Heart rate reduction, a new and old therapeutic principle?

Schaper, W.

doi:10.1093/eurheartj/8.suppl_l.1

Cited by 6 publications

(4 citation statements)

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“…It is well known that bradycardia improves the oxygen balance of the heart by reducing demand and increasing supply, particularly in the sub-endocardial layers, through better perfusion during a prolonged diastolic period [1]. There is also an acknowledged inverse relationship between heart rate and capillary supply in that 'athletic' animals such as the hare or wild rat have a lower heart rate and higher capillary density (CD) when compared with related sedentary species such as the rabbit and laboratory rat [2,3].…”

Section: Bradycardia and The Coronary Circulationmentioning

confidence: 99%

Angiogenesis in ischaemic and hypertrophic hearts induced by long-term bradycardia

2005

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Angiogenesis and improved left ventricular function as a consequence of long-term bradycardia were first demonstrated in normal hearts, either electrically paced (rabbits, pigs) or treated with a selective sinus blocking drug alinidine (rats). Here we review the evidence that chronic heart rate reduction can have similar effects in the heart with compromised vascular supply, due to either hypertensive or haemodynamic overload hypertrophy (rats, rabbits) or ischaemic damage (rats, rabbits, pigs). Bradycardia induced over several weeks increased capillarity in all hypertrophied hearts, and in border and remote left ventricular myocardium of infarcted hearts. In some, but not all cases, coronary blood flow was improved by heart rate reduction, suggesting enlargement of the resistance vasculature in some circumstances. Cardiac or left ventricular function indices, which were depressed by hypertrophy or ischaemic damage, were preserved or even enhanced by chronic heart rate reduction. The expansion of the capillary bed in the vascularly compromised heart induced by bradycardia may be stimulated by mechanical stretch of the endothelium and/or VEGF activated by chamber dilation and myocyte stretch. The increased number of capillaries and more homogeneous distribution of capillary perfusion would support the better pump function, even in the absence of higher coronary flow. The beneficial impact of chronic heart rate reduction on myocardial angiogenesis and function in cardiac hypertrophy and infarction may be major factor in the success of beta-blockers in treatment of human heart failure.

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Section: Bradycardia and The Coronary Circulationmentioning

confidence: 99%

Angiogenesis in ischaemic and hypertrophic hearts induced by long-term bradycardia

2005

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“…The prolonged APD leaves the membrane depolarized, allowing Ca2+ influx to persist longer. The bradycardic effect sf SL-B could be expected to reduce myocardid oxygen consumption amd ts increase &astolic coronary perfusion time (Schaper 1987), and this effect together with cardiotsnic action could be beneficial in the improvement of ischemic heart diseases and heart failure. The study on the inotropic mechanisms of SL-1 dso provides ologicd profile of the 1 -phenyl-THE derivatives.…”

Section: Discussionmentioning

confidence: 99%

Mechanical and electrophysiological effects of a hydroxyphenyl-substituted tetrahydroisoquinoline, SL-1, on isolated rat cardiac tissues

Chang

Su²,

Lee³

et al. 1995

Can. J. Physiol. Pharmacol.

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The mechanisms of the positive inotropic action of a new synthetic tetrahydroisoquinoline compound, SL-1, were investigated in isolated rat cardiac tissues and ventricular myocytes. SL-1 produced a rapidly developing, concentration-dependent positive inotropic response in both atrial and ventricular muscles and a negative chronotropic effect in spontaneously beating right atria. The positive inotropic effect was not prevented by pretreatment with reserpine (3 mg/kg) or the alpha-adrenoceptor antagonist prazosin (1 microM), but was suppressed by either the beta-adrenoceptor antagonist atenolol (3 microM) or the K+ channel blocker 4-aminopyridine (4AP, 1mM). In the whole-cell recording study, SL-1 increased the plateau level and prolonged the action potential duration in a concentration-dependent manner and decreased the maximum upstroke velocity (Vmax) and amplitude of the action potential in isolated rat ventricular myocytes stimulated at 1.0 Hz. On the other hand, SL-1 had little effect on the resting membrane potential, although it caused a slight decrease at higher concentrations. Voltage clamp experiments revealed that the increase of action potential plateau and prolongation of action potential duration were associated with an increase of Ca2+ inward current (ICa) via the activation of beta-adrenoceptors and a prominent inhibition of 4AP-sensitive transient outward K+ current (Ito) with an IC50 of 3.9 microM. Currents through the inward rectifier K+ channel (IK1) were also reduced. The inhibition of Ito is characterized by a reduction in peak amplitude and a marked acceleration of current decay but without changes on the voltage dependence of steady-state inactivation. In addition to the inhibition of K+ currents, SL-1 also inhibited the Na+ inward current (INa) with an IC50 of 5.4 microM, which was correlated with the decrease of Vmax. We conclude that the positive inotropic effect of SL-1 may be due to an increase in Ca2+ current mediated via partial activation of beta-adrenoceptors and an inhibition of K+ outward currents and the subsequent prolongation of action potentials.

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“…As heart rate is a major determinant of myocardial oxygen consumption (Boerth et al 1969;Schaper 1987), tachycardias are unfavourable in patients with ischaemic heart disease and heart failure. Sinus tachycardia occurs from variable origins, including effort, psychological stress, fever, dehydration, treatment with some cardiotonic agents and others, and increases myocardial oxygen consumption.…”

Section: Introductionmentioning

confidence: 99%

“…Zatebradine , structurally related to verapamil, has been described as a specific bradycardic agent, which directly acts on pacemaker cells and decreases heart rate with minimal other cardiovascular effects (Kobinger & Lillie 1984, 1987. It has been reported that zatebradine blocks the hyperpolarization-activated current (If) in sheep Purkinje fibres (Van Bogaert & Goethals 1987;Van Bogaert et al 1990) and that zatebradine blocks the L-type calcium current (Ic,) in guineapig and rabbit SA nodal cells at drug concentrations which had little or no effect on the amplitude of It (Doerr & Trautwein 1990).…”

Section: Introductionmentioning

confidence: 99%

Zatebradine Attenuates Cyclic Amp‐related Positive Chronotropic but Not Inotropic Responses in Isolated, Perfused Right Atria of the Dog

Sawaki

Furukawa

Inoue

et al. 1995

Clin Exp Pharma Physio

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1. Inhibition of I(f) or ICa by zatebradine has been reported in mammalian SA nodal cells. We thus investigated whether zatebradine differentially attenuates the positive chronotropic and inotropic responses to norepinephrine, isoproterenol, NKH 477 (an adenylyl cyclase activator), 3-isobutyl-1-methylxanthine (IBMX) and Bay k 8644 (a calcium channel agonist) in the isolated, blood-perfused dog atrium. 2. When zatebradine (0.03-1 mumol) decreased sinus rate from 104 +/- 4.5 to 73 +/- 4.9 beats/min dose-dependently, it selectively attenuated the positive chronotropic but not inotropic responses to norepinephrine in a dose-related manner. Zatebradine decreased the norepinephrine-induced tachycardia (by approximately 80% from the control) more effectively than the spontaneous sinus rate (by approximately 30% from the control). 3. Zatebradine similarly attenuated the positive chronotropic but not inotropic responses to isoproterenol, NKH 477 and IBMX. Fifty per cent inhibition doses of zatebradine (0.10-0.18 mumol) for the chronotropic responses to each substance were not significantly different. 4. On the other hand, zatebradine attenuated neither positive chronotropic nor inotropic responses to Bay k 8644. 5. We therefore suggest that zatebradine selectively attenuates the positive chronotropic but not inotropic responses to cyclic AMP-related substances due to inhibition of I(f) but not ICa in the dog heart.

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Heart rate reduction, a new and old therapeutic principle?

Cited by 6 publications

References 0 publications

Angiogenesis in ischaemic and hypertrophic hearts induced by long-term bradycardia

Angiogenesis in ischaemic and hypertrophic hearts induced by long-term bradycardia

Mechanical and electrophysiological effects of a hydroxyphenyl-substituted tetrahydroisoquinoline, SL-1, on isolated rat cardiac tissues

Zatebradine Attenuates Cyclic Amp‐related Positive Chronotropic but Not Inotropic Responses in Isolated, Perfused Right Atria of the Dog

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