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Query: UNIPROT:P06889 (Mol)
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In a previously reported canine model of sudden cardiac death, its authors heavily weighted the role of the autonomic nervous system in determining whether or not a combined stress of submaximal exercise and ischemia would produce a fatal arrhythmia the setting of a healed anterior wall myocardial infarction. This morphologic study of that model reveals that anatomic factors are also relevant to vulnerability to sudden death: dogs who developed ventricular fibrillation in response to such a stress (susceptible) had significantly more of the left ventricle (LV) infarcted than dogs who survived the stress (resistant): 13.14% (+/- 2.67 S.E.M.) as compared with 4.01% (+/- 2.11 S.E.M.). Moreover, areas of fibrosis were spread more widely throughout the ventricle and septum in susceptible as compared with resistant animals, which consistently showed more homogeneous areas of infarct largely confined to the apical portion of the LV. While the autonomic nervous system may well be relevant to survival to stress in an animal which has survived a myocardial infarction, we conclude that there are important anatomic factors which determine vulnerability.
J Mol Cell Cardiol 1993 May
PMID:The anatomic matrix as a factor in susceptibility to lethal arrhythmias in a canine model of sudden cardiac death. 837 11

We recently reported that modulation of anion homeostasis by substitution of extracellular chloride by nitrate prevents ischaemia- and reperfusion-induced ventricular fibrillation (VF) in rat and rabbit in vitro by an unknown mechanism independent of haemodynamic changes but related to widening of QT interval (Ridley and Curtis 1991). In the present study we have examined three possible explanations for the mechanism: modification of membrane anion permeability, alteration of cyclic nucleotide homeostasis and alteration of intracellular pH. In isolated Langerdorff-perfused rat heart (n = 12/group), substitution of chloride in modified Krebs perfusion solution by anion surrogates (methylsulphate, bromide, nitrate or iodide) inhibited left regional ischaemia- and reperfusion-induced arrhythmias only when the membrane permeability of the surrogate was greater than that of chloride (e.g., nitrate, bromide, iodide); the least permeant anion, methylsulphate, was proarrhythmic during ischaemia. Rank order of arrhythmia susceptibility correlated with the relative permeability of each anion, with near abolition of both ischaemia- and reperfusion-induced VF (P < 0.05) by the most permeant anions (iodide and nitrate). Arrhythmia suppression occurring in the iodide and nitrate groups was accompanied by significant widening of QT interval at 90% repolarization, with effects substantially more marked during ischaemia than before ischaemia. In separate studies using the same model we determined cardiac cyclic (c) AMP and cGMP content and their molar ratios by radioimmunoassay of biopsies before, during and after ischaemia. There was no meaningful relation between cyclic nucleotide content and rank order of arrhythmia susceptibility ruling out changes in the former as a contributory mechanism to the latter. In further studies we measured intracellular pH in the isolated perfused rat heart by phosphorus NMR spectroscopy. Nitrate caused a slight intracellular acidosis which was exacerbated when hearts were made globally ischaemic, indicating that its antiarrhythmic activity was not a consequence of alkalinisation (e.g., via inhibition of chloride-bicarbonate exchange). To test for inherent adverse effects on cardiac contractile function we analysed Starling curves in isolated rat hearts perfused under conditions equivalent to those used for arrhythmia studies. There was no relationship between perfusion anion composition and systolic (developed pressure at constant intraventricular volume, and pressure-volume slope) or diastolic function (end-diastolic pressure at constant intraventricular volume). In conclusion, alteration of membrane permeability is a mechanism which may be sufficient to explain modulation of arrhythmias by manipulation of extracellular anion content, appears to be devoid of deleterious effects on contractile function, and may represent a focus for future antiarrhythmic drug development.
J Mol Cell Cardiol 1993 Apr
PMID:Anion manipulation, a novel antiarrhythmic approach: mechanism of action. 839 92

The objective of this study was to determine whether electrically-induced ventricular fibrillation can elicit oxygen free radical formation, even in the absence of ischemia and reperfusion. Rat hearts (n = 8 in each group) were perfused aerobically at 37 degrees C and ventricular fibrillation was induced by pacing (20 Hz, 1200 beats/min) for 10 min, during which time no changes in coronary flow rates were observed. In this study, electron spin resonance (ESR) studies using the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) demonstrated the formation of oxygen free radicals consisting of 1:2:2:1 quartet with peak concentration at the 3rd min of fibrillation in non-ischemic electrically fibrillating hearts. Since there were no significant changes in coronary flow rates during ventricular fibrillating (22.3 +/- 1.3 ml/min in control vs 22.3 +/- 0.9 ml/min in pacing-induced fibrillating group), the formation of oxygen free radicals could not be attributed to a pacing-induced ischemic event. In additional studies, hearts were paced by 10 Hz (600 beats/min), to demonstrate whether ventricular tachycardia could elicit free radical formation. In these experiments the genesis of oxygen free radicals was not observable after 1 min, 5 min, and 10 min of tachycardia, but a small amount of OH. radicals was detected at the 3rd min of ventricular tachycardia. When DMPO was infused into the heart giving a final perfusate concentration of 2.5 mmoles/litre during the pacing-induced fibrillation period, myocardial function (aortic flow, cardiac output, left ventricular developed pressure, first derivative of left ventricular developed pressure, and end-diastolic pressure) was significantly improved after the postfibrillating period. In conclusion, our studies clearly show that electrically-induced ventricular fibrillation is capable of eliciting free radical formation even in the absence of ischemia and reperfusion, and the cardioprotective effect of the spin trap is directly originated from its free radical trapping property and not from the other pharmacological activities of DMPO.
J Mol Cell Cardiol 1993 Jun
PMID:Pacing-induced ventricular fibrillation leading to oxygen free radical formation in aerobically perfused rat hearts. 841 Nov 94

The susceptibility to ventricular arrhythmias under the conditions of cardiac ischemia and reperfusion was investigated in the Langendorff heart preparation of rats fed for eight weeks a standard chow enriched with 2% of pulverized wild garlic leaves. The isolated hearts were perfused with a modified Krebs-Henseleit solution. The incidence of ventricular fibrillation (VF) during 20 min occlusion of the descending branch of the left coronary artery (LAD) was significantly reduced in the wild garlic group as compared to untreated controls (20% vs 88%). The same holds for the size of the ischemic zone (33.6% vs 40.9% of heart weight). In the reperfusion experiments (5 min after 10 min ischemia), ventricular tachycardia (VT) occurred in 70% of the wild garlic group vs 100% in untreated controls and VF in 50% vs 90%. The time until occurrence of extrasystoles, VT or VR was prolonged. No significant alterations in cardiac fatty acid composition could be observed. Although the prostacyclin production was slightly increased in hearts of the wild garlic group, inhibition of cyclooxygenase by acetylsalicylic acid (ASA; aspirin) could not completely prevent the cardioprotective effects suggesting that the prostaglandin system does not play a decisive role in the cardioprotective action of wild garlic. Furthermore, a moderate angiotensin converting enzyme (ACE) inhibiting action of wild garlic was found in vitro as well as in vivo that could contribute to the cardioprotective and blood pressure lowering action of wild garlic. Whether a free radical scavenging activity of wild garlic is involved in its cardioprotective effects remains to be established.
Mol Cell Biochem 1993 Feb 17
PMID:Cardioprotective actions of wild garlic (allium ursinum) in ischemia and reperfusion. 845 76

Isolated Langendorff-perfused rat hearts were used to assess susceptibility to reperfusion-induced arrhythmias after different durations of ischemia in relationship to structurally related impairment of heart function, and to examine whether phase two ischemia-induced arrhythmias occur in crystalloid perfused hearts. This was achieved by subjecting the hearts to 5 min reperfusion following either sustained (240 min), intermediate (30 min), or brief (10 min) regional ischemia. Sustained ischemia induced little arrhythmogenesis upon reperfusion (no ventricular fibrillation) and impairment of recovery of coronary flow (approximately 64% of uninvolved zone flow). Electron microscopic investigation of the ischemic region revealed severe degenerative damage of the ultrastructure of cardiac myocytes and capillary endothelial cells. In contrast, reperfusion following brief ischemia caused all hearts to develop ventricular fibrillation (VF), accompanied by a persisting hyperemia throughout the course of reperfusion (flow 149 +/- 33% of that in the uninvolved zone after 1 min of reperfusion). In this group, myocardial ultrastructure exhibited negligible i.e., almost complete reversal of injury, upon reperfusion. Intermediate (30 min) ischemia led to a high incidence of reperfusion arrhythmias (92% of hearts developing VF) and modest hyperemia (flow 111 +/- 22% of that in the uninvolved zone after 1 min of reperfusion). Moderate ultrastructural alterations and their further deterioration upon reperfusion were observed in some but not all hearts in this group. During ischemia, phase 1 arrhythmias were common (57% of hearts developed VF during the first 30 min). However, phase 2 arrhythmias were absent during 120-240 min ischemia in these isolated hearts. In conclusion sustained ischemia in the rat heart renders myocardium unviable with a consequent loss of susceptibility to reperfusion arrhythmias. Phase 2 ischemia-induced arrhythmias do not occur in this model, implicating an intact autonomic nervous system and/or circulating factors from blood (e.g., neutrophils) in phase 2 arrhythmogenesis.
J Mol Cell Cardiol 1995 Sep
PMID:Brief, intermediate and prolonged ischemia in the isolated crystalloid perfused rat heart: relationship between susceptibility to arrhythmias and degree of ultrastructural injury. 852 54

Endothelin-1 (ET-1) has been demonstrated to produce numerous cardiac effects and increased production of the peptide has been shown in cardiac disease states. Although the cardiac effects of ET-1 have been examined extensively on its own, few studies have reported potential cross-talk between ET-1 with other endothelium-derived factors. We examined whether nitric oxide (NO) can modulate the effects of ET-1 on isolated rat hearts or ventricular myocytes. At 0.05 nM, ET-1 produced no effects on either systolic or diastolic function although a two-fold increase in left ventricular end-diastolic pressure (LVEDP) was observed in hearts pretreated with 10 microM of the NO synthase inhibitor L-NAME. Higher concentrations of ET-1 (0.5 and 5 nM) produced a direct elevation in LVEDP which was enhanced by L-NAME and totally blocked by the NO donor S-nitrosoacetylpenicillamine (SNAP, 10 microM) although responses to 5 nM ET-1 were highly variable with no significant differences between treatment groups. SNAP totally prevented ventricular fibrillation produced by either 0.05 or 0.5 nM ET-1 whereas the pro-fibrillatory actions of 5 nM ET-1 were unaffected. In cardiac myocytes, SNAP significantly attenuated the elevation in intracellular Ca2+ produced by ET-1 (5 nM). The positive inotropic actions of ET-1 on either hearts or myocytes were unaffected by any treatment. The protective effect of SNAP against ET-1 in both isolated hearts (reduction in LVEDP and incidence of fibrillation) as well as ventricular myocytes (attenuation of the elevation in intracellular Ca2+) was mimicked by 8-bromo-cyclic GMP (50 microM). Our study suggests that NO protects against the cardiotoxic effects of ET-1, possibly via inhibition of intracellular Ca2+ elevations, a property shared by cGMP, the likely mediator of the biological effects of NO.
J Mol Cell Cardiol 1996 Feb
PMID:Modulation of endothelin-1 effects on rat hearts and cardiomyocytes by nitric oxide and 8-bromo cyclic GMP. 872 59

Reduced glutathione (GSH) is a major myocardial antioxidant. Since reperfusion phenomena such as ventricular fibrillation (VF) are associated with oxygen free radical production during ischaemia, myocardial GSH depletion might be expected to increase susceptibility to such phenomena. This possibility was tested in isolated rat hearts using diethylmaleate (DEM) or L-buthionine-SR-sulfoximine (BSO) to deplete myocardial GSH. High dose DEM (860 mg/kg) depleted myocardial GSH from a control mean of 7.64 +/- 0.73 to 3.18 +/- 0.56, low dose DEM (215 mg/kg) to 4.29 +/- 0.53 nmol/mg protein and BSO (4 mmol/kg) from a control mean of 6.94 +/- 0.54 to 2.18 +/- 0.14 nmol/mg protein. Hearts were perfused in the Langendorff mode at 37 degrees C with bicarbonate buffer (K+ = 4.3 mM). Regional ischaemia was induced for 5, 8.5, 10, 20 or 40 min (DEM groups: n = 10/treatment/time point) or 8.5 min only (BSO groups: n = 10/treatment) then hearts were reperfused for 5 min. Reperfusion VF incidence showed a classical "bell-shaped" curve, but there was no difference in VF incidence, VF time-to-onset, arrhythmia duration and "arrhythmia scores" between GSH-depleted and control hearts. Depleting myocardial GSH is not proarrhythmic for reperfusion-induced arrhythmias. It would appear GSH is not significantly involved in protecting against the oxidant stress of reperfusion, or conversely that the reserve of this redox system is so high only severe depletion might show an effect.
J Mol Cell Cardiol 1996 Apr
PMID:Ventricular arrhythmias induced by ischaemia-reperfusion are unaffected by myocardial glutathione depletion. 873 96

Vulnerability to ventricular fibrillation (VF) is frequently evaluated by VF threshold, a variable which may not be free of confounding factors and which may not be sensitive to all factors contributing to vulnerability. Therefore, we tested whether VF threshold determination affects intracellular free Ca2+ ([Ca2+]i) and whether VF thresholds are sensitive to changes in [Ca2+]i. For this purpose, we analysed [Ca2+]i by surface fluorometry and indo-1 in intact perfused rat hearts undergoing VF threshold determination by a single pulse method and tested whether such thresholds are lowered by increased [Ca2+]i. Additionally, we sought to determine the importance of Ca2+ for the vulnerability to VF under nonischemic conditions. For this purpose, we measured VF thresholds by a new pulse number method which scanned the vulnerable period by an increasing number of sequential pulses at increasing prematurity but constant intensity. We found that VF threshold determination by a single pulse method led to a rise in systolic [Ca2+]i. However, this rise does not perturb VF threshold interpretation because such thresholds were insensitive to changes in [Ca2+]i. Nevertheless, [Ca2+]i is of importance for the vulnerability to VF under nonischemic conditions because the number of VF-free tolerated premature pulses was dependent on [Ca2+]i. This relationship may only be detectable if evaluated by sequential pulse methods. These findings suggest that the method of VF threshold determination may be crucial for the result of studies testing Ca2+ antagonists or situations of altered [Ca2+]i and could explain controversial results of VF threshold studies testing Ca2+ antagonists by varying methods.
J Mol Cell Cardiol 1996 May
PMID:Importance of calcium for the vulnerability to ventricular fibrillation detected by premature ventricular stimulation: single pulse versus sequential pulse methods. 876 43

RP58866 (1-[-2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4- (3,4-dimethoxyphenyl)-piperidine), a specific blocker of the inwardly rectifying K+ current (IK1), is an extremely effective antiarrhythmic agent in rat, rabbit and primate (marmoset) isolated hearts in the settings of acute ischaemia and reperfusion (Rees and Curtis, 1993a). In the present study we further examined the mechanism of action of RP58866. We used the new dual coronary perfusion cannula that allows left and right sides of the heart to be perfused independently. The model has not previously been used for pharmacological investigations. Isolated rat hearts (n = 112) were randomized to one of four groups: perfusion of the left and right coronary beds with drug-free solution (n = 28), perfusion of the left coronary bed with 3 mumol/l RP58866 (n = 28), perfusion of the right coronary bed with 3 mumol/l RP58866 (n = 28) or perfusion of left and right coronary beds with 3 mumol/l RP58866 (n = 28). After 5 min perfusion, left regional ischaemia was induced and maintained for 30 min. Regional coronary flow was measured by in-line flowmeters. Epicardial monophasic action potentials (MAP) were recorded from the left (n = 15/group) and right (n = 13/group) perfusion regions using a suction electrode. Delivery of RP58866 to the uninvolved zone (right perfusion bed) suppressed ischaemia-induced ventricular fibrillation (VF): incidences (%) of VF were 80, 60, 33 (P < 0.05) and 27% (P < 0.05) in groups with no drug, with RP58866 delivered to the left bed, with RP58866 to the right bed and with RP58866 to the left plus right beds, respectively. Protection correlated with widening of MAP duration in the uninvolved zone which at 100% repolarization was 130.6 +/- 8.0, 129.1 +/- 7.0, 155.8 +/- 6.5 (P < 0.05 versus control) and 155.3 +/- 8.7 (P < 0.05) in the four groups, respectively after 5 min of ischaemia (just prior to the onset of ventricular arrhythmias). Corresponding values recorded from the involved zone (left perfusion bed) were 102.6 +/- 7.8, 131.2 +/- 11.1 (P < 0.05), 138.2 +/- 11.6 (P < 0.05) and 147.1 +/- 8.9 ms (P < 0.05), suggesting that RP58866 may gain access to ischaemic tissue via collatoral flow from the right perfusion bed. In order to suppress ischaemia-induced VF, it appears that the IK1 blocker RP58866 must widen APD in uninvolved tissue. APD widening activity restricted to the involved tissue alone is insufficient to prevent VF. However, caution should be exercised when using the dual coronary perfusion model to assess pharmacological activity since, even in rat, a species with extremely low collateral flow, there is evidence of cross-flow between the left and right ventricles.
J Mol Cell Cardiol 1995 Dec
PMID:Further investigations into the mechanism of antifibrillatory action of the specific IK1 blocker, RP58866, assessed using the rat dual coronary perfusion model. 882 80

Nitric oxide (NO) is an endogenous protectant against reperfusion-induced ventricular fibrillation (VF) in the rat isolated heart. Here, the following were investigated: (1) the tissue source of cardioprotective NO using a novel inhibitor (7-nitro indazole; 7-NI) of the neuronal form of NO synthase (NOS) and direct detection of coronary effluent NO by chemiluminescence; and (2) the species dependence by comparing rat and rabbit hearts. Perfusion with modified Krebs solution was followed by 60 min left regional ischemia and 10 min reperfusion. 7-NI (1 microM) increased the incidence of VF from 0% to 60% in rat hearts (n = 10; P < 0.05). Co-perfusion with L-arginine (1 mM) reduced VF incidence to 20% (P:N.S. v controls). The inactive analog of 7-NI (6-amino indazole: 6-AI) had no pro-fibrillatory activity. Neither 7-NI nor 6-AI affected coronary flow or recovery of flow during reperfusion. 7-NI reduced basal coronary effluent NO levels to below the limit of detection (< 1 pmol), but a massive increase in NO levels occurred when L-arginine was co-perfused with 7-NI. Although 7-NI had no effect on basal coronary flow and, by implication, resting NO release, it was found, in separate studies, to antagonise substance P-induced vasodilatation and NO release, suggesting that its neuronal selectivity is lost in the presence of an exogenously administered activator of endothelial NOS in rat hearts. In rabbit hearts, in contrast, 7-NI had no effect on VF or NO levels. However, in rabbit hearts the isozyme non-selective NO synthase blocker, NG-nitro-L-arginine methyl ester (L-NAME; 100 microM), increased VF incidence from 0 to 50% (P < 0.05) and, during the first minute of reperfusion, reduced NO levels from 4929 +/- 893 to 2505 +/- 483 pmol/min/g (P < 0.05) and recovery of coronary flow by 22% (P < 0.05). Each of these effects were prevented by L-arginine co-perfusion. These data indicate a role for basally released NO as an endogenous antifibrillatory cardioprotectant in rat and rabbit isolated heart and indicate that the tissue source (neuronal in rat but not in rabbit heart) is species-dependent.
J Mol Cell Cardiol 1996 Oct
PMID:Endogenous protection against reperfusion-induced ventricular fibrillation: role of neuronal versus non-neuronal sources of nitric oxide and species dependence in the rat versus rabbit isolated heart. 893 Aug 5


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