High-dose erythropoietin has no long-term protective effects in sheep with reperfused myocardial infarction

High-dose erythropoietin has been claimed to be cardioprotective in experimental acute myocardial infarction. In large mammals, however, results are controversial and long-term follow-up data are lacking. We thus assessed the long-term effects of high-dose erythropoietin on left ventricular infarct size and function in an ovine model of reperfused myocardial infarction. After 90 minutes of coronary occlusion followed by reperfusion, sheep received recombinant human erythropoietin (rhEPO) 3000 units/kg on 3 consecutive days (rhEPO group, n=7) or vehicle (placebo group, n=6). Ten weeks later, ventricular function was assessed by echocardiography and catheterization. Infarct size, evaluated as percent fibrotic myocardium (morphometry) and by hydroxyproline quantification, was similar in both groups (morphometry: rhEPO: 22.1 +/- 5.5%, placebo: 18.1 +/- 3.3%, P not significant; hydroxyproline: rhEPO: 6.6 +/- 1.3 microg/mg wet weight, placebo: 7.1 +/- 0.9 microg/mg, P not significant). Ventricular function was diminished in the rhEPO group, as indicated by lower septal wall thickening at the infarct border zone (rhEPO: -1.9 +/- 16.4%, placebo: 20.5 +/- 17%, P<0.04), higher end systolic volume (rhEPO: 47 +/- 14.3 mL, placebo: 32.6 +/- 7.3 mL, P<0.05), and higher end diastolic pressure (rhEPO: 17 +/- 6.5 mm Hg, placebo: 10.1 +/- 2.8 mm Hg, P<0.03). In the rhEPO group, left ventricular endocardial area was larger, suggesting dilatation. High-dose erythropoietin has no cardioprotective effects in sheep with reperfused myocardial infarction.     

Effects of pinacidil on myocardial blood flow and infarct size after acute left anterior descending coronary artery occlusion and reperfusion in awake dogs with and without a coexisting left circumflex coronary artery stenosis

To determine whether partial stenosis of a second major coronary artery promoted vasodilator-induced coronary steal and increased infarct size after acute coronary artery occlusion, we produced acute myocardial infarction by 4-h left anterior descending coronary artery occlusion and 20-h reperfusion in awake dogs with and without a mild to moderate stenosis (33-72%) of the proximal left circumflex coronary artery. Dogs were randomized to receive intravenous (i.v.) normal saline or pinacidil, a new antihypertensive agent with a marked coronary dilator property, beginning 40 min after onset of coronary artery occlusion and continuing throughout the occlusion and the first hour of reperfusion. Pinacidil was titrated to decrease mean aortic pressure 25 mm Hg, which resulted in an increase in heart rate (HR), cardiac output (CO), and left ventricular (LV) dP/dt and LVdP/dt/P. Saline infusion had no effects. Blood flows to ischemic and remote myocardium did not differ between dogs with and without coronary stenosis. Pinacidil increased blood flow threefold in normal myocardium, but had no effect on infarct zone myocardial blood flow or infarct size (58 +/- 4% of region at risk vs. 56 +/- 4% in animals receiving normal saline) in dogs without coronary stenosis. In contrast, similar administration of pinacidil in dogs with coronary stenosis reduced infarct size zone myocardial blood flow and increased infarct size (69 +/- 3% vs. 55 +/- 5% in the saline group, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of zoledronate in the repair of chronically infarcted rat myocardium

Zoledronate (Zol), one of the class of bisphophonate drugs, is commonly used to treat postmenopausal osteoporosis. Treatment of liposomal bisphosphonates has been shown to worsen myocardial infarct repair in an experimental model. The purpose of this study was to investigate the effect of Zol in the repair of chronically infarcted myocardium without liposomal encapsulation to mimic the clinical setting. Zol (20 μg/kg, a dose known to treat experimental osteoporosis in rats, n = 15) was administered subcutaneously to female Sprague-Dawley rats 1 day before coronary artery ligation. Rats receiving phosphate-buffered saline (n = 12) were used as controls. Left ventricular function, infarct size, and remodeling were studied at 4 weeks postinfarction. Zol pretreatment did not affect left ventricular ejection fraction in hearts with myocardial infarction (49.5 ± 1.4% in Zol; 50.6 ± 2.1% in phosphate-buffered saline). Infarct size was similar in Zol versus untreated hearts (34.2% ± 2.9% in Zol; 33.4% ± 2.9% in phosphate-buffered saline). Left ventricular cavity volume and circumference, infarct thickness, and expansion index were comparable between the groups. To investigate a potential effect of Zol on tissue macrophage infiltration after myocardial infarction, heart specimens were harvested 48 hours postinfarction and sections were immunostained with CD68 antibody, a macrophage-specific marker. Results of macrophage immunostaining revealed that the level of tissue macrophage infiltration was similar between groups. In conclusion, administration of Zol before myocardial infarction had no adverse effects on cardiac contractile function, infarct size, or remodeling. These results suggest that treatment of Zol given before the onset of myocardial infarction does not cause worsening of infarct repair.     

A nonpeptide angiotensin II type 2 receptor agonist does not attenuate postmyocardial infarction left ventricular remodeling in mice

Cardiac overexpression of the angiotensin II type 2 receptor (AT2 R) attenuates left ventricular (LV) remodeling after myocardial infarction (MI) in transgenic mice. We hypothesized that a novel nonpeptide AT2 R agonist, compound 21 (C21), would attenuate post-MI LV remodeling. Fifty-nine mice were studied for 28 days after 1-hour surgical occlusion-reperfusion of the left anterior descending coronary artery. Immediately thereafter, 23 mice received 0.3 mg·kg·d of C21 via Alzet osmotic minipump, 16 received 10 mg·kg·d of the AT1 R antagonist candesartan in drinking water, and 20 were untreated controls. Cardiac magnetic resonance imaging measured ejection fraction (EF), LV end-systolic, and end-diastolic volumes (ESVI and EDVI) indexed to weight serially post MI. Infarct size was measured on day 1 by late gadolinium-enhanced cardiac magnetic resonance imaging. At baseline, heart rate, blood pressure, EDVI, ESVI, and EF were similar between groups. Mean infarct size (42%-45% of LV mass) was similar between groups. C21-treated animals demonstrated adverse LV remodeling (increased EDVI and ESVI at all post-MI time points) compared with control. Candesartan therapy preserved left ventricular EF at day 28 compared with the C21-treated group. Thus, direct stimulation of the AT2 R by C21 at 0.3 mg·kg·d does not attenuate post-MI LV remodeling in reperfused MI in mice.     

The long-acting Ca2+-channel blocker azelnidipine prevents left ventricular remodeling after myocardial infarction

Long-acting Ca(2+)-channel blockers have been reported to be effective in treating ischemic heart disease. However, their effects on cardiac remodeling after myocardial infarction (MI) are still unclear. We performed this study to examine the effect of azelnidipine on left ventricular (LV) remodeling, including systolic and diastolic dysfunction, in rats with MI. MI was induced by ligation of the left anterior descending artery. The rats were then separated into 3 groups: a sham-operated group (n = 9), untreated MI group (n = 10), and azelnidipine-treated MI group (n = 10). Four weeks after MI, hemodynamic measurements and Doppler echocardiographic assessment were performed. LV weight and LV end-diastolic dimension were significantly higher in the untreated MI group than in the sham-operated group. Azelnidipine significantly prevented the increases in these parameters. Azelnidipine also improved the ejection fraction (42 +/- 3%, P<0.05) and the E wave to A wave ratio (3.2 +/- 0.5, P<0.05), compared with the untreated MI group (31 +/- 3% and 5.3 +/- 0.8, respectively). In conclusion, azelnidipine can prevent LV remodeling and improve systolic and diastolic function after MI. Administration of long-acting Ca(2+)-channel blockers after MI is an effective strategy for treating MI.     

Cardioprotective effects of the vasodilator/beta-adrenoceptor blocker, carvedilol, in two models of myocardial infarction in the rat.

The purpose of this study was to evaluate the cardioprotective effects of carvedilol, a beta-adrenergic blocker and vasodilator, in two models of ischemic myocardial damage in the rat. Following coronary artery occlusion for 0.5 h and reperfusion for 24 h (MI/R group), left ventricular (LV) injury was determined by planimetric analysis of triphenyltetrazolium chloride-stained tissue, and polymorphonuclear leukocyte infiltration was assessed by measuring myeloperoxidase (MPO) activity. In the vehicle-treated MI/R group, infarct size was 14.2 +/- 1.3% of the LV (n = 16), and MPO activity was increased to 2.8 +/- 0.7 from 0.14 +/- 0.03 U/g tissue in the vehicle-treated sham-occluded group (p less than 0.01). Carvedilol (1 mg/kg i.v., 15 min prior to coronary artery occlusion and at 3.5 h following reperfusion) reduced myocardial infarct size to 7.5 +/- 1.2% of the LV (n = 14; p less than 0.01) and attenuated the increase in MPO activity to 1.4 +/- 0.4 U/g tissue (p less than 0.05). A lower dose of carvedilol (i.e. 0.3 mg/kg i.v.) did not limit myocardial infarct size or the increase in MPO activity. In a model of permanent coronary artery occlusion, 24-hour survival was reduced from 85% in sham-occluded animals (n = 38) to 44% in the vehicle-treated MI group (n = 84; p less than 0.01). In comparison to the vehicle-treated MI group, carvedilol (0.3 mg/kg i.v., 15 min prior to coronary artery occlusion and 1 mg/kg 4 h after occlusion) improved survival by 55% (n = 64; p less than 0.05, compared to the vehicle-treated MI group), whereas the same dose of propranolol (n = 42) had no significant effect on survival. These results indicate that carvedilol reduces myocardial ischemia/reperfusion injury, and significantly improves survival in a permanent coronary artery occlusion model of myocardial infarction.     

Absence of hemodynamic deterioration in the presence of amlodipine following experimental myocardial infarction.

In general, calcium channel blockers have not been used in patients during acute myocardial infarction as they may exacerbate heart failure, possibly by neuro-humoral stimulation. Amlodipine, a new dihydropyridine calcium channel blocker without neurohumoral stimulation, was tested in an experimental model of acute myocardial infarction with assessment of hemodynamics, left ventricular (LV) function, and infarct size. Anesthetized dogs were subjected to 3 h of coronary artery occlusion followed by 3 h of reperfusion. At 2 h of occlusion, they were randomized to receive either amlodipine (250 micrograms/kg, n = 11) or saline (n = 11). Before treatment, all variables were similar in both groups. The diastolic pressure was unchanged following saline, but was reduced following amlodipine by 1 h after therapy (from 94 +/- 5 to 71 +/- 3 mm Hg, p < 0.0001 vs. saline) and for the duration of the protocol. Indices of left ventricular (LV) function did not deteriorate with amlodipine treatment compared with saline. After 3 h of reperfusion, the LV dP/dt was 1,720 +/- 114 mm Hg/s in the saline group and 1,958 +/- 167 mm Hg/s with amlodipine (p = ns). The area ejection fraction, assessed by echocardiography, was similar in both groups (43 +/- 5%, saline; 45 +/- 3%, amlodipine; p = ns), as was the LV end-diastolic pressure (8 +/- 1 mm Hg, saline; 7 +/- 1 mm Hg, amlodipine; p = ns). Subendocardial regional myocardial blood flow, measured by radioactive microspheres, was 0.75 +/- 0.08 ml/min/g with saline and 1.34 +/- 0.33 ml/min/g with amlodipine in the previously ischemic reperfused subendocardium (p = 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)     

A characterization of myocardial infarction induced by thrombotic occlusion and a comparison with mechanical ligation of the rat coronary artery.

In the present study we examined two different methods for inducing myocardial infarction in rats. We previously developed an animal model of coronary artery thrombotic occlusion induced by a photochemical reaction, which occurs when rose bengal (a photosensitizer dye) is injected into the animal and is irradiated with green light. Arterial occlusion is thereby achieved nonmechanically. Using this method, we investigated the effect of thrombolytic intervention on myocardial infarct size. Infarct size was determined 24 h after the induction of myocardial infarction. When tisokinase (3 mg/kg), a native tissue-type plasminogen activator, was administered 3 min after the ST-segment elevation on a lead II electrocardiogram, the infarct size was 20.6 +/- 5.1%, which was significantly smaller than that of control rats (37.3 +/- 4.6%). When tisokinase was administered 10 min after the ST-segment elevation, the infarct size was 27.1 +/- 2.1%, which was not significantly smaller than that of controls. The rat coronary artery thrombosis model incorporates many aspects of coronary thrombosis. It differs from the coronary ligation model in that it lends itself to the study of thrombolytic agents on animal models of myocardial infarction.     

Chronic propranolol treatment promotes left ventricular dilation without altering systolic function after large myocardial infarction in rats.

In rats with chronic myocardial infarction (MI), we have examined the effects of prolonged beta-adrenergic blockade with propranolol on left ventricular (LV) performance, weight, and volumes. Sham-operated rats and rats with large MI (greater than 30%) were evaluated. Four groups of rats were studied: control, sham-operated (n = 12); control, MI (n = 12); propranolol (500 mg/L of drinking water)-treated, sham-operated (n = 10); and propranolol treated, MI (n = 10). Treatment was started 3 weeks after coronary ligation. After 5-6 weeks, LV, systemic arterial, and right atrial pressures in addition to aortic blood flow before and during volume loading were measured. LV pressure-volume relations were measured ex vivo. The rats with chronic MI demonstrated expected decreases in LV systolic performance and increased LV end-diastolic and right atrial pressures. Propranolol had no independent effect on LV systolic pressure, LV end-diastolic pressure, resting cardiac index, stressed cardiac index during volume loading, peak developed aortic pressure during aortic occlusion, or ejection fraction index in either sham-operated or infarcted rats; however, heart rate was decreased. LV weight/body weight was 2.17 +/- 0.04 mg/g in control sham-operated rats, which was not different from the propranolol-treated sham-operated rats (2.09 +/- 0.04 mg/g). The LV weight/body weight was increased (p less than 0.01) to 2.21 +/- 0.08 mg/g in the propranolol-treated MI group from 1.94 +/- 0.06 mg/g in the control MI group. The LV pressure-volume relation was not altered by propranolol in the sham-operated rats but was shifted to the right by MI.(ABSTRACT TRUNCATED AT 250 WORDS)     

Can moderate alcohol intake limit the size of myocardial infarction?

Several observational and epidemiologic analyses suggest that moderate drinking of alcohol (usually two drinks per day) may have beneficial effects on the heart. Specifically it may reduce the incidence of ischemic heart disease and improve the outcome after a myocardial infarction. The purpose of this study was to test the hypothesis that long-term, moderate consumption of alcohol has a direct cardioprotective effect, reducing myocardial infarct size in rats subjected to ischemia/reperfusion. Two groups of rats were given alcohol in their drinking water at concentrations of 15% or 36%; control rats received water (n = 10 for all groups). After 16 weeks of treatment, the rats were anesthetized and subjected to 60 min of coronary artery occlusion and reperfusion. The ischemic risk region (% LV) was not significantly different among groups. Infarct size (% risk zone) was 49+/-7%, 44+/-4%, and 50+/-8%, respectively (p = 0.79). Thus no significant differences in infarct size between control and alcohol-fed rats were observed. There was no correlation between alcohol level and infarct size in alcohol-treated rats (r = 0.20, p = 0.45). Arterial pressures were lower in the 36% group at baseline and throughout the study compared with the control and 15% groups, but heart rates were similar in all groups. Moderate consumption of alcohol failed to alter infarct size compared with control and thus it is unlikely that alcohol drinking has a direct myocardial-protecting effect on the outcome of ischemia and reperfusion.     

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.     

Antibody to granulocyte macrophage colony-stimulating factor reduces the number of activated tissue macrophages and improves left ventricular function after myocardial infarction in a rat coronary artery ligation model

Granulocyte macrophage colony-stimulating factor (GM-CSF) promotes infarct expansion and inappropriate collagen synthesis in a myocardial infarction (MI). This study was designed to determine if treatment with anti-GM-CSF will inhibit macrophage migration, preserve function, and limit left ventricular (LV) remodeling in the rat coronary artery ligation model. Treatment with a monoclonal antibody to GM-CSF (5 mg/kg) was initiated 24 hours before coronary artery ligation and continued every 3 days for 3 weeks. Left coronary arteries of rats were ligated, animals were recovered, and cardiac function was evaluated 3 weeks postligation. Tissue samples were processed for histochemistry. Anti-GM-CSF treatment increased LV ejection fraction (37 ± 3% vs 47 ± 5%) and decreased LV end systolic diameter (0.75 ± 0.12 vs 0.59 ± 0.05 cm) with no changes in LV systolic pressure (109 ± 4 vs 104 ± 5 mm Hg), LV end diastolic pressure (22 ± 4 vs 21 ± 2 mm Hg), LV end diastolic diameter (0.96 ± 0.04 vs 0.92 ± 0.05 cm), or the time constant of LV relaxation tau (25.4 ± +2.4 vs 22.7 ± 1.4 milliseconds) (P < 0.05). Significantly lower numbers of tissue macrophages and significant reductions in infarct size were found in the myocardium of antibody-treated animals (81 ± 21.24 vs 195 ± 31.7 positive cells per 0.105 mm, compared with controls. These findings suggest that inhibition of macrophage migration may be beneficial in the treatment of heart failure after MI.     

Long-term oral treatment with nicorandil prevents the progression of left ventricular hypertrophy and preserves viability

Left ventricular (LV) hypertrophy and myocardial infarction play important roles in the progressive LV dysfunction. We hypothesized that the potassium-channel opener and nitrate-like vasodilator nicorandil prevents the development of LV hypertrophy and preserves myocardial viability. Twenty-four rats were subjected to aortic stenosis for 8 weeks to produce LV hypertrophy and assigned to non-treated and nicorandil-treated (3 mg/kg/d) groups. A third group (n = 12) without stenosis or treatment served as control. All 36 animals were subjected to reperfused infarction by 25-minute occlusion of the left coronary artery followed by 3 hours of reperfusion. Spin-echo magnetic resonance (MR) images were acquired to measure infarction size, LV mass, volumes, ejection fraction, and wall thickness. A necrosis-specific contrast agent, Gadophrin-3, was used to delineate necrotic myocardium. Aortic and LV pressures were measured invasively. At postmortem, LV mass and infarction size were determined and compared with MR findings. Nicorandil prevented the development of LV hypertrophy. Infarction size of nicorandil-treated animals was similar to control animals. Non-treated animals with aortic banding had higher LV mass (P < 0.001), lower ejection fraction (P = 0.006), and larger infarction size (P < 0.001) than treated and control animals. MR and postmortem data showed close agreement. Nicorandil therapy prevented the development of cardiac hypertrophy and protected myocardium against ischemia.     

Treatment with the gap junction modifier rotigaptide (ZP123) reduces infarct size in rats with chronic myocardial infarction

Treatment with non-selective drugs (eg, long-chain alcohols, halothane) that reduce gap junction intercellular communication (GJIC) is associated with reduced infarct size after myocardial infarction (MI). Therefore, it has been suggested that gap junction intercellular communication stimulating compounds may increase infarct size. The antiarrhythmic peptide analogue rotigaptide (ZP123) increases cardiac gap junction intercellular communication and the purpose of the present study was to examine the effects of rotigaptide treatment on infarct size. Myocardial infarction was induced in male rats by ligation of the left anterior descending artery (LAD). Rats (n = 156) were treated with rotigaptide at three dose levels or vehicle from the onset of ischemia and for 3 weeks following LAD occlusion. Infarct size was determined using histomorphometry after 3 weeks treatment. Rotigaptide treatment producing steady state plasma levels of 0.8 +/- 0.1, 5.5 +/- 0.5, and 86 +/- 8 nmol/L had no effect on mortality, but reduced infarct size to 90 +/- 10% (P = 0.41), 67 +/- 7% (P = 0.005), and 82 +/- 7% (P = 0.13), respectively relative to vehicle-treated myocardial infarction rats (100 +/- 12%). In contrast to what was predicted, our data demonstrates that rotigaptide treatment was associated with a significant infarct size reduction. We conclude that whereas treatment with non-selective inhibitors of gap junction intercellular communication cause a reduction in infarct size, this information cannot be extrapolated to the effects of compounds that selectively increase gap junction intercellular communication.     

STREPTOKINASE ALTERS MYOCARDIAL CREATINE KINASE DEPLETION AFTER ISCHAEMIA AND REPERFUSION IN RABBITS

The efficacy of streptokinase as an intracoronary thrombolytic agent is well-recognized. The effect of streptokinase, distinct from its thrombolytic action, on ischaemic myocardium distal to an area of coronary artery occlusion when reperfusion occurs has not been well-defined. In order to do this, myocardial creatine kinase depletion and the histopathology of infarctions produced in rabbits after 1 h of circumflex coronary artery occlusion and mechanical release of the occlusion were assessed. Streptokinase or saline was infused intravenously for 1 h beginning 0.5 h after occlusion. Rabbits were divided into two time intervals: early (less than 10 h) and late (24 h) after release of coronary artery occlusion. When streptokinase was infused in early infarctions, haemorrhage did not correlate with infarction cross-sectional area or myocardial creatine kinase depletion. However, myocardial creatine kinase depletion was 40% less when streptokinase was infused than when saline was infused, suggesting that streptokinase might limit infarct size. In late infarctions, the degree of haemorrhage, infarction cross-sectional area, and myocardial creatine kinase depletion were similar after reperfusion with streptokinase or saline. By 24 h, the beneficial effect of a single dose of streptokinase given early in the course of occlusion-reperfusion myocardial injury was no longer evident in limiting infarct size.     

CO inhalation at dose corresponding to tobacco smoke worsens cardiac remodeling after experimental myocardial infarction in rats.

We hypothesized that inhalation of carbon monoxide (CO) (500 ppm), similar to that in tobacco smoke, disturbs the cardiovascular adaptation after myocardial infarction by increasing remodeling. Four groups of rats were assessed. Two groups had myocardial infarction induced by the ligation of the left coronary artery: the first group was exposed to air (infarcted air group, n = 12), and the second was exposed to CO (infarcted CO group, n = 11). They were compared to two sham-operated groups, a control air group (n = 10), and a control CO group (n = 7) exposed (3 weeks) to CO. Aerobic endurance capacity was assessed in both the infarct CO and infarct air group (endurance capacity = 0.043 +/- 0.006 m.min(-1).g(-1) vs. 0.042 +/- 0.005 m.min(-1).g(-1), not significant). In the infarcted CO group compared to the infarcted air group, the dilatation of the left ventricle observed 3 weeks after infarction was increased, (left ventricular diastolic (LVD) diameter (D) = 9 +/- 0.4 vs. 7 +/- 0.4 mm, p < 0.05; left ventricular systolic (LVS) diameter (D) = 6 +/- 0.6 vs. 4.1 +/- 0.4, p < 0.05), and the diastolic posterior wall thickness was augmented (posterior wall diastolic thickness = 1.7 +/- 0.1 vs. 1.3 +/- 0.1 mm, p < 0.05). Hemodynamic pressure measurements in both ventricles and pulmonary artery showed elevated diastolic pressure after CO exposure compared to air exposure (LVD pressure = 32 +/- 1.6 vs. 19 +/- 2.3 mm Hg, p < 0.05; right ventricular diastolic pressure = 16 +/- 1.6 vs. 8.6 +/- 1.6 mm Hg, p < 0.05; pulmonary arterial pressure in diastole (PAD) = 27 +/- 1.6 vs. 20 +/- 2.3 mm Hg, p < 0.05). In the infarcted CO group, the infarct size increased. Echocardiography and histology showed hypertrophy of the contralateral wall similar to that observed in the noninfarcted control CO group. In conclusion, chronic CO inhalation worsens heart failure in rats with myocardial infarction by an increase in the infarct size and hypertrophy remodeling.     

Mechanisms of Post-Infarct Left Ventricular Remodeling

Heart failure secondary to myocardial infarction (MI) remains a major source of morbidity and mortality. Long-term outcome after MI can be largely be defined in terms of its impact on the size and shape of the left ventricle (i.e., LV remodeling). Three major mechanisms contribute to LV remodeling: 1) early infarct expansion, 2) subsequent infarct extension into adjacent noninfarcted myocardium, and 3) late hypertrophy in the remote LV. Future developments in preventing post-MI heart failure will depend not only on identifying drugs targeting each of these individual mechanisms, but also on diagnostic techniques capable of assessing efficacy against each mechanism.     

Sulprostone-induced reduction of myocardial infarct size in the rabbit by activation of ATP-sensitive potassium channels.

1. This study examined whether (i) a 1 h pretreatment with or (ii) a continuous infusion of sulprostone reduces myocardial infarct size arising from coronary artery occlusion (60 min) and reperfusion (120 min) in the anaesthetized rabbit. In addition, we investigated whether the observed cardioprotective effect of this selective agonist of prostanoid EP1/EP3 receptors were due to the activation of ATP-sensitive potassium (KATP) channels. 2. In anaesthetized rabbits pretreated with vehicle (5% ethanol in 0.9% saline; 0.05 ml min-1, i.v.) infarct size (expressed as a percentage of the area at risk) after 60 min of coronary artery occlusion followed by 120 min of reperfusion was 59 +/- 4% (n = 10). Pretreatment of rabbits with sulprostone (1.0 microgram kg-1 min-1 for 1 h, discontinued immediately prior to coronary artery occlusion) did not reduce infarct size (60 +/- 4%; n = 4). In contrast, a continuous infusion of sulprostone (1.0 microgram kg-1 min-1) starting 10 min prior to the onset of LAL occlusion and continued throughout the experiment, significantly reduced infarct size (41 +/- 5%, n = 6) when compared to the respective vehicle-treated controls (57 +/- 4%, n = 10; P < 0.05). Sulprostone (pretreatment or continuous infusion) had no effect on any of the haemodynamic parameters measured. 3. The reduction in infarct size afforded by continuous infusion of sulprostone was abolished by pretreatment of rabbits with the KATP channel blocker 5-hydroxydecanoate (5-HD 5 micrograms kg-1; 63 +/- 4%; n = 6). When administered alone, 5-HD had no effect on infarct size when compared to control (52 +/- 6, n = 10). 4. We propose that a continuous infusion of the selective EP1/EP3 prostanoid receptor agonist, sulprostone, reduces infarct size in the anaesthetized rabbit by a mechanism that involves the opening of KATP channels.     

Beneficial effects of a new prostacyclin analogue, KP-10614, on acute myocardial infarction in rats.

The potential therapeutic value of a new prostacyclin analogue, (4z, 16s)-4,5,18,18,19,19-hexadehydro-16,20-dimethyl-delta 6(9a)- 9-(O)-methano-PGI1 (KP-10614), was studied in acute myocardial infarction in rats. Myocardial infarction was induced by ligation of the left coronary artery and ischemic injury was followed up to 4 h. The infarct size, evaluated by the area unstained by 2,3,5-triphenyltetrazolium chloride, reached 41.1 +/- 1.4% of the left ventricle at 4 h. KP-10614 (3 ng/kg/min x 4 h) reduced the infarct size at 4 h significantly (26.5 +/- 2.9%). At the same dose, KP-10614 inhibited ADP-induced ex vivo platelet aggregation significantly (21.5 +/- 4.0% of the control aggregation), but did not alter the arterial blood pressure or heart rate. To assess the role of platelets in myocardial infarction, circulating platelets were reduced by about 95% with rabbit antiserum to rat platelets. In platelet-depleted rats, the infarct size decreased significantly to 24.1 +/- 4.6% of the left ventricle at 4 h. These results suggest that platelets play an important role in expression of myocardial ischemic injury resulting from coronary artery occlusion in rats, and the ability of KP-10614 to decrease the infarct size appeared to be attributable, at least in part, to the inhibition of platelet aggregation or cellular metabolic effects produced by platelets at the site of tissue injury.     

Effects of SM-20550, a new Na(+)/H(+) exchange inhibitor, on survival and infarct size in rat myocardial infarction

The effect of a novel potent Na(+)/H(+) exchange inhibitor, SM-20550 [N-(aminoiminomethyl)-1,4-dimethyl-1H-indole-2-carboxamide methanesulfonic acid], on survival after myocardial infarction was studied. Anesthetized rats underwent occlusion of the coronary artery (30 min) followed by reperfusion (14 days). SM-20550 was administered intravenously before ischemia (1-day treatment group) or before ischemia and on the 2 days following (3-day treatment group). The infarct size was significantly reduced on the 14th day after surgery by approximately 17 and 20% in 1- and 3-day treatment groups, respectively. The survival rate on day 14 was significantly enhanced in both treatment groups (96%) compared with the vehicle-treated control group (70%). These results suggest that SM-20550 improved survival after myocardial infarction, at least due to its antinecrotic effect.