Rabbit Model Of Myocardial Infarction Research Articles

A new rabbit model of myocardial infarction without endotracheal intubation

Introduction When establishing a myocardial infarction model in rabbits, artificial ventilation under endotracheal intubation is required to prevent pulmonary collapse caused by pneumothorax. However, it is difficult to carry out endotracheal intubation due to the rabbit anatomy. We therefore attempted to develop a myocardial infarction model in rabbits without endotracheal intubation. Materials and methods A facial oxygen mask with a flow rate of 200 mL/min was placed on anesthetized rabbits ( n = 17). The sternum was carefully incised along the midline to avoid injury to the parietal pleura. The major branch of the left coronary artery was then ligated and the surgical wound was closed. To investigate the effects of the surgical procedure on physiological parameters, blood pressure and blood gas were measured during the same procedure using 10 other rabbits. Results During the surgery, Pa o 2 and Pa co 2 were stable at approximately 230 and 50 mm Hg, respectively. In addition, the animals did not experience severe ventilatory impairment. Four weeks after the myocardial ischemia, the overall mortality rate was 29.4% (5/17). All of the surviving animals showed Q-waves on ECG and myocardial infarction upon histological examination. Conclusions Our new method established a chronic rabbit model of myocardial infarction without the need for endotracheal intubation.

The Expression of the CD18 Leucocyte Integrin in a Rabbit Model of Acute Myocardial Infarction: A Pilot Study of Temporal Changes and Relationship to Infarct Size

CD18 integrins mediate leucocyte adhesion to vascular endothelium. This represents the initial step in inflammatory cell infiltration following myocardial necrosis. The current studyassessed whether the expression of these rapidly activated and readily measured adhesion receptors on circulating neutrophils would reflect the extent of cardiac damage in a rabbit model of acute myocardial infarction. Myocardial ischaemia/infarction was induced in anaesthetised adult male New Zealand white rabbits (n = 8) by ligation of the circumflex or marginal coronary artery. To control for the effects of anaesthesia and surgery, 4 rabbits underwent identical procedures without the induction of infarction. Absolute infarct size (in mg) and infarct size as a percentage of total left ventricular mass (relative infarct size) were calculated by differential staining and weighing of necrotic myocardium. Flow cytometry was used to determine cell surface expression of CD18 at six time points (baseline, 20 and 45 min of ischaemia and 20, 60 and 180 min of reperfusion). Absolute neutrophil CD18 expression and changes in expression over baseline were correlated with absolute and relative infarct size. Mean neutrophil CD18 expression increased significantly (from 2.42 ± 0.20 to 3.07 ± 0.29; p = 0.04) within 20 min of ischaemia. CD18 expression at 3 h did not predict absolute or relative infarct size (r = 0.40 and 0.37, respectively). The percentage change in cell surface CD18 expression (above baseline levels) was, however, correlated with both measures of infarct size (r = 0.76, p = 0.03, and r = 0.92, p = 0.001, respectively). In conclusion, in this rabbit model of myocardial infarction, neutrophil CD18 expression rises within 20 min of the induction of ischaemia but absolute values after 3 h of reperfusion are poor indicators of infarct size. Although percentage change in neutrophil CD18 levels over baseline correlates with infarct size there is considerable variation between individuals, limiting any clinical application.

Pravastatin restored the infarct size-limiting effect of ischemic preconditioning blunted by hypercholesterolemia in the rabbit model of myocardial infarction

OBJECTIVESWe tested to find out whether pravastatin restores the infarct size (IS)-limiting effect of ischemic preconditioning (IP) and if it has any effect on the IP-induced activation of adenosine producing enzyme ecto-5′-nucleotidase which plays a key role in the IP-induced cardioprotection.BACKGROUNDThe IS-limiting effect of IP is blunted by hypercholesterolemia. Recently, HMG-CoA reductase inhibitors are shown to have direct cytoprotective effects.METHODSRabbits were fed with a normal or cholesterol (1%) added diet with or without pravastatin (5 mg/kg/day) treatment. Infarct size was measured after 30 min occlusion and 3 h reperfusion of circumflex coronary artery with or without the IP procedure (5 min occlusion and 10 min reperfusion). Additionally, ecto-5′-nucleotidase activities of ischemic and nonischemic myocardium were measured immediately after IP procedure.RESULTSThis dose of pravastatin did not normalize the increased level of serum cholesterol. The IS-limiting effect of preceding IP (IS reduced from 36.7% to 9.6%, p < 0.001) was abolished by hypercholesterolemia (from 46.1% to 31.3%, p = NS) and restored by pravastatin treatment (from 35.2% to 9.4%, p < 0.001). Pravastatin treatment did not affect IS or the effect of IP under normocholesterolemia. The activation of ecto-5′-nucleotidase presented as the activity ratio of ischemic to nonischemic myocardium (3.1-fold in normocholesterolemia) was blunted by hypercholesterolemia (1.8-fold, p < 0.05) and restored by pravastatin treatment (2.9-fold).CONCLUSIONSPravastatin, at the dose serum cholesterol was not normalized, restored the IS-limiting effect of IP and IP-induced ecto-5′-nucleotidase activation, which were both blunted by hypercholesterolemia. The activation of ecto-5′-nucleotidase may be worth further investigation as a possible mechanism for the hypercholesterolemia-induced retardation and pravastatin-mediated restoration of the cardioprotective effect of IP.

Myocardial hypothermia: a potential therapeutic technique for acute regional myocardial ischemia.

The importance of temperature in the development of necrosis after myocardial ischemia in the beating heart is becoming apparent. Recent studies have shown that the proportion of the ischemic risk zone that becomes necrotic is directly correlated with temperature. This fact suggests the potential therapeutic benefits of reducing myocardial temperature after coronary artery occlusion. We have shown in a number of experimental protocols in the rabbit model of myocardial infarction that topical regional hypothermia reduces infarct size even when instituted after coronary artery occlusion. The reduction in myocardial temperature required to obtain this benefit is modest ( 30 degrees C to 34 degrees C). Topical regional hypothermia allows targeted cooling of a zone of the heart. Myocardial cooling can also be achieved by perfusing the pericardial sac with a chilled fluid by using a closed-circuit catheter system that does not cause cardiac tamponade. This technique also protects myocardium during ischemia. Myocardial hypothermia might be a useful technique to limit ischemic damage during infarction or as adjunctive therapy during minimally invasive cardiac surgery.

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.

Do angiotensin converting enzyme inhibitors limit myocardial infarct size?

1. Effects of captopril, ramiprilat and Hoe 140, a specific bradykinin receptor antagonist, on infarct size were assessed in a rabbit model of myocardial infarction. 2. Rabbits were untreated or pretreated with 0.5 mg/kg of captopril, 0.05 mg/kg of ramiprilat or 20 nmol/kg of Hoe 140 before 30 min coronary artery occlusion and 72 h reperfusion. 3. Captopril and ramiprilat treatment reduced systemic blood pressure by about 10 mmHg without alteration of heart rate, and the dose of Hoe 140 almost completely blocked hypotensive response to intravenous injection of bradykinin (100 ng/kg). 4. Infarct size expressed as percentage of area at risk was 44.5 +/- 3.3% in the control group, 41.9 +/- 1.6% in the captopril group, 51.8 +/- 2.7% in the ramiprilat group and 46.7 +/- 2.2% in the Hoe 140 group. All percentages were not significantly different. 5. These data suggest that angiotensin converting enzymes (ACE), with or without sulfhydryl groups do not limit myocardial infarct size and that endogenous bradykinin in ischaemic myocardium does not play a major protective role against ischaemic myocardial necrosis.

Pretreatment with the adenosine A1 selective agonist, 2-chloro-N6-cyclopentyladenosine (CCPA), causes a sustained limitation of infarct size in rabbits

The highly selective adenosine A1 receptor agonist, 2-chloro-N6-cyclopentyl-adenosine (CCPA), has been shown to be as cardioprotective as ischaemic preconditioning when evaluated with an early staining method using tetrazolium. However, tetrazolium-positive tissue measured 3 h after reperfusion may still overestimate the long term salvage. To test for this possible artefact, a 72 h reperfusion rabbit model of myocardial infarction was used, and infarct size was assessed by histology. Myocardial infarction was induced by a 30 min coronary occlusion. Rabbits were assigned to a control group receiving no treatment, pretreatment with 0.125 mg.kg-1 CCPA, or 0.25 mg.kg-1 pretreatment with CCPA (0.25 mg.kg-1) followed by an A1 selective antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) 30 min after reperfusion to reverse the haemodynamic side effects. In the 0.125 mg.kg-1 CCPA group, 30.8(SEM 4.2)% of the ischaemic zone was infarcted, which was significantly less than that seen in the control group [46.5(3.0)%; p < 0.01]. Reversing the side effects of CCPA by giving DPCPX soon after reperfusion did not block the protective effects [26.2(1.9)% infarction; p < 0.01 v control]. This finding confirms a genuine anti-infarct effect of adenosine A1 receptor stimulation when given prior to the onset of ischaemia. Furthermore blocking the A1 receptors soon after reperfusion reverses the side effects but does not block protection.

Role of adenosine receptor activation in myocardial infarct size limitation by ischaemic preconditioning.

The aims were to examine the role of adenosine receptors in the mechanism of preconditioning in a chronic rabbit model of myocardial infarction; to assess whether the preconditioning effect is blocked by an adenosine receptor antagonist, 8-phenyltheophylline; and to determine whether an adenosine A1 receptor agonist, R(-)N6-2-phenylisopropyl adenosine (R-PIA), mimics infarct size limitation by preconditioning. Myocardial infarction was induced in male rabbits by occlusion of the left coronary artery for 30 min, which was followed by 72 h reperfusion. Before the 30 min ischaemia, rabbits were subjected to one of the following six protocols: (1) untreated control; (2) intravenous injection of 8-phenyltheophylline; (3) preconditioning with 5 min ischaemia; (4) pretreatment with 8-phenyltheophylline plus preconditioning; (5) intravenous injection of R-PIA; or (6) R-PIA plus atrial pacing (240.min-1). Infarct size and area at risk were determined by histology and fluorescent particles, respectively. Preconditioning significantly limited infarct size, normalised as a percent of area at risk (%IS/AR), to 19.2 (SEM 2.3)% v control value of 46.5(2.8)%. 8-Phenyltheophylline alone did not modify the %IS/AR, but its injection before preconditioning attenuated the preconditioning effect such that IS/AR = 34.4(2.5)%. While R-PIA did not achieve statistically significant myocardial salvage, R-PIA plus atrial pacing limited infarct size to 33.7(3.0)% (p<0.05 v control). The R-PIA group had severe hypotension and their infarct sizes were inversely correlated with diastolic blood pressure at reperfusion. There was no such correlation in the R-PIA plus pacing group in which bradycardia and hypotension induced by R-PIA were attenuated by atrial pacing. The infarct size limiting effect of preconditioning was attenuated by 8-phenyltheophylline, and pretreatment with R-PIA was able to limit myocardial infarct size when severe hypotension was avoided by atrial pacing. These findings suggest that adenosine receptor activation plays a crucial role in the mechanism of preconditioning.