© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
A new, sympathetic look at KATP channels in the heart
aDepartment of Clinical and Experimental Cardiology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
bDepartment of Clinical Electrophysiology, Heart–Lung Institute, University Hospital, Utrecht, The Netherlands
* Corresponding author. Tel.: +31-20-566-3265; fax: +31-20-697-5458 c.a.remme{at}amc.uva.nl
Received 25 March 1999; accepted 25 March 1999
KEYWORDS Norepinephrine; Release; Myocardium; K-ATP channel; Ischaemia
See article by Oe et al. ([10], pages 125–134) in this issue.
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1 Introduction |
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 Top 1 Introduction 2 Catecholamine release, uptake...3 Catecholamine release during...4 Modulation of catecholamine...References |
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Myocardial ATP-sensitive potassium (KATP) channels are closed during physiological conditions but are activated by a decrease in intracellular ATP-concentration [1]. KATP activation during myocardial ischaemia postpones the onset of irreversible damage, and reduces the size of the area of myocardial infarction (reviewed in [2]). Blockade of KATP channels by sulfonylurea derivatives and sodium 5-hydroxydecanoate (5-HD) reverses these cardioprotective effects [2]. The exact mechanism of cardioprotection by KATP activation has not yet been unravelled. Shortening of action potential duration due to the opening of KATP channels [4,5], the previously supposed underlying mechanism, is not a prerequisite for cardioprotection to occur [3]. Mitochondrial KATP channels may play a role, but further studies are needed for clarification [6].
Another potential contributing mechanism involves KATP channels in cardiac sympathetic nerve-endings. Throughout the central nervous system, KATP channels are located on both pre- and postsynaptic neurones [7]. Release of neurotransmitters in the brain can be influenced by neuronal KATP modulation, both under normoxic and ischaemic-like conditions [8,9]. In this edition of Cardiovascular Research, Oe et al. show a relationship between KATP modulation and norepinephrine release from the atrium under physiological conditions [10]. To correctly interpret their results and appreciate the potential role of KATP channels in catecholamine release modulation during myocardial ischaemia, understanding of the mechanisms of catecholamine secretion during physiological and pathophysiological conditions is essential.
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2 Catecholamine release, uptake and metabolism in the normal heart |
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Top1 Introduction2 Catecholamine release, uptake...3 Catecholamine release during...4 Modulation of catecholamine...References |
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In the sympathetic nerve terminals, norepinephrine (NE) is contained in granular storage vesicles. Activation of the sympathetic nerve fibres leads to influx of calcium through voltage-gated calcium channels and subsequent calcium-dependent exocytotic release of NE from the vesicles into the extracellular space [11]. Secreted NE can influence further NE release from the nerve ending via activation of presynaptic
-adrenoceptors (inhibitory effect) and β-adrenoceptors (facilitatory effect). Furthermore, activation of postsynaptic adrenoceptors by NE has a positive inotropic and chronotropic effect. Excess NE may be removed from the extracellular space by three different mechanisms: (1) re-uptake into the nerve terminal from where it was originally secreted (uptake-1); (2) diffusion of NE into the surrounding body fluids and tissues (uptake-2); (3) breakdown of NE extracellularly by the enzyme catechol-0-methyl transferase (COMT). Uptake-1 is an active carrier-mediated, sodium-dependent transport process capable of removing large amounts of secreted NE from the extracellular space back into the nerve terminal [12]. During physiological conditions, the high extracellular sodium concentration as opposed to inside the nerve terminal ensures that carrier-mediated NE transport is almost exclusively inward [13]. Besides its regulation by presynaptic adrenoceptors, NE release is inhibited by activation of presynaptic muscarinic acetylcholine receptors and A1 adenosine receptors [14]. In addition, recent reports have shown a possible regulatory role for neuronal ATP-sensitive potassium channels [8,9,15]. Oe et al. describe an inhibitory effect of cromakalim, a KATP channel opener, on the stimulation-evoked NE-release from the isolated guinea pig, but not human, atrium [10]. This effect was antagonised by the addition of glibenclamide, a KATP channel blocker, suggesting the involvement of the channel. In addition, glibenclamide alone increased both resting and stimulation-evoked NE release. However, since glibenclamide is not a specific KATP channel blocker and since high concentrations of both the KATP blockers and openers were necessary for the mentioned effects, it remains unclear whether the observed effects are a direct result of modulation of the channel. The more specific KATP channel antagonist 5-hydroxydecanoate (5-HD) did not influence stimulation-evoked NE-release, making a direct involvement of the KATP channel more questionable. However, as suggested by the authors, the possibility of selectivity of 5-HD for mitochondrial rather than plasmalemmal channels remains. In addition, molecular heterogeneity of KATP channels may lead to pharmacological diversity, which may also explain the observed paradoxical increase in NE release due to pinacidil [10,16], a compound with KATP activating properties in vascular smooth muscle and pancreas. It is of interest that the effects of KATP modulation observed by Oe et al. in the guinea pig atrium was attenuated in human atria. In particular, KATP channel opening did not affect exocytotic NE release. Since these tissues were obtained from patients suffering from cardiovascular disease, it is possible that due to chronic ischaemia in these patients, the open state, the number of available channels, or the responsiveness of these channels was altered.
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3 Catecholamine release during myocardial ischaemia/infarction |
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During myocardial ischaemia, local norepinephrine accumulation in the myocardium may occur as a result of exocytotic or non-exocytotic release from sympathetic nerve-endings. Reflex stimulation of sympathetic nerves and subsequent increased NE release occurs due to local metabolic changes in the myocardium as well as decreases in blood pressure and cardiac output. During early ischaemia, increased re-uptake of NE into the nerve ending (uptake-1) can successfully prevent local NE accumulation in the myocardium. However, as the ischaemic episode progresses, the intact sodium gradient across the cell membrane necessary for this re-uptake is gradually lost, and excessive NE will start to accumulate [17]. After an even longer duration of ischaemia, ATP-depletion of the nerve terminals occurs and exocytotic NE release will cease. Instead, after about 10 min of ischaemia, local non-exocytotic norepinephrine release is responsible for the observed massive amounts of NE accumulated in the ischaemic myocardium. Here, a two-step release mechanism is thought to occur [18], comprising NE loss from the storage vesicles and consequent increased axoplasmic NE concentrations, followed by a carrier-mediated outward transport of NE into the synaptic cleft. For this purpose, the uptake-1 carrier is used in reverse mode, the altered sodium gradient across the neuronal membrane enabling binding of NE to the carrier and transportation to the extracellular space [19]. This release is independent of extracellular calcium concentrations and is completely prevented by the presence of glucose [20]. Non-exocytotic release during ischaemia can lead to extracellular NE concentrations in the micromolar range (1000-fold increase) [21] with potentially harmful consequences for the ischaemic heart such as increased myocardial damage (calcium overload) and increased propensity to ventricular arrhythmias.
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4 Modulation of catecholamine release from the ischaemic myocardium |
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Any intervention capable of reducing or preventing NE-release during myocardial ischaemia has a potential beneficial effect. Many studies have focused on possible ways of modulating excessive NE accumulation in the myocardium, often with apparent conflicting results. However, the outcome depends on the dominant mechanism of NE release present at the time of investigation (for review, see [18]). For instance, during early ischaemia, when exocytotic release is still predominant, blockade of the re-uptake carrier by desipramine will result in an increase in NE release. During longer periods of ischaemia, non-exocytotic release using this carrier in the reverse direction will lead to decreased release due to desipramine. Also, stimulation of presynaptic adenosine-receptors will only influence exocytotic release and therefore will have no significant effect during longer periods of ischaemia.
Opening of neuronal KATP channels during ischaemia has been suggested to be able to modulate NE release in various tissues. Indeed, during simulated ischaemia, KATP activation reduced the release of various neurotransmitters in brain tissue, whereas KATP inhibition aggravated its release [8,9,22]. As suggested by Oe et al., KATP channel activation may also attenuate NE release during myocardial ischaemia, with potentially favorable impact on cardiac metabolism, ventricular arrhythmias and infarct size. Indeed, preliminary results from our laboratory show a significant decrease in release of NE by cromakalim in globally ischaemic rabbit hearts as compared to control hearts [23].
In conclusion, these data on endogenous myocardial norepinephrine release [10,23] provide alternative explanations for the many consequences of pharmacological KATP channel modulation.
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Acknowledgements |
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C.A.R is supported by a grant from the Dutch Heart Foundation (NHS grant 96.018). A.A.M.W is a clinical investigator for the Dutch Heart Foundation (NHS, grant 95.014).
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