Chronotropic effects of the reversed carboxyl (RC) analogue of acetylcholine (β-homobetaine methylester) at defined intraluminal pressures on isolated right rabbit atria

Rossberg, F; Seim, Hermann; Strack, Erich

doi:10.1007/bf01854899

Cited by 4 publications

(4 citation statements)

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“…Since these seminal initial observations, results have been confirmed in rabbit isolated atria ( Bolter, 1996 , Cermak and Rossberg, 1988 , Himmel and Rossberg, 1983 , Pathak, 1958 , Rossberg et al., 1985 ) and SAN ( Arai et al., 1996 , Golenhofen and Lippross, 1969 , Hoffman and Cranefield, 1960 , Kamiyama et al., 1984 , Ushiyama and Brooks, 1977 ), as well as in ex situ preparation from various other mammalian species ( Quinn and Kohl, 2012b ), and it is now well established that the SAN can intrinsically respond to acute stretch on a beat-by-beat basis.…”

Section: Mechano-electric Coupling In the Heartmentioning

confidence: 88%

“…It should be noted, however, that the enhanced stretch-response may also be directly related to the reduced beating rate, as when background rate is lower, stretch-induced changes in rate are increased ( Coleridge and Linden, 1955 , Cooper and Kohl, 2005 ). At the same time, the opposite effect (a decreased response to stretch) has been shown in rabbit atria with application of the muscarinic agonist β-homobetaine methylester, a structural isomer of acetylcholine ( Rossberg et al., 1985 ). Even so, interaction of extrinsic BR regulation and intrinsic stretch-induced mechanisms may be an important mechanism for preventing excessive slowing and diastolic (over-)distension, while maintaining cardiac output and adequate circulation during haemodynamic changes that increase both venous return and arterial pressure (by invoking competing regulatory responses, i.e.…”

Section: Mechano-electric Coupling In the Heartmentioning

confidence: 97%

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Rabbit models of cardiac mechano-electric and mechano-mechanical coupling

Quinn

Kohl

2016

Progress in Biophysics and Molecular Biology

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Cardiac auto-regulation involves integrated regulatory loops linking electrics and mechanics in the heart. Whereas mechanical activity is usually seen as ‘the endpoint’ of cardiac auto-regulation, it is important to appreciate that the heart would not function without feed-back from the mechanical environment to cardiac electrical (mechano-electric coupling, MEC) and mechanical (mechano-mechanical coupling, MMC) activity. MEC and MMC contribute to beat-by-beat adaption of cardiac output to physiological demand, and they are involved in various pathological settings, potentially aggravating cardiac dysfunction. Experimental and computational studies using rabbit as a model species have been integral to the development of our current understanding of MEC and MMC. In this paper we review this work, focusing on physiological and pathological implications for cardiac function.

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Section: Mechano-electric Coupling In the Heartmentioning

confidence: 88%

Section: Mechano-electric Coupling In the Heartmentioning

confidence: 97%

Rabbit models of cardiac mechano-electric and mechano-mechanical coupling

Quinn

Kohl

2016

Progress in Biophysics and Molecular Biology

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“…In contrast, it has been observed that stretch, caused by increased pressure in isolated rabbit right atria, potentiates the dose-dependent decrease in BR upon application of the muscarinic agonist β-homobetaine methylester, a structural isomer of acetylcholine (Rossberg et al., 1985). Thus, intrinsic and systemic BR modulations occur in conjunction, and may amplify, or dampen, each other’s effect (part of this may be indicative of possible differences between neural and humoural effects).…”

Section: Direct Mechanical Effects On Cardiac Pacemaker Activitymentioning

confidence: 99%

Mechano-sensitivity of cardiac pacemaker function: Pathophysiological relevance, experimental implications, and conceptual integration with other mechanisms of rhythmicity

Quinn

Kohl

2012

Progress in Biophysics and Molecular Biology

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Cardiac pacemaker cells exhibit spontaneous, rhythmic electrical excitation, termed automaticity. This automatic initiation of action potentials requires spontaneous diastolic depolarisation, whose rate determines normal rhythm generation in the heart. Pacemaker mechanisms have been split recently into: (i) cyclic changes in trans-sarcolemmal ion flows (termed the ‘membrane-clock’), and (ii) rhythmic intracellular calcium cycling (the ‘calcium-clock’). These two ‘clocks’ undoubtedly interact, as trans-sarcolemmal currents involved in pacemaking include calcium-carrying mechanisms, while intracellular calcium cycling requires trans-sarcolemmal ion flux as the mechanism by which it affects membrane potential. The split into separate ‘clocks’ is, therefore, somewhat arbitrary. Nonetheless, the ‘clock’ metaphor has been conceptually stimulating, in particular since there is evidence to support the view that either ‘clock’ could be sufficient in principle to set the rate of pacemaker activation.Of course, the same has also been shown for sub-sets of ‘membrane-clock’ ion currents, illustrating the redundancy of mechanisms involved in maintaining such basic functionality as the heartbeat, a theme that is common for vital physiological systems.Following the conceptual path of identifying individual groups of sub-mechanisms, it is important to remember that the heart is able to adapt pacemaker rate to changes in haemodynamic load, even after isolation or transplantation, and on a beat-by-beat basis. Neither the ‘membrane-’ nor the ‘calcium-clock’ do, as such, inherently account for this rapid adaptation to circulatory demand (cellular Ca2+ balance changes over multiple beats, while variation of sarcolemmal ion channel presence takes even longer). This suggests that a third set of mechanisms must be involved in setting the pace. These mechanisms are characterised by their sensitivity to the cyclically changing mechanical environment, and – in analogy to the above terminology – this might be considered a ‘mechanics-clock’.In this review, we discuss possible roles of mechano-sensitive mechanisms for the entrainment of membrane current dynamics and calcium-handling. This can occur directly via stretch-activation of mechano-sensitive ion channels in the sarcolemma and/or in intracellular membrane compartments, as well as by modulation of ‘standard’ components of the ‘membrane-’ or ‘calcium-clock’. Together, these mechanisms allow rapid adaptation to changes in haemodynamic load, on a beat-by-beat basis.Additional relevance arises from the fact that mechano-sensitivity of pacemaking may help to explain pacemaker dysfunction in mechanically over- or under-loaded tissue. As the combined contributions of the various underlying oscillatory mechanisms are integrated at the pacemaker cell level into a single output – a train of pacemaker action potentials – we will not adhere to a metaphor that implies separate time-keeping units (‘clocks’), and rather focus on cardiac pacemaking as the result of interactions of a set of coupled osci...

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“…In large mammals with inherently slow HR, stretch increases HR, while in smaller mammals such as the mouse and rat with resting HR of ≥500 bpm, SAN stretch can increase or decrease the beating rate. [134][135][136][137] Stretch-induced changes in beating frequency occur in isolated hearts, 138,139 isolated right atria, [140][141][142] SAN tissue, 137 and individual SAN cells, 143 all of which lack autonomic innervation. These and other experiments (for details, please see reference 134 ) suggest that the chronotropic response of the heart to stretch is, at least in part, intrinsic to the SAN.…”

Section: The Membrane Clock Is the Motor Of The Pacemaker Potentialmentioning

confidence: 99%

Pacemaker Channels and the Chronotropic Response in Health and Disease

Hennis,

Piantoni,

Biel

et al. 2024

Circulation Research

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Loss or dysregulation of the normally precise control of heart rate via the autonomic nervous system plays a critical role during the development and progression of cardiovascular disease—including ischemic heart disease, heart failure, and arrhythmias. While the clinical significance of regulating changes in heart rate, known as the chronotropic effect, is undeniable, the mechanisms controlling these changes remain not fully understood. Heart rate acceleration and deceleration are mediated by increasing or decreasing the spontaneous firing rate of pacemaker cells in the sinoatrial node. During the transition from rest to activity, sympathetic neurons stimulate these cells by activating β-adrenergic receptors and increasing intracellular cyclic adenosine monophosphate. The same signal transduction pathway is targeted by positive chronotropic drugs such as norepinephrine and dobutamine, which are used in the treatment of cardiogenic shock and severe heart failure. The cyclic adenosine monophosphate–sensitive hyperpolarization–activated current (I f ) in pacemaker cells is passed by hyperpolarization-activated cyclic nucleotide-gated cation channels and is critical for generating the autonomous heartbeat. In addition, this current has been suggested to play a central role in the chronotropic effect. Recent studies demonstrate that cyclic adenosine monophosphate–dependent regulation of HCN4 (hyperpolarization-activated cyclic nucleotide-gated cation channel isoform 4) acts to stabilize the heart rate, particularly during rapid rate transitions induced by the autonomic nervous system. The mechanism is based on creating a balance between firing and recently discovered nonfiring pacemaker cells in the sinoatrial node. In this way, hyperpolarization-activated cyclic nucleotide-gated cation channels may protect the heart from sinoatrial node dysfunction, secondary arrhythmia of the atria, and potentially fatal tachyarrhythmia of the ventricles. Here, we review the latest findings on sinoatrial node automaticity and discuss the physiological and pathophysiological role of HCN pacemaker channels in the chronotropic response and beyond.

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Chronotropic effects of the reversed carboxyl (RC) analogue of acetylcholine (β-homobetaine methylester) at defined intraluminal pressures on isolated right rabbit atria

Cited by 4 publications

References 8 publications

Rabbit models of cardiac mechano-electric and mechano-mechanical coupling

Rabbit models of cardiac mechano-electric and mechano-mechanical coupling

Mechano-sensitivity of cardiac pacemaker function: Pathophysiological relevance, experimental implications, and conceptual integration with other mechanisms of rhythmicity

Pacemaker Channels and the Chronotropic Response in Health and Disease

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