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Query: UNIPROT:P06889 (Mol)
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Studies in cats suggest alpha-adrenergic contributions to arrhythmias during myocardial ischemia and reperfusion. The validity of this concept in other species, however, remains uncertain. Thus, 106 chloralose-anesthetized open-chest dogs undergoing a 25 min coronary artery occlusion followed by reperfusion received saline (n = 52), prazosin (1 mg/kg, n = 26), phentolamine (5 mg/kg, n = 18), or phentolamine (same dose) + propranolol (1 mg/kg, n = 10). Alpha-blockade was confirmed by alpha-agonist dose-response studies. In phentolamine-treated dogs, arterial pressure and heart rate were kept constant to prevent exacerbation of ischemia. Control and treated groups were comparable with respect to variables known to affect arrhythmias, such as size of occluded and reperfused vascular beds, coronary collateral flow, severity of ischemia estimated from intramyocardial CO2 tension, and peak reactive hyperemia. During coronary occlusion, the number of single premature ventricular complexes was reduced by phentolamine (P less than 0.01), but not by prazosin or phentolamine + propranolol; no treatment affected the total number of couplets, ventricular tachycardia episodes and ventricular ectopic complexes, or the incidence of ventricular tachycardia and ventricular fibrillation. During coronary reperfusion, arrhythmias did not differ in control and treated groups. Thus, selective alpha 1-(prazosin), nonselective alpha 1- and alpha 2-(phentolamine), and combined alpha- and beta-blockade (phentolamine + propranolol) failed to attenuate complex arrhythmias induced by acute myocardial ischemia and reperfusion. Alpha-adrenergic mechanisms appear unimportant in the genesis of these arrhythmias in the canine model.
J Mol Cell Cardiol 1984 Dec
PMID:Effect of alpha-adrenergic blockade on arrhythmias induced by acute myocardial ischemia and reperfusion in the dog. 615 73

The effects of the antithrombotic drug nafazatrom (BAY g 6575) were investigated in chloralose-anaesthetized greyhounds subject to coronary artery occlusion and reperfusion. Pretreatment with nafazatrom 10 mg/kg p.o. did not significantly reduce the number of extrasystoles or the incidence of ventricular fibrillation (VF) during the first 30 min occlusion of the left anterior descending coronary artery. However, the incidence of VF resulting from release of a 40-min coronary artery occlusion was markedly reduced (from 88% in the controls to 14% in the nafazatrom group). Both thromboxane B2 (TxB2) and 6-keto PGF1 alpha (breakdown products of TxA2 and prostacyclin respectively) were released from the acutely ischaemic myocardium in control dogs. Nafazatrom did not alter the release of TxB2 but the concentrations of 6-keto PGF1 alpha were elevated in blood draining from both the ischaemic and normal regions of the myocardium. The pronounced anti-fibrillatory effect of nafazatrom during reperfusion of the ischaemic myocardium may be related to the ability of this drug to elevate prostacyclin concentrations in the coronary circulation.
J Mol Cell Cardiol 1984 Jan
PMID:The effects of nafazatrom on arrhythmias and prostanoid release during coronary artery occlusion and reperfusion in anaesthetized greyhounds. 636 41

Stimulation of alpha 1-adrenoceptors (AR) during ischaemia in the rat heart by exogenous phenylephrine exacerbates reperfusion arrhythmias, an effect apparently mediated by the alpha 1A-AR subtype. We tested whether alpha 1A-AR stimulation by endogenous catecholamines, released during ischaemia, could modulate reperfusion arrhythmias, using as pharmacological tools the selective alpha 1A-AR antagonists abanoquil (UK52046) and WB4101. Isolated rat hearts (n = 12/group) were subjected to dual coronary perfusion. After 15 min of aerobic perfusion of both coronary beds, abanoquil or WB4101 was infused selectively into the left coronary bed (LCB) for 5 min. The LCB was then subjected to 10 min of zero-flow ischaemia and 5 min of reperfusion. Effects on PR interval, width of the ventricular complex (QRST90) and reperfusion arrhythmias were assessed. Abanoquil at concentrations of 0.03, 0.1 and 0.3 microM tended to reduce the incidence of reperfusion-induced ventricular fibrillation (VF) in a dose-dependent manner from 75% in controls to 58, 33 and 25%, but this effects did not achieve statistical significance. Similarly, WB4101 at 0.1, 0.3 and 1 microM also tended to reduce VF incidence from 67% in controls to 67, 42% and 33% (NS). The incidence of ventricular tachycardia (VT) was 100% in all groups and ECG parameters were not altered significantly by either drug. These results suggest that, in this denervated isolated heart preparation, alpha 1A-AR stimulation during ischaemia by endogenous catecholamines does not significantly modulate reperfusion arrhythmias.
Mol Cell Biochem
PMID:Effects of selective alpha 1A-adrenoceptor antagonists on reperfusion arrhythmias in isolated rat hearts. 749 47

Ventricular fibrillation (VF) is one of the most life threatening events. Although in humans VF is generally sustained (SVF) requiring artificial defibrillation, in various mammals and in some cases in humans VF terminates by itself, reverting spontaneously into sinus rhythm. Since VF is one of the main causes of sudden death, one of the important clinical problems today is if and how we can transform the fatal SVF into a self limited transient one (TVF). From electrophysiological studies carried out on anaesthetized open chest animals, we have found that TVF requires a high degree of intercellular coupling and synchronization. Cardiac myocytes are electrically coupled with adjacent cells. The intercellular coupling is a focus of low electrical resistance which allows rapid transmission of electrical impulses between cells. Any decrease in intercellular coupling decreases the ability of the heart for self defibrillation. The cell-to-cell coupling decreases with age, ischemia, VF and variations in physiological conditions probably due to an increase in intercellular resistance (Ri), widening in the internexal gaps, decrease in electrotonic space constant (lambda) etc. All of these factors are known to be affected by intracellular concentration of free Ca++ ([Ca++]). On the basis of studies carried out on various mammals at different ages, we hypothesized that the ability of the heart to defibrillate depends on the cardiac catecholamine level [CA], during VF. This hypothesis is supported by the facts, known from the literature, that increase in [CA] decreases intracellular free Ca++ concentration, decreases Ri and increases lambda.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Biochem
PMID:The role of catecholamines on intercellular coupling, myocardial cell synchronization and self ventricular defibrillation. 749 48

Although there is good evidence that adenosine contributes to the ability of ischaemic preconditioning to reduce myocardial ischaemic damage (infarct size) there is no evidence that it contributes to the marked antiarrhythmic effects of this endogenous protective mechanism. We have examined this in anaesthetized open-chest mongrel dogs by administering the non-selective adenosine receptor blocking drug 8-sulfophenyltheophylline (8-SPT) (1 mg/kg) given by intracoronary administration 10 min before both 5 min preconditioning coronary artery occlusions and also before the prolonged 25 min LAD occlusion i.e. in a total dose of 3 mg/kg. The only haemodynamic effect of 8-SPT was a reduction in coronary (LAD) blood flow and an increase in cardiovascular resistance. It was difficult to precondition dogs in the presence of 8-SPT; the number of ventricular premature beats was significantly higher (61 +/- 6 v 8 +/- 4; P < 0.01) during the initial preconditioning occlusion and the incidence of ventricular fibrillation during the preconditioning procedure was higher in the presence of the drug (5/11 v 4/20; P < 0.05). Nevertheless, it was still possible to precondition these dogs in the presence of the drug. No VF occurred during the prolonged occlusion (cf. 50% in the controls) and the number of episodes of ventricular tachycardia, and the number of ventricular premature beats in dogs preconditioned in the presence of 8-SPT was similar to those in dogs preconditioned without 8-SPT and significantly (P < 0.01 or P < 0.05) less than in control, non-preconditioned dogs.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1995 Jan
PMID:Pronounced antiarrhythmic effects of preconditioning in anaesthetized dogs: is adenosine involved? 776 Mar 56

Partial coronary sinus obstruction (CSO) in the dog prevents or delays the predictable ventricular fibrillation (VF) of the early phase of acute ischemia, by normalizing regional electrophysiological disparities which presumably reflect inhomogeneous extracellular potassium ([K+]o) accumulation. To clarify whether CSO indeed affects [K+]o inhomogeneity, we determined in 12 chloralose anesthetized dogs the dynamic [K+]o changes occurring early during reversible coronary artery occlusion (CAO) involving the mid-left anterior descending branch. These changes were compared to those observed during CAO preceded by CSO sufficient to increase the coronary sinus pressure to 40 mmHg. [K+]o was determined using valinomycin coated electrodes implanted within the ischemic (IZ) and the normal (NZ) zones, as well as immediately inside (BZi) and outside (BZo) the visible border. [K+]o increased rapidly within the IZ and the BZi reaching plateau 5 min after CAO, at about three-fold control (11.89 +/- 1.12 mEq/l). Unexpectedly, [K+]o also increased initially outside the border (BZo) but declined after 3 min to a lower level (7.00 +/- 0.40 mEq/l), thus creating a steep gradient of up to 5.54 +/- 0.20 mEq/l, P < 0.001) across the visible border. In four trials, the gradient coincided with VF. With CSO preceding CAO, the development of this border zone gradient was entirely prevented. Moreover, [K+]o reached a significantly lower and similar level in the IZ, BZi and BZo (9.5 +/- 0.89 mEq/l, P < 0.001) and no VF was observed. Thus the beneficial electrophysiologic and antiarrhythmic effects of CSO in acute ischemia may be explained by [K+]o equalization.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1994 Oct
PMID:Prevention of extracellular K+ inhomogeneity across the ischemic border by coronary venous obstruction in the dog: salutary antiarrhythmic effects of enhanced myocardial hydration. 786 95

Brief episodes of ischaemia and reperfusion (preconditioning) can increase the resistance of the myocardium to ischaemic injury. We investigated the temporal characteristics of anti-arrhythmic protection by preconditioning. Rat hearts underwent regional ischaemia (+/- reperfusion) of the left coronary territory. Control isolated blood-perfused hearts underwent 40 min ischaemia; in the preconditioned groups this was preceded by one, two or three cycles of 5 min ischaemia and 5 min reperfusion. Control anaesthetized rats underwent 60 min ischaemia; this was preceded by three cycles of 3 min ischaemia and 3 min reperfusion in the preconditioned group. Preconditioning led to: (i) the abolition of ventricular fibrillation in both in vivo and in vitro preparations; (ii) a reduced incidence of ventricular tachycardia (from 100% to 8% in vitro and 100% to 25% in vivo); and (iii) a reduced incidence of ventricular premature beats (from 246 +/- 36 to 8 +/- 5 in vitro and 85 +/- 21 to 24 +/- 13 in vivo). In isolated hearts protection was proportional to the number of preconditioning cycles. Although preconditioning caused a dramatic reduction in the severity of arrhythmias it did not result in any significant alteration in their temporal profiles. We conclude that protection by preconditioning against ischaemia-induced arrhythmias is "dose"-dependent in rat hearts in vitro and results in an absolute reduction in the severity of ischaemia-induced arrhythmias rather than an alteration in their time-course, both in vivo and in vitro.
J Mol Cell Cardiol 1993 Dec
PMID:"Dose"-dependency and temporal characteristics of protection by ischaemic preconditioning against ischaemia-induced arrhythmias in rat hearts. 815 59

Using a paced Lagendorff-perfused rabbit heart paradigm, we investigated the role of protein kinase C (PKC) in the development of ventricular fibrillation (VF) in hearts subjected to hypoxia (12 min) and re-oxygenation (40 min). We studied the effect of putative activators and inhibitors of PKC on the incidence of VF. Hearts exposed to 4 beta-phorbol,12,13-dibutyrate (PDBu), isophorbol or the membrane permeant diacylglycerol analog, 1-oleoyl-2-acetyl-rac-glycerol (OAG), during the prehypoxic phase had an increased incidence of VF during the hypoxic and reoxygenation periods. The incidence of VF was 90%, 83% and 75% in hearts exposed to PDBu, isophorbol and OAG, respectively (P < 0.05 vs control). Perfusion of hearts with PDBu was associated with a significant increase in the membrane fraction of cardiac PKC activity. In the presence of the inactive phorbol ester 4 alpha-phorbol didecanoate, the incidence of VF was 17% (P > 0.05 vs control). PKC activators were profibrillatory at concentrations that did not affect cardiac function: neither left ventricular developed pressure nor coronary perfusion pressure were affected. The effect of PDBu was antagonized by staurosporine: the incidence of VF was 17% in PDBu+staurosporine treated hearts (P < 0.05 vs control). To further study the profibrillatory effect of PDBu, hearts were exposed to PDBu in the presence of the ATP-dependent potassium channel antagonist glibenclamide. The latter prevented PDBu-induced VF. The results show that under the conditions employed, PDBu-induced activation of PKC induces redistribution of PKC activity and is associated with the development of VF.
J Mol Cell Cardiol 1993 Dec
PMID:Phorbol ester-induced ventricular fibrillation in the Langendorff-perfused rabbit heart: antagonism by staurosporine and glibenclamide. 815 62

Heat stress provides protection against mechanical dysfunction and myocardial necrosis after prolonged ischemia. We have investigated whether this protection extends to reperfusion arrhythmias occurring after a short (non-lethal) ischemic insult. Anaesthetized open chest rats were subjected to a 5-min occlusion of the left coronary artery. The incidence and duration of reperfusion arrhythmias and the duration of sinus rhythm were assessed in the first 5 min of reperfusion. Prior heat stress led to a reduction in the incidence (100-63%, P < or = 0.05) and duration (66.2 +/- 15.8 to 9.4 +/- 2.9 s, P < or = 0.05) of ventricular tachycardia and a non-significant reduction in the incidence (76-50%) and duration (74.3 +/- 23.4 to 42.9 +/- 24.4 s, P = 0.09) of ventricular fibrillation. This resulted in a significant increase in the duration of sinus rhythm (142.1 +/- 27.6 to 216.7 +/- 24.8 s, P < or = 0.05) and reduction in arrhythmia score (P < or = 0.05) in heat stressed rats compared with controls. This protection against reperfusion arrhythmias was associated with a two-fold increase in endogenous catalase activity and expression of the inducible heat stress protein HSP 70. Inhibition of catalase with pre-administered 3-amino triazole resulted in a paradoxical protection in both sham and heat stress hearts. We conclude that heat stress leads to protection against reperfusion arrhythmias; however, we have been unable to resolve whether the changes in catalase activity or HSP expression are the mediators of the demonstrated cardioprotection.
J Mol Cell Cardiol 1993 Dec
PMID:The protective effect of heat stress against reperfusion arrhythmias in the rat. 815 65

The effects of perfusate calcium reduction, allopurinol and dimethylthiourea on reperfusion-induced arrhythmias and purine wash-out in isolated rabbit and rat hearts were compared. The overall incidence of reperfusion-induced ventricular tachycardia (VT) was 88% and 94% and that of ventricular fibrillation (VF) was 44% and 88% in the control rabbit and rat hearts, respectively. VF was reduced to 10% and 0% in rat and rabbit hearts subjected to perfusate calcium reduction (0.4 mM for 1 min before ischemia and for 1 min before and throughout reperfusion), respectively. In allopurinol, 1 mM, perfused rat hearts the overall incidence of VF was not changed and only the incidence of a sustained VF (that lasting for at least 10 min) was reduced. VT and VF were prevented in allopurinol-perfused rabbit hearts. Dimethylthiourea, 10 mM, reduced the incidence of VF in rat hearts to 16% and did not significantly affect VT and VF in rabbit hearts. In untreated rat hearts, the major purine compounds washed out upon reperfusion were inosine, hypoxanthine, xanthine and urate. Allopurinol augmented the wash-out of adenosine and abolished that of xanthine and urate. In untreated rabbit hearts, the major purine washed out were inosine, adenosine and hypoxanthine. Allopurinol did not cause further increase in adenosine wash-out in rabbit hearts. We speculate that: (1) calcium mediated arrhythmogenic mechanism is operating both in reperfused rat and rabbit heart; (2) free radical mediated mechanism is of an importance only in rat heart; (3) neither a decreased free radical production secondary to xanthine oxidase inhibition nor the augmentation of adenosine wash-out is a likely explanation for the antiarrhythmic effect of allopurinol in reperfused hearts; and (4) high level of myocardial adenosine accumulation during ischemia, probably secondary to low xanthine oxidase activity, may play a role of a natural defence mechanism in ischemic/reperfused rabbit heart.
J Mol Cell Cardiol 1993 Jul
PMID:Reperfusion arrhythmias and purine wash-out in isolated rat and rabbit heart. Effect of allopurinol, dimethylthiourea and calcium reduction. 823 Feb 46


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