A novel anti-diabetic drug, miglitol, markedly reduces myocardial infarct size in rabbits

1. We examined whether N-hydroxyethyl-1-deoxynojirimycin (miglitol), a new human anti-diabetic drug with effects to inhibit alpha-1, 6-glucosidase glycogen debranching enzyme and reduce the glycogenolytic rate as well as to inhibit alpha-1,4-glucosidase, could reduce infarct size in the rabbit heart. Rabbits were subjected to 30-min coronary occlusion followed by 48-h reperfusion. 2. The infarct size as a percentage of area at risk was not reduced by pre-ischaemic treatment with 1 mg kg(-1) miglitol (42.7+/-4.0%, n=10) compared with the saline control group (41.7+/-2.3%, n=10). However, it was significantly and dose-dependently reduced by pre-ischaemic treatment with 5 or 10 mg kg(-1) of miglitol (25.7+/-4. 5%, n=10, and 14.6+/-2.4%, n=10, respectively) without altering the blood pressure, heart rate or blood glucose level. However, there was no evidence of an infarct-size reducing effect after pre-reperfusion treatment with 10 mg kg(-1) of miglitol (35.0+/-3.0%, n=10). 3. Another 40 rabbits given 1, 5 and 10 mg kg(-1) of miglitol or saline before ischaemia (n=10 in each) were sacrificed at 30 min of ischaemia for biochemical analysis. Miglitol preserved significantly the glycogen content, and attenuated significantly the lactate accumulation in a dose dependent manner in the ischaemic region at 30 min of ischaemia. 4. Pre-ischaemic treatment, but not pre-reperfusion treatment, with miglitol markedly reduced the myocardial infarct size, independently of blood pressure and heart rate. A dose-dependent effect of miglitol on infarct size, glycogenolysis and lactate formation suggests that the mechanism may be related to the inhibition of glycogenolysis. Thus, miglitol may be beneficial for coronary heart disease as well as diabetes mellitus.     

CO-MP4, a polyethylene glycol-conjugated haemoglobin derivative and carbon monoxide carrier that reduces myocardial infarct size in rats

BACKGROUND AND PURPOSE: MP4 (Hemospan) is a Hb-based oxygen therapeutic agent, based on polyethylene-glycol (PEG) conjugation to Hb, undergoing clinical trials as an oxygen carrier. This study describes the functional interaction between MP4 and carbon monoxide (CO), as a CO delivery agent, and the effects of CO-MP4 on myocardial infarct size following ischaemia and reperfusion in rats. EXPERIMENTAL APPROACH: Kinetic measurements of CO-MP4 binding were used to evaluate the effects of PEG modification on Hb subunit structure/function and to calculate CO-MP4 equilibrium constants. CO transport by CO-MP4 was shown by ligand (O2/CO) partitioning between MP4 and red blood cell (RBC)-Hb. Pharmacological effects of CO-MP4 were studied on myocardial infarction in rats. KEY RESULTS: CO binding kinetics show primary structural/functional effects on beta chains in MP4, with alpha chains maintaining the ability to undergo tertiary conformational transition. CO confers long-term, room-temperature stability and is able to rapidly re-equilibrate between MP4 and RBCs. In a rat model of myocardial infarct, in contrast to oxy-MP4, CO-MP4 reduced infarct size when administered prior to the induction of ischaemia. CONCLUSIONS AND IMPLICATIONS: MP4 PEGylation chemistry modifies the individual function of Hb subunits, but results in an overall CO equilibrium constant similar to that for unmodified Hb. CO-MP4 is able to deliver CO to the circulation and reduces ischaemia/reperfusion injury in rats, providing the first evidence for this drug as a CO therapeutic agent.     

Oral bimoclomol elevates heat shock protein 70 and reduces myocardial infarct size in rats.

Bimoclomol has been shown to increase an inducible member of the heat shock protein 70 family (HSP70) and cytoprotect in vitro. Here, we addressed whether oral pretreatment of rats with bimoclomol could elevate myocardial HSP70 and reduce infarct size in a rat model of ischemia and reperfusion. Rats were pretreated with bimoclomol at 3, 6 or 18 h or with 42 degrees thermal stress 24 h before ischemia. Infarct size was significantly decreased 6 h after oral administration of bimoclomol and 24 h after thermal stress. Left ventricles from a separate group of rats were examined for HSP70 levels. Western blots showed a significant increase in HSP70 6 h after oral administration of bimoclomol and 24 h after thermal stress. There was a significant correlation (P<0.05) between HSP70 induction and infarct size reduction, whether produced by thermal stress or oral administration of bimoclomol. Thus, bimoclomol can increase HSP70 and reduce infarct size in a rat model of ischemia and reperfusion.     

T-0162, a novel free radical scavenger, reduces myocardial infarct size in rabbits

1. We investigated the effects of 1-(3-tert-butyl-2-hydroxy-5-methoxyphenyl)-3-(3-pyridylmethyl)urea hydrochloride (T-0162), a novel low-molecular weight free radical scavenger, on the generation of superoxide anions and hydroxyl radicals in vitro and in vivo and on myocardial infarct (MI) size in an in vivo model of MI in rabbits. 2. It was found that T-0162 scavenged both superoxide anions and hydroxyl radicals in a concentration-dependent manner in vitro. 3. In an in vivo rabbit model with 30 min coronary occlusion and 30min reperfusion, T-0162 scavenged hydroxyl radicals generated in the myocardium during reperfusion. 4. Anaesthetized open-chest Japanese white male rabbits were subjected to 30 min coronary occlusion and 48 h reperfusion. The control group (n = 10) was infused with 10% lecithin solution for 220 min from 10 min before occlusion to 180 min after reperfusion. The pretreatment group (n = 10) was infused with T-0162 dissolved in 10% lecithin solution for 220 min from 10 min before occlusion to 180 min after reperfusion at a rate of 400 microg/kg per min. The post-treatment group (n = 10) was injected with an i.v. bolus of 10 mg/kg T-0162 and was then infused with 400 microg/kg per min T-0162 for 190 min from 10 min before reperfusion to 180 min after reperfusion. After 48 h reperfusion, infarct size was measured histologically and expressed as a percentage of area at risk (AAR). 5. There was no significant difference in haemodynamic parameters among the three groups throughout the experimental period. The per cent infarct size of the AAR in the T-0162 groups (24.8+/-4.3 and 30.5+/-3.9% for pre- and posttreatment groups, respectively) was significantly reduced compared with control (44.7+/-4.1%; P<0.05). There was no significant difference in the AAR among the three groups. 6. In conclusion, T-0162 reduces MI size through the inhibition of reperfusion injury.     

Apstatin, a selective inhibitor of aminopeptidase P, reduces myocardial infarct size by a kinin-dependent pathway

1. Inhibitors of the angiotensin converting enzyme (ACE) have been shown to exert their cardioprotective actions through a kinin-dependent mechanism. ACE is not the only kinin degrading enzyme in the rat heart. 2. Since aminopeptidase P (APP) has been shown to participate in myocardial kinin metabolism to the same extent as ACE, the aims of the present study were to investigate whether (a) inhibition of APP leads to a reduction of myocardial infarct size in a rat model of acute ischaemia and reperfusion, (b) reduction of infarct size is mediated by bradykinin, and (c) a combination of APP and ACE inhibition leads to a more pronounced effect than APP inhibition alone. 3. Pentobarbital-anaesthetized rats were subjected to 30 min left coronary artery occlusion followed by 3 h reperfusion. The APP inhibitor apstatin, the ACE-inhibitor ramiprilat, or their combination were administered 5 min before ischaemia. Rats receiving HOE140, a specific B(2) receptor antagonist, were pretreated 5 min prior to enzyme inhibitors. Myocardial infarct size (IS) was determined by tetrazolium staining and expressed as percentage of the area at risk (AAR). 4. IS/AAR% was significantly reduced in rats that received apstatin (18+/-2%), ramiprilat (18+/-3%), or apstatin plus ramiprilat (20+/-4%) as compared with those receiving saline (40+/-2%), HOE (43+/-3%) or apstatin plus HOE140 (49+/-4%). 5. Apstatin reduces IS in an in vivo model of acute myocardial ischaemia and reperfusion to the same extent than ramiprilat. Cardioprotection achieved by this selective inhibitor of APP is mediated by bradykinin. Combined inhibition of APP and ACE did not result in a more pronounced reduction of IS than APP-inhibition alone.     

SSR69071, an elastase inhibitor,reduces myocardial infarct size following ischemia-reperfusion injury

Neutrophil elastase contributes to the severity of cardiac damage following coronary ischemia and reperfusion. We evaluated the effects of 2-(9-(2-piperidinoethoxy)-4-oxo-4H-pyridol[1,2-a]pyrimidin-2-yloxymethyl)-4-(1-methyethyl)-6-methoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide hemihydrate (SSR69071), a novel, potent and selective inhibitor of neutrophil elastase, on infarct size in anaesthetized rabbits subjected to coronary artery occlusion for 30 min followed by reperfusion for 120 min. SSR69071 (3 mg/kg i.v.) reduced cardiac infarct size when administered before ischemia (-39%, P<0.05) or just prior to reperfusion (-37%, P<0.05). Subsequent experiments using the latter administration protocol confirmed the ability of SSR69071 (1 and 3 mg/kg i.v.) to reduce infarct size. This cardioprotective activity was associated with inhibition of cardiac elastase.     

Defibrotide reduces infarct size in a rabbit model of experimental myocardial ischaemia and reperfusion.

1. Defibrotide, a single-stranded polydeoxyribonucleotide obtained from bovine lungs, has significant anti-thrombotic, pro-fibrinolytic and prostacyclin-stimulating properties. 2. The present study was designed to evaluate the effects of defibrotide on infarct size and regional myocardial blood flow in a rabbit model of myocardial ischaemia and reperfusion. 3. Defibrotide (32 mg kg-1 bolus + 32 mg kg-1 h-1, i.v.) either with or without co-administration of indomethacin (5 mg kg-1 x 2, i.v.) was administered 5 min after occlusion of the left anterior-lateral coronary artery and continued during the 60 min occlusion and subsequent 3 h reperfusion periods. 4. Defibrotide significantly attenuated the ischaemia-induced ST-segment elevation and abolished the reperfusion-related changes (R-wave reduction and Q-wave development) in the electrocardiogram. In addition, defibrotide significantly improved myocardial blood flow in normal and in ischaemic, but not in infarcted sections of the heart. The improvement in blood flow in normal perfused myocardium, but not in the ischaemic area was prevented by indomethacin. 5. Although the area at risk was similar in all animal groups studied, defibrotide treatment resulted in a 51% reduction of infarct size. Indomethacin treatment abolished the reduction of infarct size seen with defibrotide alone. 6. The data demonstrate a considerable cardioprotective effect of defibrotide in the reperfused ischaemic rabbit myocardium. This effect may be related, at least in part, to a stimulation of endogenous prostaglandin formation. Other possible mechanisms are discussed.     

Edaravone reduces myocardial infarct size and improves cardiac function and remodelling in rabbits

1. In the present study, we investigated the effect of 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone), a free radical scavenger, on myocardial infarct (MI) size and cardiac function in an in vivo model of MI in rabbits. We further investigated the contribution of hydroxyl radicals, superoxide and nitric oxide (NO) to its effects. 2. Anaesthetized open-chest Japanese white male rabbits were subjected to 30 min coronary occlusion and 48 h reperfusion. The control group (n = 10) was injected with saline 10 min before reperfusion. The edaravone group (n = 10) was injected with a bolus of 3 mg/kg edaravone 10 min before reperfusion. The edaravone + N(G)-nitro-L-arginine methyl ester (L-NAME) group (n = 5) was given 10 mg/kg, i.v., L-NAME 10 min before the administration of 3 mg/kg edaravone. The L-NAME group (n = 5) was given 10 mg/kg, i.v., L-NAME 20 min before reperfusion. Infarct size was measured using the triphenyl tetrazolium chloride method and is expressed as a percentage of area at risk. Cardiac function was assessed by echocardiography 14 days after infarction. 3. In another series of experiments, rabbits were subjected to 30 min coronary occlusion and 30 min reperfusion and myocardial interstitial 2,3-dihydroxybenzoic acid (DHBA) and 2,5-DHBA levels, indicators of hydroxyl radical, were measured using a microdialysis technique. 4. Infarct size in the edaravone group was significantly reduced compared with that in the control group (27.4 +/- 6.8 vs 43.4 +/- 6.8%, respectively; P < 0.05). The edaravone-induced reduction of infarct size was abolished by pretreatment with L-NAME. Myocardial interstitial levels of 2,3-DHBA and 2,5-DHBA increased 20 and 30 min after ischaemia and peaked at 10 min reperfusion in the control group. Edaravone significantly inhibited the increase in 2,3-DHBA and 2,5-DHBA levels seen during reperfusion. Dihydroethidium staining showing in situ detection of superoxide was less intense in ischaemic myocardium in the edaravone-treated group compared with the control group. Edaravone improved cardiac function and left ventricular remodelling 14 days after infarction. 5. In conclusion, edaravone significantly reduces MI size and improves cardiac function and LV remodelling by decreasing hydroxyl radicals and superoxide in the myocardium and increasing the production of NO during reperfusion in rabbits.     

Effect of azapropazone and allopurinol on myocardial infarct size in rats

The effect of the xanthine oxidase inhibitor allopurinol and the non-steroidal antiinflammatory agent azapropazone on infarct size in rats, subjected to 48 h of occlusion of the left anterior descending coronary artery, were studied. Allopurinol (50 mg/kg i.p., twice daily from 24 h before to 48 h after LAD occlusion) and azapropazone (100 mg/kg i.p twice daily from 24 h before to 48 h after LAD occlusion) significantly reduced infarct size when compared to saline-treated rats. These data point towards involvement of xanthine oxidase derived free radicals in evolving myocardial infarction in rats; beneficial effect of azapropazone in this model may be related to the drug's ability to inhibit xanthine oxidase as well as various key neutrophil functions.     

Mildronate, a novel fatty acid oxidation inhibitor and antianginal agent, reduces myocardial infarct size without affecting hemodynamics

Mildronate is a fatty acid oxidation inhibitor approved as an antianginal drug in parts of Europe. We carried out the first study to determine whether a 10-day course of mildronate could reduce myocardial infarct size (IS) during acute myocardial ischemia. Sprague Dawley rats received 200 mg/kg/d of mildronate (treated group, n = 16) or sterile water (control group, n = 14) subcutaneously for 10 days before ischemia-reperfusion. Rats were then subjected to 45 minutes of left coronary artery occlusion and 2 hours of reperfusion. The 2 groups had identical areas at risk: treated 38 +/- 3%; controls 38 +/- 2%. The amount of necrosis was smaller in the mildronate group at 16 +/- 2% of the left ventricle versus controls, 22 +/- 2% (P = 0.05); and for any amount of risk >25%, necrosis was smaller in the treated group (P = 0.0035). Myocardial IS (% of risk zone) was 43+/-3% in the mildronate-treated rats, and 57+/-4% in controls (P = 0.004). During occlusion, there were no differences between the 2 groups in heart rate (216 +/- 12 bpm, mildronate and 210 +/- 9 bpm, control), in mean arterial pressure (60 +/- 2 mm Hg, mildronate and 64 +/- 3 mm Hg, control) or in the frequency of arrhythmias. Our study for the first time demonstrated that a 10-day treatment with mildronate reduced myocardial IS in an experimental model of acute myocardial ischemia, without any effect on hemodynamics.     

A cardioselective, hydrophilic N,N,N-trimethylethanaminium alpha-tocopherol analogue that reduces myocardial infarct size

The alpha-tocopherol analogue 3,4-dihydro-6-hydroxy-N,N,N,2,5,7,8- heptamethyl-2H-1-benzopyran-2-ethanaminium 4-methylbenzenesulfonate (1a, MDL 73404) and its O-acetate 1b (MDL 74270) were synthesized. Compound 1a was found to be hydrophilic (log P = -0.60) and to prevent lipid autoxidation in rat brain homogenate with an IC50 of 1.7 +/- 0.9 microM. Tissue distribution studies with [14C]-1b in rats (1 mg/kg iv) showed that radioactivity accumulates in the heart (ratio 20:1 vs blood after 1 h). Infusion of 1 mg/kg per h of 1b bromide reduced infarct size by 54% in rats subjected to coronary artery occlusion for 60 min followed by reperfusion for 30 min, compared to saline-infused controls. By comparison, the tertiary amine analogue 5 was found not to accumulate in heart tissue, to be an equally effective free-radical scavenger in vitro, but to require a higher dose to reduce infarct size in rats. This shows that the cardioselectivity of compound 1 contributes to its potency in salvaging myocardial tissue in rats after ischemia and reperfusion.     

Uridine-5'-triphosphate (UTP) reduces infarct size and improves rat heart function after myocardial infarct

We have previously found that uridine 5'-triphosphate (UTP) significantly reduced cardiomyocyte death induced by hypoxia via activating P2Y(2) receptors. To explore the effect of UTP following myocardial infarction (MI) in vivo we studied four groups: sham with or without LAD ligation, injected with UTP (0.44microg/kg i.v.) 30min before MI, and UTP injection (4.4microg/kg i.v.) 24h prior to MI. Left ventricular end diastolic area (LVEDA), end systolic area (LVESA) fractional shortening (FS), and changes in posterior wall (PW) thickness were performed by echocardiography before and 24h after MI. In addition, we measured different biochemical markers of damage and infarct size using Evans blue and TTC staining. The increase in LVEDA and LVESA of the treated animals was significantly smaller when compared to the MI rats (p<0.01). Concomitantly, FS was higher in groups pretreated with UTP 30min or 24h (56+/-14.3 and 36.7+/-8.2%, p<0.01, respectively). Ratio of infarct size to area at risk was smaller in the UTP pretreated hearts than MI rats (22.9+/-6.6, 23.1+/-9.1%, versus 45.4+/-7.6%, respectively, p<0.001). Troponin T and ATP measurements, demonstrated reduced myocardial damage. Using Rhod-2-AM loaded cardiomyocytes, we found that UTP reduced mitochondrial calcium levels following hypoxia. In conclusion, early or late UTP preconditioning is effective, demonstrating reduced infarct size and superior myocardial function. The resulting cardioprotection following UTP treatment post ischemia demonstrates a reduction in mitochondrial calcium overload, which can explain the beneficial effect of UTP.     

Carvedilol (Kredex) reduces infarct size in a canine model of acute myocardial infarction.

Carvedilol (Kredex) is a multiple action, antihypertensive agent that may also prove to be useful in the treatment of angina and congestive heart failure. Carvedilol combines in one molecule both beta-adrenoceptor blocking and vasodilating activities. Inasmuch as beta-adrenoceptor blocking agents are known to be cardioprotective and thereby reduce infarct size, it is logical to assume that carvedilol, likewise, would possess this desirable activity. Furthermore, the additional vasodilating activity of carvedilol could contribute to further reductions in infarct size by reducing myocardial work (and therefore myocardial oxygen demand) through reductions in both afterload and myocardial wall tension. As such, we have investigated the ability of carvedilol to reduce infarct size in a canine model of acute myocardial infarction. Carvedilol (1 mg/kg i.v.) or its vehicle, dimethylformamide, were administered 15 min before left circumflex coronary artery (LCX) occlusion. Following 1 h of LCX occlusion, dogs were reperfused through a critical stenosis and then allowed to recover for 24 h. Carvedilol-treated animals exhibited a 78% reduction in infarct size compared to vehicle controls, such that the percentage of the left ventricle infarcted was reduced significantly from 16.2 +/- 4.1% in control animals to 3.6 +/- 1.3% in animals treated with carvedilol (p = 0.017, n = 6). Stained tissue sections of the left ventricle were photographed, digitized and color-enhanced using an Image Analysis Computer System, and three-dimensional reconstruction of the left ventricle, including the infarcted areas, was performed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ranolazine, a partial fatty acid oxidation inhibitor, reduces myocardial infarct size and cardiac troponin T release in the rat

Ranolazine reduces cellular acetyl-CoA content via inhibition of fatty acid beta-oxidation and activates pyruvate dehydrogenase. This metabolic switch increases ATP production per mole of oxygen consumed, reduces the rise in lactic acid and acidosis, and maintains myocardial function under conditions of reduced myocardial oxygen delivery. It is still unclear whether ranolazine causes a reduction of (i) infarct size and (ii) cardiac troponin T release, in a male Wistar rat model of left anterior descending coronary artery occlusion (25 min) and reperfusion (2 h). Rats were subjected to saline infusion (n=12) or ranolazine (bolus injection: 10 mg/kg plus infusion: 9.6 mg/kg/h, n=12), 30 min prior to left anterior descending coronary artery occlusion-reperfusion, respectively. Ranolazine caused a significant reduction in myocardial infarct size of approximately 33% compared to saline control (P<0.05). In addition, infusion of ranolazine significantly attenuated the release of cardiac troponin T into the plasma from 65+/-14 (controls) to 12+/-2 ng/ml. This study demonstrates for the first time that ranolazine significantly reduces (i) infarct size and (ii) cardiac troponin T release in rats subjected to left anterior descending coronary artery occlusion-reperfusion.     

3',4'-Dihydroxyflavonol reduces infarct size and injury associated with myocardial ischaemia and reperfusion in sheep

1 The antioxidant properties of flavonols in vivo and their potential benefits in myocardial ischaemia/reperfusion (I/R) injury have been little investigated. We evaluated the ability of a synthetic flavonol, 3',4'-dihydroxyflavonol (DiOHF) to scavenge superoxide in post-I/R myocardium and to prevent myocardial I/R injury. 2 Anaesthetized sheep were studied in four groups (n=5-6): control, ischaemic preconditioning (IPC), vehicle and DiOHF (before reperfusion, 5 mg kg(-1), i.v.). The left anterior descending coronary artery was occluded distal to the second diagonal branch for 1 h followed by 2 h of reperfusion. Infarct size, myocardial function, NADPH-activated superoxide generation and biochemical markers of injury were measured. 3 DiOHF (10(-8)-10(-4) m) incubated in vitro with post-I/R myocardium from the vehicle group suppressed superoxide production dose-dependently. 4 DiOHF administered in vivo also significantly reduced superoxide generation in vitro. DiOHF and IPC markedly reduced infarct size, which was 73+/-2% of the area at risk in vehicle, 50+/-4% in DiOHF, 75+/-5% in control and 44+/-4% in IPC. Post-I/R segment shortening within the ischaemic zone was greater in DiOHF (2.3+/-0.7%; P<0.01) and IPC (1.7+/-0.5%; P<0.01) than those in corresponding controls (-1.7+/-0.4; -2.1+/-0.4%). 5 DiOHF and IPC improved coronary blood flow to the ischaemic area and preserved higher levels of nitric oxide metabolites in the venous outflow from the ischaemic zone. 6 DiOHF attenuated superoxide production in post-I/R myocardium, and significantly reduced infarct size and injury following I/R in anaesthetized sheep. The extent of protection by DiOHF is comparable to that afforded by IPC. Thus, DiOHF has clinical potential for improving recovery from acute myocardial infarction and other ischaemic syndromes.     

UTP reduces infarct size and improves mice heart function after myocardial infarct via P2Y2 receptor

Pyrimidine nucleotides are signaling molecules, which activate G protein-coupled membrane receptors of the P2Y family. P2Y₂ and P2Y₄ receptors are part of the P2Y family, which is composed of 8 subtypes that have been cloned and functionally defined. We have previously found that uridine-5′-triphosphate (UTP) reduces infarct size and improves cardiac function following myocardial infarct (MI). The aim of the present study was to determine the role of P2Y₂ receptor in cardiac protection following MI using knockout (KO) mice, in vivo and wild type (WT) for controls. In both experimental groups used (WT and P2Y₂^−/− receptor KO mice) there were 3 subgroups: sham, MI, and MI + UTP. 24 h post MI we performed echocardiography and measured infarct size using triphenyl tetrazolium chloride (TTC) staining on all mice. Fractional shortening (FS) was higher in WT UTP-treated mice than the MI group (44.7 ± 4.08% vs. 33.5 ± 2.7% respectively, p < 0.001). However, the FS of P2Y₂^−/− receptor KO mice were not affected by UTP treatment (34.7 ± 5.3% vs. 35.9 ± 2.9%). Similar results were obtained with TTC and hematoxylin and eosin stainings. Moreover, troponin T measurements demonstrated reduced myocardial damage in WT mice pretreated with UTP vs. untreated mice (8.8 ± 4.6 vs. 12 ± 3.1 p < 0.05). In contrast, P2Y₂^−/− receptor KO mice pretreated with UTP did not demonstrate reduced myocardial damage. These results indicate that the P2Y₂ receptor mediates UTP cardioprotection, in vivo.     

Quinaprilat reduces myocardial infarct size involving nitric oxide production and mitochondrial KATP channel in rabbits

This study examined whether quinaprilat, an angiotensin-converting enzyme inhibitor, reduces the infarct size, and investigated the mechanisms for its infarct size-reducing effect, in rabbits. Japanese white rabbits underwent 30 min of ischemia and 48 h of reperfusion. Quinaprilat (100 microg/kg/h or 300 microg/kg/h for 70 min, IV) was administered 20 min before ischemia with or without pretreatment with Nomega-nitro-l-arginine methyl ester (l-NAME) (10 mg/kg, IV, a nitric oxide synthase inhibitor), 5-hydroxydecanoic acid sodium salt (5-HD) or posttreatment with 5-HD (5 mg/kg, IV, a mitochondrial KATP channel blocker). The area at risk as a percentage of the left ventricle was determined by Evans blue dye and the infarct size was determined as a percent of the area at risk by triphenyl tetrazolium chloride staining. Using a microdialysis technique, myocardial interstitial levels of 2,5-dihydroxybenzoic acid (2,5-DHBA), an indicator of hydroxyl radicals, and NOx, an indicator of nitric oxide, were measured before, during, and after 30 min of ischemia. Quinaprilat significantly reduced the infarct size in a dose-dependent manner (30.1 +/- 3%, n = 10, and 27.6 +/- 2%, n = 7, respectively) compared with the control (46.5 +/- 4%, n = 10). The infarct size-reducing effect of quinaprilat was completely blocked by pretreatment with l-NAME (43.8 +/- 2%, n = 8) and 5-HD (50.1 +/- 3%, n = 8) and posttreatment with 5-HD (50.3 +/- 2%, n = 8), respectively. Quinaprilat did not affect the myocardial interstitial 2,5-DHBA level but significantly increased the NOx level during ischemia and reperfusion. Quinaprilat reduces myocardial infarct size involving NO production and mitochondrial KATP channels in rabbits without collateral circulation.     

Effects of a combination of metoprolol and dazmegrel on myocardial infarct size in rats.

The effects of acute pretreatment with metoprolol, dazmegrel and a combination of these two drugs has been examined on myocardial infarct size in rats. Ischaemic damage was assessed 4 h after coronary artery occlusion in anaesthetized rats and after 48 h of ischaemia in conscious rats. Infarct size was measured histochemically (by using periodic-acid-Schiff diastase reaction for glycogen) and by standard histological examination (haematoxylin and eosin stain). There was some evidence of protection of the myocardium by metoprolol following 4 h of ischaemia (determined histologically) but this was not apparent 48 h after occlusion. When given alone, dazmegrel had no significant effects on infarct size assessed by either method. A clear reduction in the extent of glycogen depletion and histological damage was observed with the combination of metoprolol and dazmegrel 48 h after the onset of ischaemia. This protection was seen to occur in the horizontal plane of the heart, preventing the extension of the infarct towards the posterior wall of the left ventricle and showing some salvage of the epicardial surfaces.     

Combination of miglitol, an anti-diabetic drug, and nicorandil markedly reduces myocardial infarct size through opening the mitochondrial K(ATP) channels in rabbits

The anti-diabetic drug miglitol, an alpha-glucosidase inhibitor, which is currently used clinically, reduces myocardial infarct size by reducing the glycogenolytic rate through inhibition of the alpha-1,6-glucosidase of glycogen-debranching enzyme in the heart. Nicorandil, a K(ATP) channel opener with a nitrate-like effect, which is also currently used clinically, also reduces the infarct size. Therefore, we hypothesized that combination of nicorandil and submaximal dose of miglitol could markedly reduce myocardial infarct size more than miglitol or nicorandil alone, and investigated the mechanism for the infarct size-reducing effect. Japanese white rabbits without collateral circulation were subjected to 30 min coronary occlusion followed by 48 h reperfusion. Pre-ischaemic treatment with submaximal dose of miglitol (5 mg kg(-1), i.v.) and nicorandil alone (100 microg kg(-1) min(-1) 5 min) moderately reduced the infarct size as a percentage of area at risk (24+/-4 and 25+/-4%, respectively), and 10 mg kg(-1) of miglitol markedly reduced the infarct size (15+/-2%) compared with the controls (42+/-2%). Combination of 5 mg kg(-1) of miglitol and nicorandil (100 microg kg(-1) min(-1) 5 min), and 10 mg kg(-1) of miglitol and nicorandil (100 microg kg(-1) min(-1) 5 min) significantly reduced the infarct size (13+/-4 and 12+/-3%, respectively) more than miglitol or nicorandil alone. Pretreatment with 5HD completely abolished the infarct size-reducing effect of 10 mg kg(-1) of miglitol alone (36+/-7%) and that of combination of 5 mg kg(-1) of miglitol and nicorandil (46+/-2%). Combination of nicorandil and submaximal dose of miglitol markedly reduced the myocardial infarct size more than miglitol or nicorandil alone. This effect was suggested to be related to the opening of mitochondrial K(ATP) channels.     

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.