The antiarrhythmic effects of ischaemic preconditioning in anaesthetized dogs are prevented by atropine; role of changes in baroreceptor reflex sensitivity

1. Dogs, anaesthetized with chloralose and urethane, were subjected to a 25 min occlusion of the left anterior descending coronary artery. This resulted in ventricular ectopic activity, a reduction in baroreflex sensitivity (BRS, measured following the intravenous administration of phenylephrine), elevations in the epicardial ST-segment and increases in the degree of inhomogeneity of electrical activation, both measured from the ischaemic region of the left ventricular wall. 2. These changes were markedly reduced when the 25 min occlusion was preceded, 20 min earlier, by a 5 min (preconditioning) occlusion of the same coronary artery (e.g. VF during ischaemia reduced from 40% in the controls to 0%; P<0.05; BRS increased from 1.22+/-0.23 pre-occlusion to 1.61+/-0.25 mmHg ms(-1) post-occlusion in preconditioned dogs; cf. 1.28+/-0.29 to 0.45+/-0.12 mmHg ms(-1) respectively in the controls, P<0.05). 3. These beneficial effects of preconditioning were prevented by the administration, 10 min prior to the 25 min coronary artery occlusion, of atropine (1 mg kg(-1) i.v. followed by a continuous infusion of 0.04 mg kg(-1) h(-1)). For example, VF during occlusion was increased from 0% in the preconditioned dogs to 40% (P<0.05) in the presence of atropine and BRS was again reduced during occlusion (from 1.75+/-0.29 to 0.30+/-0.08 mmHg ms(-1); P<0.05). 4. We conclude that preconditioning reduces arrhythmia severity during ischaemia by favourably modifying cardiac autonomic receptor mechanism through enhancing vagal influences.     

Attenuation of the antiarrhythmic effects of ischaemic preconditioning by blockade of bradykinin B2 receptors.

1. The possibility that bradykinin is involved in the pronounced antiarrhythmic effects of ischaemic preconditioning in anaesthetized mongrel dogs was examined with the use of the selective B2 antagonist, icatibant (Hoe-140). 2. Preconditioning, achieved by two 5 min occlusions of the left anterior descending coronary artery, followed 20 min later by a 25 min occlusion of the same artery resulted, during this prolonged occlusion, in less severe arrhythmias (VF 0% versus 47% in control non-preconditioned dogs), reductions in the incidence and number of episodes of ventricular tachycardia (VT) and in the number of ventricular premature beats and increased survival following reperfusion (50% versus 0% in the controls). 3. Hoe-140 was given in a dose of 300 micrograms kg-1 either before the preconditioning procedure or after preconditioning but before the prolonged occlusion. This dose of Hoe-140 had insignificant haemodynamic effects and failed to modify the increase in coronary blood flow that occurred in the circumflex coronary artery when the anterior descending branch was occluded. 4. It was difficult to precondition dogs in the presence of Hoe-140. There were more ventricular arrhythmias during the initial 5 min occlusion (44 +/- 12 versus 10 +/- 3) and a higher incidence of ventricular fibrillation (50% versus 21%) during the preconditioning procedure. There was also a more pronounced ST-elevation (recorded from epicardial electrodes) during the preconditioning occlusions in those dogs given Hoe-140. 5. In those dogs that survived to the long (25 min) occlusion, Hoe-140 prevented the antiarrhythmic effects of preconditioning (reduction in ventricular premature beats and in VT) although all the dogs survived the occlusion period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Contribution of peroxynitrite to the beneficial effects of preconditioning on ischaemia-induced arrhythmias in rat isolated hearts

We studied the effects of urate, a peroxynitrite scavenger, on ischaemia- and peroxynitrite-induced preconditioning in rat isolated hearts. Isolated hearts perfused with Krebs-Henseleit solution were preconditioned either by 3 min of coronary artery occlusion or by peroxynitrite administration (1 microM) for 3 min, followed by 10 min of reperfusion and 30 min of coronary artery occlusion. Both ischaemia and peroxynitrite produced a marked reduction in arrhythmias. Urate (1 mM) added to the perfusate 10 min prior to ischaemic preconditioning or peroxynitrite infusion and maintained until coronary artery occlusion, markedly reversed the beneficial effects in the ischaemic and peroxynitrite-treated groups. Urate administration in the peroxynitrite-treated group increased the incidence of ventricular tachycardia from 57% (n = 11) to 100% (n = 6) and total ventricular fibrillation from 0% (n=0) to 44% (n=4). Similarly, urate augmented the incidence of ventricular tachycardia from 47% (n=8) to 85% (n = 6) in the ischaemic preconditioning group. On its own, urate did not affect the severity of cardiac arrhythmias. Peroxynitrite infusion caused a marked increase in the effluent nitrate levels, from 0.05 +/- 0.1 microM (n = 5) to 0.4 +/- 0.2 microM (n = 6), and urate significantly decreased these levels to 0.08 +/- 0.03 microM (n = 9). These results suggest that peroxynitrite at low concentrations contributes to the beneficial effects of preconditioning on ischaemia-induced arrhythmias in rat isolated hearts.     

Evidence for the involvement of peroxynitrite in ischaemic preconditioning in rat isolated hearts

1. The aim of this study was to investigate the involvement of peroxynitrite, reactive metabolite originating from nitric oxide and superoxide, in preconditioning of the ischaemic myocardium in rat isolated hearts. 2. Isolated hearts perfused with Krebs-Henseleit solution were preconditioned either by 3 min of coronary artery occlusion (CAO) or by peroxynitrite administration at three different concentrations (0.1, 1, 10 microM) for 3 min, followed by 10 min reperfusion and 30 min of CAO. Peroxynitrite, at 1 microM concentration, decreased the incidence of VT from 100% (n=14) to 62% (n=13) and abolished the occurrence of VF (50% in the control group). 3. N-2-mercaptopropionylglycine (MPG, 1 microM - 10 mM) produced a concentration-dependent inhibition of peroxynitrite signals in luminol chemiluminescence and 67+/-1% inhibition was observed at 100 microM (n=7). MPG (at 300 microM, n=7) added to the perfusate 10 min prior to ischaemic preconditioning or peroxynitrite infusion and maintained until CAO, significantly reversed the beneficial effects of the ischaemic and peroxynitrite-treated groups. MPG administration in the peroxynitrite-treated group increased the incidence of VT from 62% (n=13) to 100% (n=10) and total VF from 0% (n=0) to 67% (n=10). Similarly, MPG elevated the incidence of VT from 50% (n=10) to 100% (n=8) in the ischaemic preconditioned group. On its own, MPG did not affect the severity of cardiac arrhythmias. 4. These results suggest that endogenously produced peroxynitrite plays a significant role in the antiarrhythmic effect of ischaemic preconditioning in the rat isolated hearts.     

Involvement of protein kinase C in the delayed cytoprotection following sublethal ischaemia in rabbit myocardium.

Rabbit hearts were preconditioned with four 5 min coronary artery occlusions 24 h before 30 min coronary occlusion with 120 min reperfusion. Preconditioning significantly reduced the percentage of myocardium infarcting within the risk zone from 49.1 +/- 4.3% to 31.8 +/- 3.5% (P < 0.05). When the protein kinase C (PKC) inhibitor, chelerythrine, was administered just before preconditioning, the delayed protection against infarction 24 h later was abolished. We conclude that the delayed cytoprotective response associated with ischaemic preconditioning of myocardium is likely to involve the early activation of one or more PKC subtypes.     

Protective effect of a novel thromboxane synthetase inhibitor, CV-4151, on myocardial damage due to coronary occlusion and reperfusion in the hearts of anesthetized dogs

The protective effect of a novel thromboxane (TX) synthetase inhibitor, (E)-7-phenyl-7-(3-pyridyl)-6-heptenoic acid (CV-4151), on myocardial damage due to an ischemic episode and reperfusion was investigated in anesthetized, open-chested dogs. The left anterior descending coronary artery (LAD) was occluded for 60 min and subsequently reperfused for 60 min. CV-4151 was infused i.v. at a dose of 1 mg/kg over a 10-min period starting 20 min before the LAD occlusion. The agent had no acute hemodynamic effects. Within 30 min after LAD occlusion, 15.6-33.3% of dogs experienced ventricular fibrillation (VF); CV-4151 had no significant effect on the incidence of VF. After reperfusion, the frequency of ventricular extrasystoles (PVCs) was markedly increased, and 33.3% (9 of 27 dogs) died of VF in the control group. CV-4151 suppressed the exaggerated PVCs, and the incidence of VF in the group was 0% (0/18, p less than 0.05). Myocardial infarct size determined 60 min after reperfusion by a p-nitroblue tetrazolium (p-NBT) staining technique was significantly reduced by CV-4151. Increase in TXB2 release into the great coronary vein during reperfusion was completely inhibited by CV-4151, whereas release of 6-keto-PGF1 alpha tended to increase during occlusion and reperfusion. Thus, the ratio of 6-keto-PGF1 alpha to TXB2 levels was significantly increased throughout occlusion and reperfusion periods. These results suggest that inhibition of TXA2 synthesis is beneficial for protection of the myocardium during reperfusion from ischemic damage.     

Lidoflazine in the early stages of acute myocardial ischaemia.

1 Pretreatment of anaesthetized rats with intravenously administered lidoflazine (an antianginal agent) reduced the incidence and severity of ventricular arrhythmias which resulted from acute coronary artery ligation. Ventricular fibrillation was completely prevented by doses of 50 micrograms/kg and 2 mg/kg and no animal so treated died ( contrast 50% incidence of fibrillation in the controls and 30% mortality). 2 In anaesthetized greyhound dogs, lidoflazine (2 mg/kg) administration resulted in transient reductions in systemic arterial pressure, LV dP/dt max and cardiac output. Coronary sinus Po2 was markedly increased, indicating pronounced coronary vasodilatation. 3 Lidoflazine pretreatment inhibited the increase in epicardial ST-segment elevation which resulted, in dogs, from short (3 min) occlusions of the left anterior descending coronary artery. This effect was especially marked at sites where, in control occlusions, ST-segment elevation was most pronounced. 4 Lidoflazine greatly reduced the number of ventricular ectopic beats which usually resulted from more prolonged (30 min) periods of acute coronary artery occlusion. There was no ventricular fibrillation in these dogs (contrast 25% incidence in the controls). 5 Lidoflazine did not modify the ventricular fibrillation which results from reperfusion of a previously ischaemic area of the left ventricular wall.     

Effects and interaction, of cariporide and preconditioning on cardiac arrhythmias and infarction in rat in vivo.

1. Although Na+-H+ exchange (NHE) inhibitors are reported to protect the myocardium against ischaemic injury, NHE activation has also been proposed as a potential mechanism of ischaemic preconditioning-induced protection. This study was performed to test any modifiable effect of cariporide, an NHE inhibitor, on cardioprotective effects of preconditioning. 2. Anaesthetized rats were subjected to 30 min of coronary artery occlusion and 150 min of reperfusion. The preconditioning (PC) was induced by 3 min of ischaemia and 10 min of reperfusion (1PC) or three episodes of 3 min ischaemia and 5 min reperfusion (3PC). Cariporide (0.3 mg kg(-1)) an NHE inhibitor, was administered 30 min (cari(30)) or 45 min (cari(45)) before coronary ligation (n=8-11 for each group). 3. Ventricular arrhythmias during 30 min ischaemia and infarct size (measured by triphenyltetrazolium (TTC) and expressed as a per cent area at risk (%AAR)) were determined. Cari(30) reduced ventricular fibrillation (VF) incidence and infarct size (from 45 to 0% and 34+/-4 to 9+/-2%; each P<0.05), whereas cari(45) did not. Likewise, 3PC reduced these variables (to 0% and 10+/-2%; P<0.05 in each case) whereas 1PC did not. Moreover, subthreshold preconditioning (1PC) and cariporide (cari(45)), when combined, reduced VF incidence and infarct size (to 0% and 15+3%; each P<0.05 ). 4. In conclusion, changes in NHE activity do not seem to be responsible for the cardioprotective action of ischaemic preconditioning. Protective effects of NHE inhibition and subthreshold preconditioning appear to act additively.     

The role of mitochondrial K(ATP) channels in antiarrhythmic effects of ischaemic preconditioning in dogs

1. In the canine a single brief (5 min) coronary artery occlusion protects the myocardium against the severe ventricular arrhythmias and reduces the ischaemic changes that result from a subsequent, more prolonged (25 min) occlusion. The main purpose of the present study was to examine whether mitochondrial K(ATP) channels are involved in this protection. 2. In chloralose-urethane anaesthetized dogs, preconditioning (PC) was induced by a single 5 min period occlusion of the left anterior descending (LAD) coronary artery, 20 min prior to a 25 min occlusion of the same artery. In some of these PC dogs 5-hydroxydecanoate (5-HD; 150 micro g kg(-1) min(-1) by intracoronary infusion) was given over a period of 30 min either before, or after PC. In other dogs the mitochondrial K(ATP) channel opener diazoxide (1 mg kg(-1); i.c.) was given, either alone or in the presence of 5-HD. Control dogs (infused with saline) were simply subjected to a 25 min occlusion and reperfusion. 3. Compared to controls, both PC and diazoxide significantly reduced the number of ventricular premature beats (VPBs; 295+/-67 to 89+/-28 and 19+/-11, respectively; P<0.05), the number of episodes of ventricular tachycardia (VT; 8.3+/-4.2 to 1.6+/-0.9 and 0.2+/-0.1; P<0.05) and the incidences of VT (100 to 43 and 33%; P<0.05) and ventricular fibrilation (VF; 60 to 0 and 17%; P<0.05) during the 25 min occlusion of the LAD. Further, 43% of the PC dogs and 58% of the diazoxide treated dogs survived the combined ischaemia-reperfusion insult (cp. 0% in the controls; P<0.05). The protection afforded by PC and diazoxide was abolished by 5-HD, especially when it was given prior to the PC occlusion. In the presence of 5-HD, three out of 10 dogs fibrillated during the PC occlusion and another three dogs died following reperfusion. Furthermore, there were no survivors in this group from the prolonged ischaemia/reperfusion insult. 5-HD given after PC only attenuated the antiarrhythmic protection. 4. Opening of mitoK(ATP) channels prior to ischaemia by preconditioning and diazoxide protects the myocardium against ischaemia and reperfusion-induced arrhythmias. This protection is abolished if the opening of these channels is prevented by the prior administration of 5-HD but only attenuated if 5-HD is given after preconditioning. The results indicate that opening of mitoK(ATP) channels prior to ischaemia is mandatory for protection against ischaemia and reperfusion-induced arrhythmias.     

An antiarrhythmic effect of adenosine during myocardial ischaemia and reperfusion

Adenosine (10 micrograms kg-1 min-1, infused into the lumen of the left ventricle) and dipyridamole (0.25 mg kg-1 intravenously, a dose that potentiated markedly the fall in arterial pressure in response to bolus doses of adenosine) each reduced the number of extrasystoles which occurred during the first 30 minutes following coronary artery occlusion in anaesthetised greyhound dogs (from 786 +/- 115 in control dogs to 156 +/- 44 in those treated with adenosine and to 388 +/- 167 with dipyridamole). Intracoronary adenosine (1 microgram kg-1 min-1, infused into the ischaemic area) however appeared to increase the number of extrasystoles to 1230 +/- 214. Left ventricular infusion of adenosine reduced the incidence of ventricular fibrillation (from 88 to 43%) when the ischaemic myocardium was perfused at the end of a 40 min occlusion period. In the dose used in this study (10 micrograms kg-1 min-1) adenosine caused a sustained fall in blood pressure but did not alter blood gases. In control dogs the levels of purine derivatives in blood draining the myocardium rendered ischaemic by coronary artery occlusion (local coronary venous samples) increased gradually during the ischaemic period (from 9 +/- 3 microM pre-occlusion to 25 +/- 7 microM post-occlusion). Dipyridamole increased the resting plasma concentration of purines prior to occlusion by approximately 90%; these remained raised for the occlusion period. These results support the suggestion that adenosine may act as a locally produced endogenous antiarrhythmic agent.     

Effects of Bordetella pertussis toxin pretreatment on the antiarrhythmic action of ischaemic preconditioning in anaesthetized rats.

1. Bordetella pertussis toxin, which catalyses the ADP-ribosylation of certain guanine nucleotide binding proteins (G proteins), thus functionally uncoupling them from associated receptors, was examined to determine whether it modified the antiarrhythmic effect of ischaemic preconditioning in anaesthetized rats. 2. Pertussis toxin (25 micrograms kg-1, i.p., 48 h prior to heart isolation) attenuated the negative chronotropic effect of acetylcholine (ACh) in rat isolated Langendorff perfused hearts. ACh (10 microM) reduced heart rate by 4% in hearts taken from pertussis toxin-treated animals, compared to a reduction of 57% in hearts taken from animals treated only with vehicle. 3. In anaesthetized rats, ischaemic preconditioning (a single 3 min occlusion of the left main coronary artery followed by 10 min reperfusion) had a pronounced antiarrhythmic effect during a subsequent 30 min period of regional myocardial ischaemia. Compared to hearts receiving only a 30 min period of left coronary occlusion, there was a reduced mortality (67% and 0% for control and preconditioned groups, respectively; P < 0.01) and decreased incidences of ventricular tachycardia (VT) and ventricular fibrillation (VF). Pretreatment with pertussis toxin (25 micrograms kg-1, i.p., 48 h previously) did not modify the arrhythmias associated with a 30 min period of regional myocardial ischaemia, neither did it modify the reduction in mortality (from 56% to 0%; P < 0.05) associated with preconditioning. Furthermore, the decrease in total ventricular premature beat count induced by preconditioning seen in controls (from 427 +/- 130 to 95 +/- 45) was also seen in pertussis toxin-treated rats (from 252 +/- 190 to 57 +/- 25).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of Z13752A, a combined ACE/NEP inhibitor, on responses to coronary artery occlusion; a primary protective role for bradykinin

The effects on the responses to coronary artery occlusion of a combined ACE/NEP inhibitor (Z13752A) were examined in anaesthetized dogs. A 1 h infusion of Z13752A (128 microgram kg(-1) min(-1) intravenously) decreased arterial blood pressure (by 11+/-3%; P<0. 05) and increased coronary blood flow (by 12+/-4%, P<0.05). There were no other significant haemodynamic changes. Z13752A inhibited both NEP and ACE enzymes both in dog plasma and in tissue (lung ACE; kidney NEP). Pressor responses to angiotensin I in vivo were inhibited and systemic vasodilator responses to bradykinin were potentiated. When the left anterior descending coronary artery was occluded for 25 min, Z13752A markedly reduced the severity of the resultant ventricular arrhythmias. No ventricular fibrillation (VF) occurred (compared to 7/16 in the controls; P<0.05), and ventricular tachycardia (VT) was reduced (VT in 2/9 dogs treated with Z13752A cp. 16/16 of controls; episodes of VT 0.2+/-0.1 c.p. 10.7+/-3.3; P<0. 05). Reperfusion of the ischaemic myocardium led to VF in all control dogs but occurred less frequently in dogs given Z13752A (survival from the combined ischaemia-reperfusion insult 67% c.p. 0% in controls; P<0.05). Z13752A reduced two other indices of ischaemia severity; epicardial ST-segment elevation and inhomogeneity of electrical activation. These protective effects of Z13752A during ischaemia and reperfusion were abolished by the administration of icatibant (0.3 mg kg(-1), i.v.) a selective antagonist of bradykinin at B(2) receptors; the ischaemic changes in dogs given both icatibant and Z13752A were similar to those in the controls. We conclude that this ACE/NEP inhibitor is effective at reducing the consequences of coronary artery occlusion in this canine model and that this protection is primarily due to potentiation of released bradykinin.British Journal of Pharmacology (2000) 129, 671 - 680     

Local intracoronary infusions of bradykinin profoundly reduce the severity of ischaemia-induced arrhythmias in anaesthetized dogs.

Bradykinin in a dose (25 ng kg-1 min-1) which did not alter coronary flow, or saline, were infused into a small branch of the left anterior descending coronary artery in dogs anaesthetized with chloralose and urethane, for 10 min prior to coronary artery occlusion and throughout the 25 min occlusion period. The degree of inhomogeneity of conduction and epicardial ST-segment changes were measured in the ischaemic zone with a composite electrode. In control dogs, coronary artery occlusion led to severe arrhythmias with an incidence of ventricular fibrillation of 47% and tachycardia of 80% and with a mean of 528 +/- 140 ventricular premature beats. In marked contrast, those dogs administered bradykinin had no ventricular fibrillation or tachycardia and the number of premature beats was significantly less (53 +/- 19). ST-segment changes were also much less in these dogs. These results raise the possibility that bradykinin might contribute to the protective effects of preconditioning and acts as an 'endogenous myocardial protective substance'.     

Pacing-induced delayed protection against arrhythmias is attenuated by aminoguanidine, an inhibitor of nitric oxide synthase.

1. Cardiac pacing, in anaesthetized dogs, protects against ischaemia and reperfusion-induced ventricular arrhythmias when this is initiated 24 h after the pacing stimulus. Now we have examined whether this delayed cardioprotection afforded by cardiac pacing is mediated through nitric oxide. 2. Twenty-two dogs were paced (4 x 5 min periods at 220 beats min(-1)) by way of the right ventricle, 24 h prior to a 25 min period of coronary artery occlusion. Nine of these dogs were given the inhibitor of induced nitric oxide synthase, aminoguanidine (50 mg kg(-1) i.v.), 0.5 h prior to coronary artery occlusion. Sham-operated non-paced dogs with and without aminoguanidine treatment served as controls. 3. Pacing markedly (P<0. 05) reduced arrhythmia severity (ventricular fibrillation, VF, during occlusion 15%; survival from the combined ischaemia-reperfusion insult 62%) compared to control, sham-operated, unpaced dogs (VF during occlusion 58%; survival 17%). This protection was attenuated by the administration of aminoguanidine prior to coronary artery occlusion (survival from the combined ischaemia-reperfusion insult 11%, which was significantly (P<0.05) less than in the paced dogs not given aminoguanidine and similar to the controls). Aminoguanidine had no significant effects on coronary artery occlusion when given to dogs that had not been paced. In the dose used aminoguanadine transiently elevated systemic arterial pressure by a mean of 20 mmHg and reduced heart rate by a mean of 22 beats min(-1). 4. These results suggest that nitric oxide, probably derived from induced nitric oxide synthase, contributes significantly to the delayed cardioprotection afforded by cardiac pacing.     

The local intracoronary administration of methylene blue prevents the pronounced antiarrhythmic effect of ischaemic preconditioning.

Short periods of coronary artery occlusion (2 x 5 min) markedly reduce the severity of arrhythmias and the changes in ST-segment elevation and in the degree of inhomogeneity of conduction during a subsequent 25 min occlusion of the left anterior descending coronary artery in anaesthetized dogs. These changes were completely reversed if methylene blue (5 mg min-1) was infused into a side branch of the coronary artery throughout both the preconditioning and prolonged occlusions. These results suggest that the pronounced antiarrhythmic effects of preconditioning result from activation of guanylyl cyclase and result in increased levels of guanosine 3':5'-cyclic monophosphate.     

Pharmacological evidence that inducible nitric oxide synthase is a mediator of delayed preconditioning

Brief periods of myocardial ischaemia preceding a subsequent more prolonged ischaemic period 24-72 h later confer protection against myocardial infarction ('delayed preconditioning' or the 'second window' of preconditioning). In the present study, we examined the effects of pharmacological modifiers of inducible nitric oxide synthase (iNOS) induction and activity on delayed protection conferred by ischaemic preconditioning 48 h later in an anaesthetized rabbit model of myocardial infarction. Rabbits underwent a myocardial preconditioning protocol (four 5 min coronary artery occlusions) or were sham-operated. Forty-eight hours later they were subjected to a sustained 30 min coronary occlusion and 120 min reperfusion. Infarct size was determined with triphenyltetrazolium staining. In rabbits receiving no pharmacological intervention, the percentage of myocardium infarcted within the risk zone was 43.9+5.0% in sham-operated animals and this was significantly reduced 48 h after ischaemic preconditioning with four 5 min coronary occlusions to 18.5+5.6% (P<0.01). Administration of the iNOS expression inhibitor dexamethasone (4 mg kg(-1) i.v) 60 min before ischaemic preconditioning completely blocked the infarct-limiting effect of ischaemic preconditioning (infarct size 48.6+/-6.1%). Furthermore, administration of aminoguanidine (300 mg kg(-1), s.c.), a relatively selective inhibitor of iNOS activity, 60 min before sustained ischaemia also abolished the delayed protection afforded by ischaemic preconditioning (infarct size 40.0+/-6.0%). Neither aminoguanidine nor dexamethasone per se had significant effect on myocardial infarct size. Myocardial risk zone volume during coronary ligation, a primary determinant of infarct size in this non-collateralized species, was not significantly different between intervention groups. There were no differences in systolic blood pressure, heart rate, arterial blood pH or rectal temperature between groups throughout the experimental period. These data provide pharmacological evidence that the induction of iNOS, following brief periods of coronary occlusion, is associated with increased myocardial tolerance to infarction 48 h later.     

Antiarrhythmic effects of the thromboxane antagonist BM 13.177

The effects of the thromboxane antagonist BM 13.177 (5 mg kg-1 + 0.15 mg kg-1 min-1) was investigated on the ventricular arrhythmias that result from coronary artery occlusion and reperfusion in anaesthetised open-chest greyhounds. BM 13.177 markedly reduced the severity and incidence of arrhythmias resulting from ischaemia; the number of ventricular ectopic beats was reduced from 1,084 +/- 159 (in controls) to 544 +/- 179 (in dogs given BM 13.177) and the incidences of ventricular tachycardia (VT) and ventricular fibrillation (VF) were reduced from 86 to 22% and from 30 to 10% respectively. Following reperfusion the incidence of VF was 86% in controls and 44% in dogs given BM 13.177. Thus the total incidence of VF during the combined ischaemia-reperfusion insult was significantly reduced by treatment with BM 13.177 from 90% (in control dogs) to 50%. These results lend further support to the hypothesis that thromboxane is involved in the genesis of arrhythmias and that blockade of thromboxane receptors may be a suitable approach to antiarrhythmic therapy under conditions of ischaemia and reperfusion.     

Effect of vasodilator drugs on coronary occlusion and reperfusion arrhythmias in anesthetized dogs

The effect of vasodilator drugs on the incidence of ventricular arrhythmias induced during 30 min of occlusion and 15 min of reperfusion of the left anterior descending coronary artery (LAD) was studied in 65 pentobarbital-anesthetized open-chest dogs. Intravenous administration of captopril (0.5 mg/kg), enalapril (0.5 mg/kg), felodipine (4 micrograms/kg), or ketanserin (0.1 mg/kg) 30 min before LAD occlusion reduced mean arterial blood pressure by 15.5 +/- 0.6% (mean +/- SEM). Nifedipine (5 micrograms/kg bolus + 1 microgram/kg min-1) infusion reduced mean arterial blood pressure by 24.8 +/- 1.8%. In none of the dogs was the diastolic blood pressure reduced below 70 mm Hg. During LAD occlusion, reduction in arterial blood pressure by these drugs was associated with a reduced incidence of ventricular premature depolarizations, ventricular tachycardia, and ventricular fibrillation (VF). During LAD reperfusion, the incidence of VF in saline-treated animals was 6/9, whereas for captopril it was 6/9, enalapril 1/9, felodipine 7/9, nifedipine 3/8, and ketanserin 3/9 animals. Thus, only enalapril significantly lowered the incidence of VF (p less than 0.05). The mechanism responsible for this antifibrillatory effect of enalapril is unknown. The muscle mass of the left ventricle supplied by the LAD distal to the site of occlusion in dogs which survived was similar to that of dogs which developed ventricular fibrillation.     

Possible role of cardiac mast cells in norepinephrine-induced myocardial preconditioning.

The present study was designed to investigate the role of cardiac mast cells in the cardioprotective effect of norepinephrine-induced preconditioning. Isolated rat heart was subjected to 30 min of global ischemia followed by 30 min of reperfusion. Both ischemic and norepinephrine (100 microM) preconditioning markedly reduced ischemia-reperfusion-induced release of lactate dehydrogenose (LDH) in the coronary effluent and the incidence of ventricular premature beats (VPBs) and ventricular tachycardia/fibrillation (VT/VF) during the reperfusion phase. Ischemic and norepinephrine preconditioning also significantly reduced ischemia-reperfusion-induced release of mast cell peroxidase (MPO), a marker of mast cell degranulation. However, MPO release increased immediately after ischemic or norepinephrine preconditioning. Histological study with ruthenium red (0.005%) staining confirmed cardiac mast cell degranulation in ischemic and norepinephrine preconditioned isolated rat hearts. These findings tentatively suggest that pharmacological preconditioning with norepinephrine produces a cardioprotective and antiarrhythmic effect similar to ischemic preconditioning through degranulation of resident cardiac mast cells.     

Naloxone inhibits arrhythmias induced by coronary artery occlusion and reperfusion in anaesthetized dogs.

The intravenous administration of naloxone 2 min before coronary artery occlusion in anaesthetized dogs reduced the incidence and severity of cardiac arrhythmias during coronary occlusion (20 min) and reperfusion (120 min) in a dose-related manner. It also reduced the mortality. At a dose of 1 mg kg-1 (the maximum dose used in this study) naloxone abolished the appearance of the life threatening ventricular fibrillation (VF) and ventricular tachycardia (VT) and as a consequence all dogs in this group survived. The results suggest a possible involvement of endogenous opioid peptides in arrhythmogenesis during coronary occlusion and reperfusion in the dog.