Cardioprotection: definition, classification, and fundamental principles.
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Adaptation, Physiological↗
Biomedical subjects
M Haass
Publications and source records attributed to M Haass.
Intracellular compartmentation of troponin T: release kinetics after global ischemia and calcium paradox in the isolated perfused rat heart.
The marked differences in troponin T serum concentrations observed in patients with reperfused and non-reperfused myocardial infarction may be due to a perfusion dependent wash-out of an unbound fraction of cardiac troponin T. To test the release kinetics of troponin T experimentally, the isolated rat heart (Langendorff preparation) was damaged either by the calcium paradox or by no-flow ischemia. Following membrane damage by the calcium paradox troponin T (TNT) showed the same release kinetics in the coronary effluent as the cytosolic markers creatine kinase (CK) or lactate dehydrogenase (LDH). Peak levels of troponin T (282 +/- 58 micrograms/l), CK (6754 +/- 1642 U/l), and LDH (5817 +/- 1730 U/l) occurred 5 min after onset of reperfusion with calcium containing buffers and returned to 9.9%, 1.3%, and 1% of their respective peak levels within 55 min of reperfusion. During reperfusion after no-flow ischemia different release kinetics were found for cytosolic enzymes and troponin T. After 60 min of ischemia, troponin T levels in the coronary effluent increased over the entire reperfusion period of 55 min, almost doubling the 5 min value (191%). In contrast, cardiac enzymes rapidly declined to 18% (CK) and 23% (LDH) of their respective 5 min values at the end of reperfusion. Light microscopy after reperfusion with carbon black revealed a complete and homogeneous reperfusion of Langendorff hearts after no-flow ischemia. Immunoblot analysis confirmed the release of an undegraded 39 kDa troponin T molecule, both after global ischemia and the calcium paradox. These data indicate that prolonged ischemia induces a continuous liberation of cardiac troponin T, most probably from disintegrating myofibres, whereas membrane damage leads almost exclusively to leakage of a functionally unbound troponin T pool. These findings may explain the biphasic serum concentration changes of cardiac troponin T in patients with reperfused myocardial infarction.
Animals↗
Nicotine-induced exocytotic norepinephrine release in guinea-pig heart, human atrium and bovine adrenal chromaffin cells: modulation by single components of ischaemia.
The influence of single components of myocardial ischaemia, such as anoxia, substrate withdrawal, hyperkalemia and extracellular acidosis, on nicotine-induced norepinephrine (NE) release was investigated in the isolated perfused guinea-pig heart, in incubated human atrial tissue and in cultured bovine adrenal chromaffin cells (BCC). In normoxia, nicotine (1-1000 mumol/l) evoked a concentration-dependent release of NE (determined by high pressure liquid chromatography and electrochemical detection) from guinea-pig heart and human atrium. In contrast to selective anoxia (Po2 < 5 mmHg) or glucose withdrawal, respectively, anoxia in combination with glucose withdrawal (5-40 min) markedly potentiated nicotine-induced NE release both in guinea-pig heart and human atrium. The sensitization of cardiac sympathetic nerve endings to nicotine was characterized by a lower threshold concentration and an approximate two-fold increase of maximum NE release, peaking after 10 min of anoxia and glucose withdrawal. Cyanide intoxication (1 mmol/l) combined with glucose withdrawal resulted in a similar increase of nicotine-induced sympathetic transmitter release both in guinea-pig heart and human atrium. In contrast, the nicotine-induced (10 mumol/l) NE overflow was only slightly potentiated by 10 min of global ischaemia in guinea-pig heart. Both hyperkalemia ([K+] 16 mmol/l) and acidosis (pH 6.8-6.0) distinctly attenuated the stimulatory effect of nicotine in guinea-pig heart and human atrium under normoxic conditions. Consistent with an exocytotic release mechanism, NE release was dependent on the presence of extracellular calcium under all conditions tested. Furthermore, NE overflow from guinea-pig heart was accompanied by a release of the exocytosis marker neuropeptide Y (NPY; determined by radioimmunoassay). In BCC, nicotine (1-10 mumol/l) evoked a release of NE and NPY and a transient rise of [Ca2+]i (determined with fura-2) during normoxia which were both dependent on the presence of extracellular calcium. Both hyperkalemia and acidosis markedly reduced the exocytotic release of sympathetic transmitters and the corresponding [Ca2+]i-transients. These data demonstrate that nicotine-induced cardiac exocytotic NE release is markedly potentiated during short-term anoxia in combination with glucose withdrawal. In contrast, a brief period of ischaemia causes only a slight sensitization of cardiac sympathetic nerve endings to nicotine. This discrepancy may be due to an attentuation of nicotine-evoked NE release by hyperkalemia and by acidosis. The protective effect of these factors against anoxia-induced sensitization to nicotine appears to be related to the inhibition of nicotine-evoked [Ca2+]i-transients.
Adrenal Medulla↗
Role of [Na+]i and [Ca2+]i in nicotine-induced norepinephrine release from bovine adrenal chromaffin cells.
Intracellular free sodium ([Na+]i) and calcium ([Ca2+]i) concentrations were determined by sodium-binding benzofuran isophthalate (SBFI) and fura 2 microfluorimetry, respectively, in bovine adrenal chromaffin cells (BCC). Validation of SBFI microfluorimetry by in vitro and in vivo calibration revealed a reliable assessment of [Na+]i within a range of 1-30 mM in single BCC. Nicotine (0.1-10 microM) induced concentration-dependent increases of both [Na+]i (from 3.3 +/- 0.1 to 25.6 +/- 0.4 mM, n = 76, P < 0.001) and [Ca2+]i (from 64 +/- 1 to 467 +/- 16 nM, n = 87, P < 0.001), which were accompanied by an increase in [3H]norepinephrine (NE) release. Consistent with an exocytotic release mechanism, nicotine-induced increments of [Ca2+]i and [3H]NE release were reduced under calcium-free conditions and by gadolinium chloride (40 microM), whereas [Na+]i was not affected. In contrast, a parallel attenuation of nicotine-evoked changes in [Na+]i, [Ca2+]i, and [3H]NE release was observed during reduction of the extracellular sodium concentration. The nicotine-evoked responses were neutralized by the nicotinic receptor antagonist hexamethonium (100 microM) but not by blockade of voltage-dependent sodium channels (1 microM tetrodotoxin). In conclusion, the nicotine-induced exocytotic release of [3H]NE is triggered by an increase in [Ca2+]i, which is facilitated by sodium influx through the nicotinic receptor ionophore.
Adrenal Glands↗
Effect of catecholamine depletion and denervation on neuropeptide Y(NPY) and tyrosine-hydroxylase (TH) mRNA levels in rat sympathetic ganglia.
Neuropeptide Y (NPY) and noradrenaline (NA) are synthesized and stored in sympathetic nerves and concomitantly released in response to appropriate stimuli. The two substances have been reported to interact on various levels: postjunctionally, by mutually potentiating their vasoconstrictor effects, prejunctionally, by inhibiting each other's release. The possibility of an interaction on the levels of their synthesis was investigated in this study. Specific cDNA probes were used for the measurement of the steady state levels of the mRNAs encoding prepro-NPY and tyrosine hydroxylase (TH) in the superior sympathetic cervical and stellate ganglia of rats. Reserpine (5 mg/kg) was administered for inducing catecholamine depletion. This caused a large decrease in the NA content of the heart associated with an about 50% reduction in cardiac NPY levels. Ganglionic NPY and TH mRNA levels increased 3-6 fold as compared to vehicle treated animals. To determine whether this effect was due to transynaptic induction, superior cervical ganglia were decentralized in a subgroup of rats. Decentralized ganglia displayed significantly lower NPY and TH mRNA levels than intact ones. The response to reserpine was almost completely prevented by decentralization. These Observations indicate that the activation of gene expression of NPY and TH by reserpine depends on intact ganglionic innervation and is therefore reflexly mediated. Trans-synaptic induction may regulate NPY and TH mRNA levels also under basal conditions.
Animals↗
Muscarinic inhibition of cardiac norepinephrine and neuropeptide Y release during ischemia and reperfusion.
It was the aim of the present study to characterize the modulatory effect of muscarinic agonists on the overflow of norepinephrine and neuropeptide Y (NPY) from the in situ perfused guinea pig heart, induced by electrical stimulation of the left stellate ganglion (6 Hz, 5 V, 1 min). The muscarinic agonists oxotremorine (0.01-1 microM) and carbachol (0.1-10 microM) reduced norepinephrine and NPY overflow in a concentration-dependent manner to approximately 30% of control. The inhibitory effect of carbachol was antagonized by the unspecific muscarinic antagonist atropine (1 microM) but not by the nicotinic antagonist hexamethonium (100 microM). The M2-specific antagonist AF-DX-116BS was 25 times more potent than the M1-specific antagonist pirenzepine in antagonizing the inhibitory effect of carbachol [50% inhibitory concentration (IC50) = 0.2 microM for AF-DX-116BS; IC50 = 5.0 microM for pirenzepine]. These findings indicate that presynaptic muscarinic inhibition of stimulated norepinephrine and NPY release from the guinea pig heart is mediated mainly by activation of M2 receptors. As early as 2 min after stop-flow ischemia, the inhibitory effect of carbachol (10 microM) on the stimulation-evoked overflow of norepinephrine and NPY was lost. On reperfusion with oxygenated buffer after 10 min of stop-flow ischemia the inhibitory effect of carbachol (10 microM) on stimulation-induced norepinephrine and NPY overflow recovered within 3 min.
Animals↗
Modulation of vascular function by neuropeptide Y during development of hypertension in spontaneously hypertensive rats.
Neuropeptide Y (NPY) is a sympathetic cotransmitter and a platelet-derived factor which causes vasoconstriction, potentiation of norepinephrine (NE) action, and vascular mitogenic effects. Reciprocally, NE markedly enhances the actions of NPY. We studied vasopressor effects of NPY and sources of peptide release during the development of hypertension in spontaneously hypertensive rats (SHR). Conscious SHR (4 and 16 weeks old) had higher resting plasma levels of NE and epinephrine than age-matched Wistar-Kyoto (WKY) rats, but similar NPY immunoreactivity (NPY-ir) levels in platelet-poor plasmas (PPP). In both strains, NPY-ir levels in PPP were higher in 4-week-old than in older rats. However, at all ages (4-24 weeks) SHR had markedly elevated NPY-ir content in platelet-rich-plasmas than WKY rats, although levels declined with age and hypertension. In the superior mesenteric artery, NPY-ir content (per mg) was significantly higher in 4-week-old but lower in 16-week-old SHR than in WKY rats, suggesting greater sympatho-neural NPY stores and release (leading to depletion) during the development of hypertension. Four-week-old SHR also tended to have higher NPY-ir content in the adrenal medullae and coeliac ganglia but a lower content in the kidney than WKY rats; these differences disappeared with age. Pressor responsiveness to alpha-agonists and NPY were similar in both strains at 4 weeks. While unchanged by age in WKY rats, adrenergic and NPY-mediated vasopressor responses became augmented in 16- to 24-week-old SHR (compared with WKY rats); this hyperresponsiveness was not completely abolished by ganglionic blockade and not observed with vasopressin.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenal Medulla↗
[Induction of the atrial and ventricular ANF synthesis in experimental heart failure after aortocaval shunt].
Using the aortocaval shunt as a model of chronic volume overload in the rat, changes of the ANF system were analyzed. A constant shunt volume of 57% increased the heart weight after 14 days by 28% (from 917 +/- 16 to 1177 +/- 28 mg, p < 0.001). The ANF plasma concentration increased from 30.4 +/- 15.1 to 108.2 +/- 30.6 pg/ml (p < 0.05), which corresponds to levels which are reached in early stages of heart failure. ANF tissue concentrations, however, were decreased in both atria while no significant change could be observed in the ventricles. The analysis of the ANF-mRNA expression as an indicator for the ANF-synthesis showed significant increase in the ANF-mRNA/Actin-mRNA ratio in the right atrium by 56% and in the left atrium by 63%. In ventricular tissue the relative ANF-mRNA increased by 58% (right) and 83% (left ventricle). Increased ANF plasma levels during chronic volume overload are due to increased atrial and ventricular ANF-synthesis. The induced ventricular mRNA indicates the participation of the ventricles in the humoral response to volume overload.
Animals↗
Potentiation of potassium-evoked noradrenaline and neuropeptide Y co-release by cardiac energy depletion: role of calcium channels and sodium-proton exchange.
The role of the cardiac energy status in the potassium-evoked exocytosis of both noradrenaline and the sympathetic co-transmitter neuropeptide Y (NPY) was investigated in the guinea-pig perfused heart. The transmitter release was stimulated by potassium depolarization (10-80 mmol/l) during normoxic perfusion (pO2 > 100 mmHg) in the presence of glucose (11 mmol/l) and at various periods (5-40 min) of cardiac energy depletion. Energy depletion was induced either by anoxia (pO2 < 5 mmHg) or by cyanide intoxication (1 mmol/l), both in combination with glucose-free perfusion. Endogenous noradrenaline and NPY were determined in the coronary venous overflow by high-pressure liquid chromatography combined with electrochemical detection and by radioimmunoassay, respectively. Under normoxic conditions potassium depolarization evoked a co-release of both transmitters [molar ratio 862 (noradrenaline):1 (NPY)] at a threshold concentration of 40 mmol/l potassium. This transmitter overflow was characterized by its dependence on extracellular calcium and calcium influx through voltage-dependent neuronal calcium channels of the N-type. Cardiac energy depletion was accompanied by an acceleration and an enhancement of the potassium-evoked transmitter overflow. In comparison to normoxia, a 10-fold increased transmitter overflow with a comparable molar ratio [709 (noradrenaline:1 (NPY)] was evoked by 40 mmol/l potassium after 10 min of either anoxia or cyanide intoxication. This sensitization to potassium depolarization reached a peak after 10 min of energy depletion and was characterized by a markedly reduced threshold concentration (10 mmol/l potassium).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Neuropeptide Y mRNA regulation in rat sympathetic ganglia: effect of reserpine.
To study the mechanism underlying trans-synaptic neuropeptide regulation, mRNA levels of neuropeptide Y were examined in the rat stellate and superior cervical ganglia using a specific neuropeptide Y cRNA probe. Basal levels of neuropeptide Y mRNA were detectable in total RNA extracts from single ganglia. Reserpine induced a large rise in ganglion neuropeptide Y mRNA. Decentralization prevented the increase of neuropeptide Y mRNA content in the ganglia. This suggests that the reserpine induced increase in neuropeptide Y mRNA was dependent on transsynaptic stimulation. Consequently, neuropeptide mRNA levels in sympathetic ganglia may be under the control of preganglionic impulse flow.
Autonomic Fibers, Preganglionic↗
Hemodynamic and neuroendocrine response to acute administration of the phosphodiesterase inhibitor BM14.478 in patients with congestive heart failure.
The benzimidazol analogue BM14.478 is a phosphodiesterase inhibitor with both vasodilator and positive inotropic properties. Hemodynamic parameters and plasma hormone levels of 8 patients (1 female, 7 male) with chronic congestive heart failure NYHA Classes II-IV (1 patient with coronary artery disease, 7 patients with primary dilated cardiomyopathy) were assessed before and until 6 h after the intravenous application of 1.0 mg BM14.478. There was a significant decrease of mean pulmonary artery pressure (28 +/- 11 vs. 23 +/- 11 mmHg; p less than 0.05), mean right atrial pressure (8.6 +/- 5.2 vs. 5.0 +/- 4.7 mmHg; p less than 0.02), and systemic vascular resistance (1651 +/- 484 vs. 1206 +/- 252 dynes.s.cm-5; p less than 0.05) as early as 10 min after injection of BM14.478. Pulmonary vascular resistance also was reduced (128 +/- 86 vs. 61 +/- 39 dynes.s.cm-5, 30 min after injection; p less than 0.02). Simultaneously there was a significant increase of cardiac index (2.3 +/- 0.7 vs. 3.1 +/- 0.8 l.min-1.m-2, 10 min after injection; p less than 0.02), and stroke volume index (28.8 +/- 11.7 vs. 33.9 +/- 8.5 ml.min-1.m-2; 30 min after injection; p less than 0.05). Although mean heart rate did not change significantly, some patients reacted with a transient increase. There was also a slight but insignificant increase of the double product. No serious side effects were observed. The hemodynamic improvement was followed by a delayed reduction of plasma levels of epinephrine (51 +/- 20 vs. 41 +/- 21 pg/ml; p less than 0.02; 30 min after injection) and atrial natriuretic peptide (229 +/- 283 vs. 121 +/- 168 pg/ml; p less than 0.05; 1 h after injection). Mean levels of plasma norepinephrine, however, did not change significantly and individual responses showed large variations, which could not be predicted by the behavior of the hemodynamic parameters. Three of eight patients (2 of these with elevated baseline filling pressures) even showed a marked increase of plasma norepinephrine levels after BM14.478. Response of plasma renin activity and plasma vasopressin levels to BM14.478 also was heterogeneous. According to the results of this study, acute administration of the phosphodiesterase inhibitor BM14.478 has an immediate beneficial hemodynamic effect in patients with severe congestive heart failure by reducing both preload and afterload, and by increasing cardiac index and stroke volume. However, this improvement of hemodynamic parameters is not necessarily accompanied by a favorable short-term response of plasma hormones, and therefore does not allow any conclusions on survival of these patients.
Adult↗
Nicotine-induced release of noradrenaline and neuropeptide Y in guinea-pig heart: role of calcium channels and protein kinase C.
The role of calcium, calcium influx through calcium channels, and activation of protein kinase C for the nicotine-induced release of noradrenaline and of the sympathetic co-transmitter neuropeptide Y (NPY) was investigated in the guinea-pig isolated perfused heart. In the coronary venous overflow noradrenaline and NPY were determined by high-pressure liquid chromatography and radioimmunoassay, respectively. In the presence of extracellular calcium (1.85 mmol/l) nicotine (1-100 mumol/l) evoked a concentration-dependent overflow of both transmitters with a molar ratio of approximately 1500 (noradrenaline):1 (NPY). The nicotine-induced (100 mumol/l) overflow of noradrenaline and NPY was in a linear manner related (r = 0.79 and 0.90, respectively; p less than 0.05) to the extracellular calcium concentration (0-1.85 mmol/l), and it was prevented by calcium-free perfusion. The L-type calcium channel blocker felodipine (100 nmol/l) did not affect the nicotine-induced (100 mumol/l) transmitter overflow. On the other hand, the neuronal (N-type) calcium channel blockers omega-conotoxin (100 nmol/l) and cadmium chloride (50 mumol/l) reduced the nicotine-induced (100 mumol/l) transmitter overflow to 20% of the control value, suggesting a role of N-type calcium channels in mediating the calcium influx for the nicotine-induced transmitter release. The nicotine-induced (30 mumol/l) overflow of both transmitters was two- to three-fold increased by activation of protein kinase C (phorbol 12-myristate 13-acetate; 100 nmol/l). The transmitter overflow was unaffected by 4 alpha-phorbol 12,13-didecanoate (100 nmol/l), a phorbol ester which does not stimulate protein kinase C.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Calcium antagonists and cardiac noradrenaline release in ischemia.
The effects of the calcium antagonists verapamil, gallopamil, nifedipine, felodipine and diltiazem on noradrenaline release during ischemia were studied in isolated perfused rat hearts. Endogenous levels of noradrenaline and its intraneuronal metabolite dihydroxyphenylethyleneglycol (DOPEG) were determined by high pressure liquid chromatography. Global isothermic ischemia of 20 min caused a release of endogenous noradrenaline amounting to 180 +/- 15 pmol/g. The calcium antagonists tested significantly suppressed ischemia-induced noradrenaline release (IC50 in mumols/l: verapamil 1, gallopamil 0.3, nifedipine 1, felodipine 3). Noradrenaline release during ischemia and the inhibitory effect of the calcium antagonists, were independent of extracellular calcium, indicating a nonexocytotic release mechanism. Interaction of the calcium antagonists with the major components of nonexocytotic release, intraneuronal storage and carrier-mediated transport, was tested in normoxic rat hearts. Vesicular storage was not stabilized by the calcium antagonists. In fact, verapamil, gallopamil, diltiazem and felodipine disturbed storage function, as indicated by an increased DOPEG release. Direct interaction with the noradrenaline carrier (uptake1) was demonstrated for verapamil, gallopamil, and diltiazem in a model of 3H-noradrenaline uptake. In conclusion, the calcium antagonists investigated inhibit noradrenaline release in ischemia by a mechanism which is different from blockade of neuronal calcium influx, and is rather due to an interaction with carrier-mediated transport of noradrenaline across the plasma membrane.
Animals↗
Differential effects of antidepressant treatments on fenfluramine-induced increases in plasma prolactin and corticosterone in rats.
Intravenous administration of 5-HT releasing agent, fenfluramine, to rats produced increases in plasma prolactin and corticosterone concentrations. Short-term or long-term treatment with either clorgyline or imipramine did not affect baseline levels of prolactin or corticosterone. On the other hand, short-term but not long-term lithium treatment significantly increased baseline levels of corticosterone but not of prolactin. Short-term treatment with lithium but not clorgyline or imipramine potentiated fenfluramine-induced increases in plasma prolactin but not corticosterone. On the other hand, long-term treatment with clorgyline but not imipramine or lithium attenuated fenfluramine's effect on plasma prolactin but not on corticosterone. These findings demonstrate differential effects of antidepressant treatments on fenfluramine-induced increases in plasma prolactin and corticosterone in rats and are consistent with several other clinical and animal studies demonstrating dissimilar actions of different antidepressant treatments on two different 5-HT-mediated neuroendocrine functions.
Animals↗
Transcription, storage and release of atrial natriuretic factor in the failing human heart.
1. In this study the relationship between the synthesis of atrial natriuretic factor at the level of atrial natriuretic factor mRNA and the atrial storage and circulating plasma levels of atrial natriuretic factor were investigated in 15 patients with heart failure. The patients underwent right and left heart catheterization before cardiac surgery for valve replacement or coronary artery bypass grafting. 2. Plasma concentrations of atrial natriuretic factor were correlated to atrial levels of atrial natriuretic factor mRNA. Atrial levels of atrial natriuretic factor mRNA and plasma concentrations of atrial natriuretic factor exhibited a close correlation to both pulmonary artery pressure and left atrial pressure. No relationship, however, could be found between the right atrial content of atrial natriuretic factor and both the expression of atrial natriuretic factor mRNA in the atria and the plasma levels of atrial natriuretic factor. 3. From these data it may be concluded that increased plasma levels of atrial natriuretic factor in the pressure- and/or volume-overloaded heart are associated with an elevated level of atrial natriuretic factor mRNA. We suggest that not only plasma levels of atrial natriuretic factor but also the expression of atrial natriuretic factor in the atrial are related to left ventricular filling pressures in the failing human heart.
Atrial Natriuretic Factor↗
Catecholamine release and arrhythmias in acute myocardial ischaemia.
Increased sympathetic activity is assumed to contribute substantially to the occurrence of malignant arrhythmias in patients with coronary heart disease, since the rate of sudden cardiac death is significantly reduced by beta-adrenoceptor blockade, but not by antiarrhythmic agents such as flecainide or encainide. During acute myocardial ischaemia, adrenergic stimulation of the ischaemic myocardium is independent of plasma catecholamines. Rather, it is caused by the combination of excessively high local noradrenaline concentrations and an enhanced responsiveness of the myocyte to catecholamines. Myocardial ischaemia of 15 min duration results in a 100-fold increase in catecholamine concentrations within the extracellular space of the ischaemic zone, a two-fold increase in functionally coupled alpha-adrenoceptors, and a 30% increase in beta-adrenoceptors. Within the first 10 min of ischaemia, the myocardium is protected from excessive catecholamine release. Ischaemia-associated metabolic alterations, such as extracellular potassium accumulation, acidosis, and especially the accumulation of adenosine reduce the transmitter release caused by central sympathetic activation. Furthermore, the functional neuronal amine reuptake (uptake1) prevents excessive local accumulation of noradrenaline. With progression of ischaemia to more than 10 min, local nonexocytotic catecholamine release becomes predominant. This release is independent of central sympathetic nerve activity, availability of extracellular calcium, activation of both neuronal calcium channels and protein kinase C, and it is not accompanied by the release of sympathetic cotransmitters such as neuropeptide Y. It has been demonstrated to be nonexocytotic and to be caused by a carrier-mediated transport of noradrenaline from the sympathetic nerve ending into the synaptic cleft. This release is not modulated through presynaptic receptors. It is, however, suppressed by blockers of uptake1 and by inhibitors of sodium-proton exchange. Depletion of cardiac catecholamine stores by chronic surgical or chemical sympathectomy effectively suppresses malignant arrhythmias induced by experimental coronary ligature. Accordingly, inhibitors of nonexocytotic noradrenaline release, such as uptake1 blocking agents or sodium-proton exchange inhibitors, effectively reduce the occurrence of ischaemia-associated ventricular fibrillation, emphasizing the relevance of nonexocytotic release mechanisms in myocardial ischaemia.
Animals↗
Effect of digitalis glycosides on norepinephrine release in the heart. Dual mechanism of action.
The effect of ouabain on exocytotic and nonexocytotic norepinephrine release was investigated in perfused rat and guinea pig hearts. The overflow of endogenous norepinephrine and its neuronal metabolite 3,4-dihydroxyphenylethyleneglycol (DOPEG) was determined by high-pressure liquid chromatography. DOPEG served as the indicator of free axoplasmic norepinephrine concentrations. The overflow of the norepinephrine cotransmitter neuropeptide Y (NPY) was determined by radioimmunoassay and NPY was used as marker for exocytotic release. Electrical stimulation of the left stellate ganglion resulted in exocytotic norepinephrine release in rat and guinea pig hearts. Ouabain caused an increase in stimulation-induced norepinephrine overflow from rat and guinea pig hearts by 40%. However, overflow of NPY was decreased by 40%, indicating a reduced exocytosis rate. Ouabain increased both norepinephrine and NPY overflow, suggesting enhancement of exocytosis, when neuronal catecholamine uptake (uptake1) was blocked by desipramine or when presynaptic alpha 2-adrenoceptors were inhibited by yohimbine. The results demonstrate an interaction of ouabain with both calcium-dependent exocytosis and uptake1 of norepinephrine. Under calcium-free conditions, ouabain or potassium-free perfusate resulted in norepinephrine release from hearts when the axoplasmic norepinephrine concentration was elevated by the reserpinelike agent Ro 4-1284. This release was independent from neural activity, not accompanied by NPY overflow, and suppressed by the uptake1 blocker desipramine. These findings are in keeping with carrier-mediated nonexocytotic norepinephrine release that is caused by reversal of the transport direction of the uptake1 carrier. During myocardial ischemia nonexocytotic norepinephrine release was accelerated and enhanced by inhibition of Na+,K(+)-ATPase before ischemia. This study demonstrates the potential of digitalis glycosides to interact both with transmitter exocytosis and with the neuronal catecholamine transport system by Na+,K(+)-ATPase inhibition. Interaction with the catecholamine transport system involves both inhibition of norepinephrine inward transport and induction of norepinephrine outward transport, resulting in nonexocytotic norepinephrine release.
Animals↗
[Presynaptic regulation of co-release of neuropeptide Y and noradrenaline induced by electrical stimulation of the sympathetic nerve in guinea pig heart].
In the present study, co-release of noradrenaline and neuropeptide y (NPY) evoked by electrical stimulation of the left stellate ganglion, was investigated in the in situ perfused guinea pig heart with intact sympathetic innervation, a model modified from Legendorff technique. Endogenous noradrenaline was measured by HPLC and endogenous NPY was determined by RIA. Electrical stimulation of the left stellate ganglion (4, 8, 12 and 50 Hz) evoked a calcium-dependent and frequency-related overflow of noradrenaline and NPY. The release of both transmitters was positively correlated (r = 0.83, p less than 0.001). When two subsequent stimulations were performed in the same heart, adding exogenous noradrenaline before the second stimulation reduced NPY overflow on the contrary, and NPY decreased the overflow of noradrenaline. The stimulated release of noradrenaline and NPY was increased by the alpha 2-adrenergic receptor antagonist yohimbine, and attenuated by the alpha 2-adrenergic receptor agonist B-HT 920, respectively. The adenosine analogue cyclohexyladenosine significantly reduced co-release of noradrenaline and NPY. Blocking the uptake of NA with despramine or Nisoxetine significantly increased noradrenaline overflow, however, NPY release was markedly reduced. We concluded that electrical stimulation can induce calcium-dependent co-release of noradrenaline and NPY, and this co-release of both transmitters is modulated by presynaptic alpha 2-adrenoceptors.
Animals↗