Two different mechanisms of noradrenaline release during normoxia and simulated ischemia in human cardiac tissue

doi:10.1016/0022-2828(95)90052-7

Journal of Molecular and Cellular Cardiology

Volume 27, Issue 5, May 1995, Pages 1161-1172

https://doi.org/10.1016/0022-2828(95)90052-7 Get rights and content

Abstract

Species-related differences in the mechanisms of noradrenaline release during normoxia and myocardial ischemia emphasize the need for studies on human hearts. Therefore, the mechanisms of noradrenaline release were investigated during normoxia and energy depletion in incubated human atrial tissue and compared to the release characteristics in normoxic and ischemic rat heart. Potential differences of atrial versus ventricular myocardium were assessed by comparing catecholamine release during electrical stimulation and ischemia in isolated rat atrium with release characteristics in the intact perfused heart. The overflow of endogenous noradrenaline and its deaminated metabolite dihydroxyphenylethyleneglycol (DOPEG) were determined by high pressure liquid chromatography and electrochemical detection.

During normoxia noradrenaline release was evoked by electrical field stimulation. Stimulation-induced noradrenaline release depended on the extracellular calcium concentration in both species and was almost completely suppressed under calcium-free conditions. The release was significantly inhibited by neuronal (n-type) calcium channel blockers such as ω-conotoxin (100 nmol/l) and cadmium chloride (100 μmol/l), indicating a predominant role of n-type calcium channels in exocytotic noradrenaline release from sympathetic neurons in human and rat heart. Desipramine (100 nmol/l) enhanced the overflow of noradrenaline evoked by electrical stimulation in both species by blocking neuronal catecholamine uptake (uptake₁).

Myocardial ischemia was caused by interruption of perfusion flow in rat heart and simulated by anoxic and glucose-free incubation in human and rat atrial tissue. Ischemia- and anoxia-induced noradrenaline release in rat heart and human atrial tissue was unaffected by varying extracellular calcium concentrations and occurred even after omission of calcium and addition of EGTA (1 mmol/l). In both species neither ω-conotoxin (100 nmol/l) nor cadmium chloride (100 μmol/l) affected ischemia-induced noradrenaline overflow in both rat heart and atrium as well as in human atrium. In human and rat atrial tissue, blockade of energy metabolism in the presence of oxygen (cyanide model) resulted in a desipramine-sensitive release of noradrenaline, which was accompanied by DOPEG overflow, indicating increased axoplasmic noradrenaline concentration.

The data imply a dual mechanism of noradrenaline release in the human heart. During normoxia noradrenaline release is modulated by neuronal calcium influx indicating exocytotic release. Ischemia-induced noradrenaline release, however, is independent of calcium and inhibited by uptake₁ blockade suggesting nonexocytotic release mechanism. The characteristics of noradrenaline release in human atrial tissue provide evidence for carrier-mediated release of noradrenaline from sympathetic neurons operative in the ischemic human myocardium.

References (45)

PH Cobbold et al.
Calcium transients in single adrenal chromaffin cells detected with aequorin
FEBS Lett
(1987)
JM Lundberg et al.
High levels of neuropeptide Y in peripheral noradrenergic neurons in various mammals including man
Neurosci Lett
(1983)
Y Oyama et al.
Synthetic ω-conotoxin: a potent calcium channel blocking neurotoxin
Brain Res
(1987)
G Richardt et al.
Calcium antagonists and cardiac noradrenaline release in ischemia
J Mol Cell Cardiol
(1991)
G Rona
Catecholamine cardiotoxicity
J Mol Cell Cardiol
(1985)
VK Saxena et al.
Relationship between external calcium concentration and noradrenaline- and neuropeptide Y-evoked release from perfused dog spleen
Brain Res
(1989)
RD Wilkerson et al.
The antiarrhythmic action of amitriptyline on arrhythmias associated with myocardial infarction in dogs
Eur J Pharmacol
(1978)
T Abrahamsson et al.
Ischemia-induced local release of myocardial noradrenaline
J Cardiovasc Pharmacol
(1985)
G Ahnert-Hilger et al.
Ca²⁺-stimulated catecholamine release from α-toxin-permeabilized PC12 cells: Biochemical evidence for exocytosis and its modulation by protein kinase C and G proteins
Biochemistry
(1987)
GJ Augustine et al.
Calcium action in synaptic transmitter release
Annu Rev Neurosci
(1987)

PF Baker et al.

Calcium-dependent exocytosis in bovine adrenal medullary cells with leaky plasma membranes

Nature

(1978)

BP Bean

Classes of calcium channels in vertebrate cells

Annu Rev Physiol

(1989)

RD Burgoyne

The relationship between secretion and intracellular free calcium in bovine adrenal chromaffin cells

Biosci Rep

(1984)

L Carlsson et al.

Release of noradrenaline in myocardial ischemia—importance of local inactivation by neuronal and extraneuronal mechanisms

J Cardiovasc Pharmacol

(1986)

L Carlsson et al.

Early intraneuronal mobilization and deamination of noradrenaline during global ischemia in the isolated perfused rat heart

Naunyn-Schmiedebergs Arch Pharmacol

(1987)

AM Dart et al.

Release of endogenous catecholamines in the ischemic myocardium of the rat. Part B: Effect of sympathetic nerve stimulation

Circ Res

(1984)

AM Dart et al.

Metabolic requirements for release of endogenous noradrenaline during myocardial ischemia and anoxia

Br J Pharmacol

(1987)

A Daugherty et al.

The role of catecholamines in the production of ischaemia-induced ventricular arrhythmias in the rat in vivo and in vitro

Br J Pharmacol

(1986)

R Dietz et al.

Ischaemia induced noradrenaline release mediates ventricular arrhythmias

WW Douglas

Stimulus-secretion coupling: the concept and clues from chromaffin and other cells

Br J Pharmacol

(1968)

KL Dry et al.

Catecholamine release from bovine adrenal chromaffin cells during anoxia or metabolic inhibition

Circ Res

(1991)

AP Fox et al.

Kinetic and pharmacological properties distinguishing three types of calcium currents in chick sensory neurones

J Physiol (Lond.)

(1987)

Cited by (59)

Cellular and Molecular Perspectives on Cardiac Toxins
2015, Heart and Toxins
The reasons for the occurrence of the toxic effects of chemicals in the heart include accidental overdose and inappropriate therapeutic use. Chemicals act on many sites in the myocardium to produce toxic effects. Accordingly, substances can adversely influence cell function by producing abnormal inotropic, chronotropic, and/or dromotropic effects, leading to compromised cardiac function and cardiac output. High incidence of cardiac toxicity seems to be associated with certain classes of drugs, namely tricyclic antidepressants, cardioglycosides, β-adrenoceptor blockers, Ca channel antagonists, and anthracyclines. In addition, a host of other chemicals with diverse chemical structures seem to inhibit the rapid delayed rectifier K⁺ current and to prolong repolarization of cardiac cells. This leads to polymorphic ventricular tachycardia that, at times, can be fatal. In addition, certain toxins that are able to alter ion permeability in cardiomyocytes appear to have profound effects on cardiac function. For example, a group of lipid-soluble, plant-derived toxins, such as grayanotoxin, veratridine, and aconitine, are capable of increasing Na⁺ permeability in mammalian cardiomyocytes. Toxin-induced alteration of Na⁺ permeability can lead to destabilization of the resting membrane potential and cause major disruption of cardiac function.
Effects of intravenous cariporide on release of norepinephrine and myoglobin during myocardial ischemia/reperfusion in rabbits
2014, Life Sciences
Citation Excerpt :
Under physiological conditions, NE is mainly released via Ca2 +-dependent exocytosis. In myocardial ischemia, however, the predominant process of NE release is Ca2 +-independent nonexocytosis via NET (Kurz et al., 1995). Physiologically, NET relocates NE within the synaptic cleft into the axoplasm, where NE is taken up into storage vesicles or degraded by monoamine oxidase.
To examine the effects of cariporide, a Na⁺/H⁺ exchanger-1 inhibitor, on cardiac norepinephrine (NE) and myoglobin release during myocardial ischemia/reperfusion by applying a microdialysis technique to the rabbit heart.
In anesthetized rabbits, two dialysis probes were implanted into the left ventricular myocardium and were perfused with Ringer's solution. Cariporide (0.3 mg/kg) was injected intravenously, followed by occlusion of the left circumflex coronary artery. During 30-min coronary occlusion followed by 30-min reperfusion, four consecutive 15-min dialysate samples (two during ischemia and two during reperfusion) were collected in vehicle and cariporide-treated groups. Dialysate myoglobin and NE concentrations were measured by immunochemistry and high-performance liquid chromatography, respectively.
Dialysate myoglobin and NE concentrations increased significantly during myocardial ischemia/reperfusion in both vehicle and cariporide-treated groups (P < 0.01 vs. baseline). In cariporide-treated group, dialysate myoglobin concentrations were significantly lower than those in vehicle group throughout ischemia/reperfusion (P < 0.01 at 0–15 min of ischemia, P < 0.05 at 15–30 min of ischemia, P < 0.01 at 0–15 min of reperfusion, and P < 0.01 at 15–30 min of reperfusion). However, dialysate NE concentrations in cariporide-treated group were lower than those in vehicle group only during ischemia (P < 0.01 at 0–15 min of ischemia, and P < 0.05 at 15–30 min of ischemia).
When administered before ischemia, cariporide reduces myoglobin release during ischemia/reperfusion and decreases NE release during ischemia.
Protective effects of 17beta-estradiol on post-ischemic cardiac dysfunction and norepinephrine overflow through the non-genomic estrogen receptor/nitric oxide-mediated pathway in the rat heart
2013, European Journal of Pharmacology
Citation Excerpt :
In sympathetic nerve endings in the protracted ischemic condition, the potential for norepinephrine storage is reduced due to ATP depletion, resulting in massive accumulation of norepinephrine and H+ within the axoplasm (Kurz and Schömig, 1989). Compensatory activation of the Na+/H+ exchanger by increased axoplasmic H+ causes an influx of Na+ in exchange for H+ (Kurz et al., 1995). Moreover, the decrease in Na+/K+ ATPase activity due to ATP depletion also leads to axoplasmic Na+ accumulation (Kranzhöfer et al., 1991).
The present study was undertaken to examine the effect of acute treatment with 17β-estradiol on post-ischemic cardiac dysfunction and norepinephrine overflow and its possible mechanisms. Male rat hearts were perfused with the Langendorff method and subjected to 40 min of global ischemia followed by 30 min of reperfusion. Each drug was perfused from 15 min before ischemia to 5 min after reperfusion. During reperfusion, 17β-estradiol treatment showed significantly greater functional recovery of left ventricular developed pressure (LVDP), left ventricular end diastolic pressure (LVEDP), and dP/dt_max. Excessive norepinephrine release in coronary effluent from the post-ischemic heart was notably suppressed by treatment with 17β-estradiol. These beneficial effects of 17β-estradiol were not observed in the presence of the nitric oxide synthase inhibitor N^G-nitro-l-arginine and estrogen receptor antagonist ICI 182,780 ((7α, 17β)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol), respectively. When NO₂/NO₃ levels in coronary effluents after the onset of reperfusion were measured, reverse-correlation relationships between NO₂/NO₃ production and ischemia/reperfusion-induced cardiac dysfunction, as well as norepinephrine overflow were observed. These findings suggest that 17β-estradiol exerts cardioprotective effects against ischemia/reperfusion-induced cardiac dysfunction, at least in part, by suppressing norepinephrine overflow, and that nitric oxide production via estrogen receptor activation plays a key role in this process.
Hypothermia down-regulates the LPS-induced norepinephrine (NE) release in ischaemic human heart cells
2012, Brain Research Bulletin
Citation Excerpt :
Therefore, the modulation of excessive NE release would be expected to protect the myocardium, improve functional recovery, and limit reperfusion arrhythmia [11,17]. NE release from sympathetic nerve endings can occur by two major mechanisms [16,40–42]. One is Ca2+-dependent, electrical stimulus-evoked vesicular exocytosis, and the other is Ca2+-independent, carrier-mediated cytoplasmic release.
Hypothermia has been widely acknowledged as the fundamental component of myocardial protection during cardiac operations. In this work, we studied in human atrial tissue the effect of the common hypothermic protection used in cardiac surgery, and we assessed this effect by comparing catecholamine release among normoxic, ischaemic, and inflammatory conditions. Our results provide the first evidence that lipopolysaccharide treatment results in an extremely dramatic and significant increase in the resting norepinephrine release under ischaemic conditions that can be normalised by hypothermia. These findings demonstrate that inflammatory conditions increase the temperature sensitivity of the norepinephrine transporter in human cardiac tissue. When the possible pharmacological interventions are taken into consideration, the results presented here provide new insight into the protection against ischaemia/reperfusion injury during cardiac surgery.
The acute inotropic effects of cardiac contractility modulation (CCM) are associated with action potential duration shortening and mediated by β1-adrenoceptor signalling
2011, Journal of Molecular and Cellular Cardiology
Citation Excerpt :
The ventricular myocardium is richly innervated with efferent sympathetic nerve fibres and it is likely that these fibres are stimulated to release noradrenaline by the delivery of electrical signals to the epicardial surface. Importantly, several studies have previously shown that electrical signals, not specifically timed to the absolute refractory period, can be used to stimulate catecholamine release from the perfused whole hearts and from isolated samples of cardiac tissue [14,15]. The distribution of sympathetic nerve fibres throughout the ventricle has been shown to be heterogenous with a gradient of fibre density from basal (highest) to apical (lowest) regions [16,17].
Despite promising results in clinical trials conducted to date, little is known about how cardiac contractile modulation (CCM) mediated inotropic enhancement occurs and how CCM affects the electrophysiological characteristics of the heart. The aims of the present study were to 1) investigate how the stimulation parameters of the CCM signal and the location of stimulus delivery influence the contractile response, 2) characterise the effect of CCM on ventricular electrophysiology, and 3) investigate the potential physiological mechanisms underlying these acute inotropic and electrophysiological effects. Experiments were conducted in isolated rabbit hearts with simultaneous measurement of ventricular contractility and monophasic action potential duration (MAPD). Biphasic square wave pulses were applied to the left ventricle, timed to coincide with the absolute refractory period. CCM mediated responses were assessed over a range of signal amplitudes (2–30 mA), durations (2–15 ms) and delays from the activation of the locally recorded monophasic action potential (0–30 ms). Responses were assessed during perfusion with the β1-adrenoceptor antagonist metoprolol (1.8 μM) and HMR 1556 (500 nM), an inhibitor of the slow delayed rectifying potassium current. Norepinephrine content was collected and assessed by ELISA from samples of coronary effluent collected during CCM. CCM induced a significant increase in left ventricular pressure (LVP) in a manner dependent upon the amplitude and duration of the CCM signal but independent of the delay of the stimulus within the action potential plateau and was associated with an increase in norepinephrine in coronary effluent (Mean: 46 ± 9 pg/ml). CCM promoted a shortening of MAPD-90% close to the site of stimulation (− 19 ± 3%) but had no effect on those recorded at distant sites (0 ± 1%). The increase in LVP (4.7 ± 1.8 vs. 0.7 ± 0.9%, P < 0.01) and shortening of local MAPD-90% (− 15 ± 3 vs. 1 ± 1%, P < 0.01) was abolished with metoprolol. Perfusion with HMR 1556 caused a significant inhibition of local MAPD shortening (− 27 ± 2 vs. − 21 ± 3 ms, P < 0.05). CCM is associated with a shortening of ventricular MAPD in a manner dependent upon β-adrenoceptor stimulation resulting from catecholamine release, a finding which may be of clinical significance in regard to the development of malignant ventricular arrhythmias. This article is part of a Special Issue entitled Possible Editorial.
Effects of KB-R9032, a new Na<sup>+</sup>/H<sup>+</sup> exchange inhibitor, on canine coronary occlusion/reperfusion-induced ventricular arrhythmias
2005, Journal of Pharmacological Sciences
We investigated the effects of KB-R9032 (N-(4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl) guanidine methanesulfonate), a new Na⁺/H⁺ exchange inhibitor, on a coronary artery occlusion/reperfusion-induced arrhythmia model in pentobarbital anesthetized dogs. KB-R9032 reduced the number of ventricular premature contractions seen during the coronary occlusion, while it did not alter the heart rate, mean blood pressure, or electrocardiographic parameters (PR, QRS, or QTc interval). KB-R9032 also decreased the incidence of fatal ventricular fibrillation during coronary artery occlusion and/or after reperfusion. These antiarrhythmic effects were observed not only in the pre-ischemic administration group, but also in the group given KB-R9032 at the 15th min of the 30-min occlusion. These findings support the view that Na⁺/H⁺ exchanger may play an important role in inducing coronary ischemia/reperfusion arrhythmias. This suggests that the use of Na⁺/H⁺ exchange inhibitors, such as KB-R9032, may be an effective clinical approach to suppress sudden cardiac death due to acute myocardial ischemia/reperfusion such as during coronary bypass surgery, cardiac valve surgery, or percutaneous transluminal coronary angioplasty.

View all citing articles on Scopus

View full text

Original articleTwo different mechanisms of noradrenaline release during normoxia and simulated ischemia in human cardiac tissue

Abstract

FEBS Lett

Neurosci Lett

Brain Res

J Mol Cell Cardiol

J Mol Cell Cardiol

Brain Res

Eur J Pharmacol

Ischemia-induced local release of myocardial noradrenaline

J Cardiovasc Pharmacol

Ca2+-stimulated catecholamine release from α-toxin-permeabilized PC12 cells: Biochemical evidence for exocytosis and its modulation by protein kinase C and G proteins

Biochemistry

Calcium action in synaptic transmitter release

Annu Rev Neurosci

Calcium-dependent exocytosis in bovine adrenal medullary cells with leaky plasma membranes

Nature

Classes of calcium channels in vertebrate cells

Annu Rev Physiol

The relationship between secretion and intracellular free calcium in bovine adrenal chromaffin cells

Biosci Rep

Release of noradrenaline in myocardial ischemia—importance of local inactivation by neuronal and extraneuronal mechanisms

J Cardiovasc Pharmacol

Early intraneuronal mobilization and deamination of noradrenaline during global ischemia in the isolated perfused rat heart

Naunyn-Schmiedebergs Arch Pharmacol

Release of endogenous catecholamines in the ischemic myocardium of the rat. Part B: Effect of sympathetic nerve stimulation

Circ Res

Metabolic requirements for release of endogenous noradrenaline during myocardial ischemia and anoxia

Br J Pharmacol

The role of catecholamines in the production of ischaemia-induced ventricular arrhythmias in the rat in vivo and in vitro

Br J Pharmacol

Ischaemia induced noradrenaline release mediates ventricular arrhythmias

Stimulus-secretion coupling: the concept and clues from chromaffin and other cells

Br J Pharmacol

Catecholamine release from bovine adrenal chromaffin cells during anoxia or metabolic inhibition

Circ Res

Kinetic and pharmacological properties distinguishing three types of calcium currents in chick sensory neurones

J Physiol (Lond.)

Original article
Two different mechanisms of noradrenaline release during normoxia and simulated ischemia in human cardiac tissue

Ca²⁺-stimulated catecholamine release from α-toxin-permeabilized PC12 cells: Biochemical evidence for exocytosis and its modulation by protein kinase C and G proteins