; Neumann et al, 1999 ). Negative inotropy may, however, be partially compensated by modulation of multiple downstream targets of G proteins, which may include Ca 2+ influx through Ca v 1 (L-type) channels (Wang et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

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Ion Fluxes through KCa2 (SK) and Cav1 (L-type) Channels Contribute to Chronoselectivity of Adenosine A1 Receptor-Mediated Actions in Spontaneously Beating Rat Atria

et al. 2016

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Impulse generation in supraventricular tissue is inhibited by adenosine and acetylcholine via the activation of A1 and M2 receptors coupled to inwardly rectifying GIRK/KIR3.1/3.4 channels, respectively. Unlike M2 receptors, bradycardia produced by A1 receptors activation predominates over negative inotropy. Such difference suggests that other ion currents may contribute to adenosine chronoselectivity. In isolated spontaneously beating rat atria, blockade of KCa2/SK channels with apamin and Cav1 (L-type) channels with nifedipine or verapamil, sensitized atria to the negative inotropic action of the A1 agonist, R-PIA, without affecting the nucleoside negative chronotropy. Patch-clamp experiments in the whole-cell configuration mode demonstrate that adenosine, via A1 receptors, activates the inwardly-rectifying GIRK/KIR3.1/KIR3.4 current resulting in hyperpolarization of atrial cardiomyocytes, which may slow down heart rate. Conversely, the nucleoside inactivates a small conductance Ca2+-activated KCa2/SK outward current, which eventually reduces the repolarizing force and thereby prolong action potentials duration and Ca2+ influx into cardiomyocytes. Immunolocalization studies showed that differences in A1 receptors distribution between the sinoatrial node and surrounding cardiomyocytes do not afford a rationale for adenosine chronoselectivity. Immunolabelling of KIR3.1, KCa2.2, KCa2.3, and Cav1 was also observed throughout the right atrium. Functional data indicate that while both A1 and M2 receptors favor the opening of GIRK/KIR3.1/3.4 channels modulating atrial chronotropy, A1 receptors may additionally restrain KCa2/SK activation thereby compensating atrial inotropic depression by increasing the time available for Ca2+ influx through Cav1 (L-type) channels.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Ion Fluxes through KCa2 (SK) and Cav1 (L-type) Channels Contribute to Chronoselectivity of Adenosine A1 Receptor-Mediated Actions in Spontaneously Beating Rat Atria

et al. 2016

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“…This receptor was xanthine sensitive, not coupled to adenylyl cyclase and produced effects by modulating calcium entry into cells ( Ribeiro & Sebastiao, 1986 ). Both K + efflux ( Belardinelli & Isenberg, 1983 ; Cerbai et al ., 1988 ; Visentin et al ., 1990 ; Urquhart et al ., 1991 ; 1993 ) and closure of L‐type calcium channels ( DeBiasi et al ., 1989 ; Fassina et al ., 1991 ; Jahnel et al ., 1992 ) have been implicated in the negative inotropic effects of adenosine analogues in the guinea‐pig left atria.…”

Section: Discussionmentioning

confidence: 98%

Analysis of the atypical characteristics of adenosine receptors mediating negative inotropic and chronotropic responses of guinea‐pig isolated atria and papillary muscles

Gardner

Broadley

1999

British J Pharmacology

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1 Adenosine receptor(s) mediating negative inotropy of paced left atria, isoprenaline-stimulated paced left atria and papillary muscles, and negative chronotropy of spontaneously beating right atria were characterized. 2 Isometric tension of guinea-pig isolated paced left atria and left ventricular papillary muscles and rate of contraction of spontaneously beating right atria were recorded. Papillary muscles were prestimulated with isoprenaline (1610 78 M). Concentration-response curves (CRCs) for tension or rate reduction by N 6 -cyclopentyladenosine (CPA), the stereoisomers of N 6 -(2-phenylisopropyl)adenosine ((+)-PIA and (7) -(3-iodobenzyl)adenosine-5'-N-methyuromide (IB-MECA) revealed a potency order of CPA=(7)-PIA4NECA in right atria and papillary muscles, which is consistent with involvement of A 1 -receptors. The potency order in left atria was CPA=NECA4(7)-PIA4(+)-PIA4APNEA, which is not typical of A 1 adenosine receptors. Weak activity of APNEA and IB-MECA discounts involvement of A 3 receptors. 3 pA 2 values for the antagonism of CPA by 8(p-sulfophenyl)theophylline (8-SPT) were calculated from Schild plots (log concentration-ratio against log 8-SPT concentration), the unity slopes of which indicated competitive antagonism. The pA 2 value in the papillary muscles was signi®cantly higher than for atrial preparations, indicating a possible dierence in receptor characteristics between atrial and papillary muscle responses. 4 In left and right atria there was a limit to the displacement of the CPA CRCs at higher concentrations of 8-SPT. The 8-SPT-resistant component of the response is suggested to arise from duality of coupling of a common A 1 receptor through either dierent G proteins or G protein subunits to independent transduction pathways. The results with papillary muscles can be explained by a typical A 1 receptor coupled to a single transduction pathway.

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Cholinergic and Adrenergic Modulation of Cardiac K+Channels

Parker

Fedida

2001

Potassium Channels in Cardiovascular Biology

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Potassium Channel Blockade of Atrial Negative Inotropic Responses to P1Purinoceptor and Muscarinic Receptor Agonists and to Cromakalim

Cited by 10 publications

References 0 publications

Ion Fluxes through KCa2 (SK) and Cav1 (L-type) Channels Contribute to Chronoselectivity of Adenosine A1 Receptor-Mediated Actions in Spontaneously Beating Rat Atria

Ion Fluxes through KCa2 (SK) and Cav1 (L-type) Channels Contribute to Chronoselectivity of Adenosine A1 Receptor-Mediated Actions in Spontaneously Beating Rat Atria

Analysis of the atypical characteristics of adenosine receptors mediating negative inotropic and chronotropic responses of guinea‐pig isolated atria and papillary muscles

Cholinergic and Adrenergic Modulation of Cardiac K+Channels

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