Improved recovery of myocardial segment function following a short coronary occlusion in dogs by nicorandil, a potential new antianginal agent, and nifedipine

The effects of nicorandil [SG-75, 2-nicotinamidoethyl nitrate (ester)] and nifedipine on the recovery of myocardial segment shortening were compared to a vehicle-treated group following a short occlusion (15 min) of the left anterior descending coronary artery (LAD) and reperfusion (5 h). The relationship between myocardial blood flow and myocardial segment shortening was examined by means of the radioactive microsphere technique and sonomicrometry. Nicorandil (100 micrograms/kg followed by 25 micrograms/kg/min, i.v.) or nifedipine (3 micrograms/kg followed by 1 microgram/kg/min, i.v.) was administered 10 min prior to and throughout the occlusion period. Both drugs produced similar decreases in mean arterial pressure (approximately 25 mm Hg) during LAD occlusion. Similar degrees of ischemia (flow deprivation) were produced in the vehicle, nicorandil, and nifedipine groups; however, nicorandil produced a significantly greater decrease in the heart rate-left ventricular systolic pressure product during coronary occlusion. During reperfusion of the LAD there was no difference in the hemodynamics of the vehicle, nicorandil, or nifedipine groups. Neither drug altered myocardial blood flow to the ischemic region during the occlusion or reperfusion period when compared to the vehicle-treated group; however, both nicorandil and nifedipine pretreatment significantly improved recovery of percentage of segment shortening of the ischemic region. Nicorandil improved the recovery of function (percentage of segment shortening) to a greater extent than did nifedipine throughout the reperfusion period, most likely because of the greater decrease in afterload produced by nicorandil.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative effects of nicorandil, a nicotinamide nitrate derivative, and nifedipine on myocardial reperfusion injury in dogs

The effects of the nicotinamide nitrate compound nicorandil (SG-75) and the slow channel calcium entry blocker nifedipine on the recovery of subendocardial segment shortening (% SS) were compared with a vehicle-treated group following 30 min of left anterior descending coronary artery (LAD) occlusion and 3 h of reperfusion. Sonomicrometry was used to determine % SS in ischemic and nonischemic myocardium, and radioactive microspheres were used to determine regional myocardial blood flow. Nicorandil (100-micrograms/kg bolus followed by 25 micrograms/kg/min i.v.), nifedipine (10-micrograms/kg bolus followed by 3 micrograms/kg/min i.v.), or vehicle (saline) was administered 15 min prior to and throughout the occlusion period. Both drugs produced equivalent decreases in the heart rate X systolic pressure product before and during LAD occlusion. In addition, total left ventricular weights, the area at risk, the percent of the left ventricle at risk, and collateral blood flow were similar in all three groups. During coronary occlusion, % SS in the ischemic region was equally depressed in each series and passive systolic lengthening resulted. However, following reperfusion, only the nicorandil-treated animals showed an improvement in myocardial segment function through 3 h of reperfusion as compared with the control group. Transmural myocardial blood flow within the ischemic region during reperfusion returned to control values in all three groups; however, the endocardial/epicardial blood flow ratio (endo/epi) was significantly decreased in the control and nicorandil-treated dogs. In contrast, the endo/epi was greater than the preocclusion control in the nifedipine series during reperfusion. Thus, although the mechanism of action of nicorandil in this model is unknown, the improvement in % SS in the nicorandil-treated group was not related to changes in peripheral hemodynamics or improved regional blood flow, since nifedipine produced similar changes in hemodynamics and resulted in a better recovery of perfusion.     

Coronary collateral blood flow in acute myocardial ischemia is not increased by dihydropyridine-induced coronary vasodilatation

The effect of two dihydropyridine derivatives, nifedipine and felodipine, on myocardial blood flow distribution 1 h after ligation of the left anterior descending coronary artery (LAD) was studied in open-chest dogs by means of radioactive microspheres. The myocardium normally perfused from the LAD was first labeled with 125I-labeled microspheres injected directly into the LAD before ligation. Microspheres used for blood flow measurements were given in the left atrium. An intravenous infusion rate of 0.3 nmol/kg/min felodipine slightly depressed mean aortic blood pressure (approximately 5 mm Hg) and decreased coronary vascular resistance in normal myocardium. Nifedipine, at three times the dose of felodipine, had a comparable hypotensive effect, but the decrease in coronary vascular resistance was not statistically significant. The two dihydropyridines were also compared in a dose range that was four times higher. The mean arterial blood pressure reduction (approximately 30% for both drugs) was counterbalanced by inflation of an intraaortic balloon to avoid a drastic decrease in afterload and coronary perfusion pressure. Under these circumstances, felodipine and nifedipine decreased coronary vascular resistance and increased blood flow to nonischemic myocardium comparably. However, in severely ischemic, truly collateral-dependent myocardium without admixture of interdigitating healthy myocardium, the blood flow was unaffected after administration of both felodipine and nifedipine. Although felodipine was three times more potent than nifedipine with regard to vasodilatation in the normal myocardium, the difference in vascular selectivity between the two agents did not influence the effect on the "true" collateral blood flow in acute myocardial ischemia.     

Postjunctional alpha-adrenergic stimulation of inotropy in hypoperfused myocardium outside an acute infarct.

The functional significance of myocardial postjunctional alpha-adrenergic support of inotropy in the vicinity of an acute regional ischemic zone was addressed in pentobarbital-anesthetized, beta-adrenergic blocked cats with circumflex coronary artery occlusion. Regional myocardial performance was measured by ultrasonic crystals in the anterior wall perfused by the left anterior descending coronary artery (LAD) before and during postjunctional alpha-adrenergic antagonism (SK&F 104078 2 mg/kg). A group with unrestricted flow in the LAD (control group) was compared with a group perfused below the autoregulatory pressure range (stenosis group). End-systolic pressure-length relations during dynamic after-load elevation were calculated for assessment of regional contractility. Regional myocardial blood flow (RMBF) was measured by radioactive microspheres. SK&F 104078 did not alter regional myocardial shortening or the slope of end-systolic pressure-length relations in the control group. In the stenosis group, however, alpha-adrenergic antagonism produced significant deterioration of shortening as well as consistent reduction of the slope of the end-systolic pressure-length relations (p < 0.05). As a reflection of reduced demands for perfusion, impairment of midmyocardial and endocardial blood flow occurred in the stenosis group (p < 0.05). These findings imply a negative inotropic effect of SK&F 104078 in metabolically vasodilated myocardium in the vicinity of an acute ischemic region.     

Effects of MCI-176, a new quinazolinone calcium antagonist, on myocardial energy and carbohydrate metabolism in ischemic dog hearts.

The effect of 2-(2,5-dimethoxyphenylmethyl)-3-(2-dimethylaminoethyl)- 6-isopropoxy-4(3H)-quinazolinone hydrochloride (MCI-176), a calcium antagonist, on ischemic myocardial metabolism was studied in dog hearts subjected to an occlusion of the left anterior descending coronary artery (LAD) for 3 or 30 min. MCI-176 (0.03 or 0.1 mg/kg), when injected i.v. 5 min before occlusion, increased coronary blood flow and decreased systemic aortic pressure. When the LAD was ligated, the levels of creatine phosphate, ATP, total adenine nucleotides and energy change potential decreased in the ischemic myocardium. Three minutes after ischemia, MCI-176 (0.1 mg/kg) significantly (P less than 0.05) diminished these impairments of energy metabolism. Even 30 min after ischemia, pretreatment with MCI-176 tended to lessen the depletion of ATP and total adenine nucleotides, although these effects were not statistically significant. Myocardial ischemia produced a breakdown of glycogen, an accumulation of lactate, and an inhibition of glycolytic flux through phosphofructokinase reaction. MCI-176 (0.1 mg/kg) significantly (P less than 0.05) reduced these alterations of carbohydrate metabolism after 3 min of ischemia. These results suggest that pretreatment with MCI-176 reduces the impairments of myocardial energy and carbohydrate metabolism in ischemic dog hearts, suggesting that the drug is capable of improving the imbalance between oxygen supply and oxygen demand in the ischemic myocardium.     

Stimulation of myocardial function after brief regional ischemia by glucagon

Glucagon (1.5 to 45 μg/kg, i.v.) has been examined in open-chest anesthetized dogs subjected to 15 minutes of occlusion of the left circumflex coronary artery (LCCA) and reperfusion. Regional segment lengths in myocardium supplied by the LCCA and left anterior descending (LAD) coronary arteries were measured by sonomicrometry. Occlusion of the LCCA produced paradoxical bulging. At 2.5 hours after reperfusion, segmental shortening in the LCCA area remained significantly reduced at 33 ± 11% of baseline. Regional shortening in the LAD area increased upon LCCA occlusion but was not significantly different from baseline at 2.5 hours. Glucagon increased heart rate and peak positive dP/dt while decreasing systemic pressure. After glucagon 15 μg/kg i. v., LCCA regional shortening was 71 ± 10% of baseline, a significant increase compared with the 2.5 hours reperfusion value. For comparison, isoproterenol 0.3 mg/kg increased segment shortening to 119 ± 19% of baseline. Glucagon reduced end-diastolic segment length in both LCCA and LAD regions. In conclusion, glucagon significantly improved regional function in myocardium recovering from an episode of regional ischemia.     

Nicorandil attenuates myocardial dysfunction associated with transient ischemia by opening ATP-dependent potassium channels.

The objective of this study was to determine whether ATP-dependent potassium channel activation is involved in the mechanism by which nicorandil reduces postischemic contractile dysfunction produced by a brief period of ischemia (myocardial stunning). Barbital-anesthetized dogs were subjected to 15-min left anterior descending (LAD) coronary artery occlusion followed by 3-h reperfusion. Saline or nicorandil (100 micrograms/kg + 25 micrograms/kg/min) were infused 15 min before and throughout occlusion with or without addition of the KATP channel antagonist, glibenclamide 0.3 mg/kg as an intravenous (i.v.) bolus. Regional myocardial blood flow was measured by radioactive microspheres, and left ventricular (LV) segment function was measured by sonomicrometry. There were no significant differences between the groups in area-at-risk size or collateral blood flow. In contrast, nicorandil significantly reduced mean aortic blood pressure (BP) and the rate-pressure product (RPP) which persisted throughout the occlusion period. In addition, nicorandil markedly accelerated recovery of segment shortening in the ischemic/reperfused region as compared with control dogs. Pretreatment of dogs with glibenclamide blocked none of the hemodynamic effects of nicorandil, but it did prevent improvement in reperfusion segment function. The small dose of glibenclamide used had no effect on hemodynamics or the degree of stunning. Thus, these results suggest that nicorandil attenuates stunning in anesthetized dogs by a direct cardioprotective effect as a result of KATP channel activation in ischemic myocardium.     

Blood flow regulation during acute regional ischemia in feline hearts: importance of postjunctional alpha 1- and alpha 2-adrenoceptors.

Influence of postjunctional alpha 1- and subsequent alpha 2-adrenergic antagonism on myocardial blood flow was measured in a group of anesthetized cats with acute occlusion of the left anterior descending coronary artery (LAD) and a control group (n = 10 for both). The relatively selective postjunctional alpha 1-(doxazosin) and alpha 2-adrenergic (SK&F 104078) antagonists were applied after beta-adrenergic blockade (propranolol). Regional myocardial blood flow was obtained with radiolabeled microspheres. Major hemodynamic determinants for perfusion were kept constant both within and between groups by right atrial pacing and aortic obstruction. Mean coronary resistance in nonischemic myocardium was permanently lower in the occlusion group as compared with controls (p less than 0.01). Subsequent alpha 2-adrenergic antagonism reduced mean coronary resistance in controls only (p less than 0.05). Cardiac output (CO) and dP/dt was reduced in LAD-occluded hearts after alpha 2-adrenergic blockade (p less than 0.01, p less than 0.05). The study demonstrates the significance of postjunctional alpha 2-adrenergic-mediated vasoconstriction in well-perfused myocardium of control hearts, whereas such vasoconstriction was deteriorated in LAD-occluded hearts. A role for myocardial alpha 2-adrenoceptors for maintenance of global cardiac function in acute regional ischemia was also indicated.     

Cardioprotective effects of YM934, an ATP-sensitive potassium channel opener, on stunned myocardium in anesthetized dogs.

The effects of YM934 [2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl) pyridine N-oxide], an adenosine triphosphate (ATP)-sensitive potassium channel opener, on stunned myocardium were examined. Forty eight anesthetized dogs were subjected to 15 min of left anterior descending (LAD) coronary artery occlusion followed by 3 hours of reperfusion. To elucidate the possible contribution of the cardioprotective property of YM934 to stunned myocardium, a nonhypotensive dose of YM934 was directly injected into the LAD coronary artery before the ischemic insults. Intracoronary artery infusion (i.c.) of YM934 (0.1 microg/kg/min) produced a marked improvement in post-ischemic regional contractile dysfunction. The effects were not associated with improvement of hemodynamics, including regional myocardial blood flow during ischemia, heart rate and mean arterial blood pressure. The anatomic areas at risk expressed as a percentage of the left ventricle and regional myocardial blood flow were not significantly different between groups. The cardioprotective effect of YM934 was completely blocked by pretreatment with an ATP-sensitive potassium channel blocker, glibenclamide (1.0 mg/kg i.v. bolus). These results suggest that YM934 exerts cardioprotective effect on stunned myocardium through opening myocardial ATP-sensitive potassium channels.     

Effects of nicardipine, a dihydropyridine calcium antagonist, on regional myocardial blood flow, myocardial oxygen tension, and electrical abnormalities during acute coronary artery occlusion in dogs

Effects of nicardipine, a dihydropyridine calcium antagonist, on regional myocardial blood flow (RMBF), myocardial oxygen tension (PO2), and excitation and conduction abnormalities during the occlusion of the left anterior descending coronary artery (LAD) were examined in anesthetized dogs, and compared with those of nifedipine and dipyridamole. RMBF was calculated from the H2 gas clearance curves, and PO2 was measured using a membrane-coated Pt wire. Excitation and conduction abnormalities during the LAD occlusion were represented in terms of the degree of ST-T alternans (STTA), TQ depression, and conduction delay, which appeared in epicardial electrograms. Nicardipine and nifedipine in a dose of 10 micrograms/kg increased RMBF and PO2 levels in nonischemic and mildly ischemic tissues, but not in severely ischemic tissues. Nicardipine in a dose of 100 micrograms/kg and nifedipine in a dose of 10 micrograms/kg attenuated the degree of STTA, TQ depression, and conduction delay observed in severely ischemic tissues. In mildly ischemic tissues where only TQ depression was observed without STTA, nicardipine in a dose of 30 micrograms/kg attenuated TQ depression. Dipyridamole in a dose of 1 mg/kg produced only a slight attenuation of STTA and conduction delay. These results suggest that the beneficial effects of nicardipine as well as of nifedipine on myocardial ischemia are due to the increase in the myocardial PO2 levels caused by the increased RMBF and also to direct protecting effects on ischemic myocardial cells. In the severely ischemic tissues, the latter is a main effect of the drugs. In increasing the PO2 level, nicardipine was similarly potent as nifedipine, but in the direct effect, nicardipine was less potent, and dipyridamole was almost ineffective.     

Liposome kinetics in infarcted canine myocardium

To study the mechanisms and kinetics of liposome deposition in the region of the experimental myocardial infarction, the myocardial distribution of positive and negative liposomes was determined as a function of regional myocardial blood flow and time after administration. The study was performed in dogs at 1 and 24 h following experimental myocardial infarction. Twenty-four hours after coronary artery occlusion, the initial myocardial distribution of positive and negative liposomes (2 min) is directly proportional to regional myocardial blood flow. With time, there is reduction of the radiotracer associated with negative liposomes from all myocardial regions (p less than 0.01). In contrast, in areas of moderate and severe blood flow reduction, there is progressive accumulation of tracers entrapped or incorporated in positive liposomes. This increment becomes significant in 120 min (p less than 0.005). Similar findings are observed in studies performed 1 h after coronary artery occlusion. Dual-label liposomes [( 3H]cholesterol and [99mTc]diethylenetriamine pentaacetic acid) were used to study the integrity of liposomes in normal and ischemic myocardium. Significant dissociation of the aqueous and lipid labels of positive liposomes is observed 1 h following coronary artery occlusion. In the 24-h myocardial infarction model, dissociation of the aqueous and lipid labels in ischemic myocardium is also observed. This phenomenon is more pronounced with positive than with negative liposomes (p less than 0.02). The leakage of tracers from liposomes may result from destabilization or destruction of liposomes in the ischemic myocardium by the action of phospholipases, catabolites, and local environmental changes. This effect is less marked for negative liposomes. The use of liposomes improved the regional distribution of the tracer in infarcted tissue. However, the absolute amount of tracer delivered to the myocardium is less than that achieved with the free form.     

Improvement of the metabolic and energetic situation of ischemically stressed myocardium by verapamil after experimental coronary artery occlusion

On anaesthetized open-chest mongrel dogs (n = 7) short-time (3 min), repeated ischemia of relatively large parts of the myocardium was produced by proximal, intermittent occlusion of the LAD artery in intervals of 45 min. Usually, 2-3 control occlusions and 2-3 occlusions under therapy were performed. From hemodynamic data, coronary blood flow and AVD-O2 myocardial oxygen consumption (MVO2) and energy demand (Et) were continuously recorded by use of a micro-computer. The occurring difference between MVO2 and Et (dO2) allowed to calculate during the occlusion period the O2-debt (DO2) and during the reperfusion period the O2-repayment (RO2). Furthermore, the releases of the metabolic ischemia parameters lactate, inorganic phosphate and potassium were determined in the first minute of postischemic reperfusion. Compared to control occlusions, premedication with verapamil (Isoptin) 0.12--0.2 mg/kg b.w.) led intra- and interindividually to a significantly reduced O2-debt (p less than 0.001) during the occlusion period combined with a significantly reduced amount of oxygen, additionally taken up in the early reperfusion period (p less than 0.001). Under verapamil the amounts of metabolic parameters released in the first minute of reperfusion decreased significantly: lactate: -36% (p less than 0.001), inorganic phosphate: -32% (p less than 0.001), potassium: -30% (p less than 0.001). The improvement of the metabolic and energetic situation of ischemic myocardium indicates that verapamil may be of importance in reducing the extent and severity of acute myocardial ischemic injury.     

Effect of dilazep on decrease in myocardial pH during ischemia in dogs

The present study was undertaken in order to examine whether dilazep (1,4-bis-[3-(3,4,5-trimethoxybenzoyloxy)propyl]perhydro-1, 4-diazepine dihydrochloride monohydrate) attenuates myocardial acidosis induced by coronary artery occlusion in dogs. In dogs with nonischemic normal heart, dilazep (300 or 500 micrograms/kg i.v.) increased blood flow in the left anterior descending coronary artery (LAD) with a decrease in heart rate and diastolic blood pressure. In other dogs, LAD flow was reduced by an occluder by 57 to 68% (partial occlusion) for 90 min. Partial occlusion for 30 min decreased myocardial pH by 0.67 to 0.87 pH units, increased ST segment of the surface electrocardiogram, and decreased regional myocardial contractile force. Dilazep was injected i.v. 30 min after partial occlusion. The decrease in myocardial pH induced by partial occlusion was attenuated by the injection of 300 micrograms/kg of dilazep insignificantly and by that of 500 micrograms/kg of dilazep significantly. Restoration of myocardial [H+] induced by dilazep was calculated from the myocardial pH data. Dilazep (500 micrograms/kg) restored myocardial [H+] induced by partial occlusion by 56.7%, and saline solution restored it by 27.4% 60 min after the drug injection, the actual restoration induced by dilazep being 29.3%. Dilazep, however, did not restore the ST segment elevation and contractile force decrease. It is concluded that dilazep attenuates myocardial acidosis during ischemia.     

Protective effect of a novel thromboxane antagonist, BAY-U3405, on canine myocardial damage after coronary artery occlusion and reperfusion

The effects of a novel thromboxane antagonist, (3R)-3-(4-fluorophenylsulfonmido)-1,2,3,4-tetrahydro-9-carbazol epropanoic acid (BAY-U3405), on myocardial damage due to ischemia and reperfusion (added to accelerate the initiated injury) were studied in anesthetized dogs. The left anterior descending (LAD) coronary artery was occluded for 6 hours and reperfused for 30 minutes. BAY-U3405, 1 mg/kg, was injected intravenously 15 minutes after LAD occlusion, followed by continuous infusion of 10 mg/kg/hour starting at 30 minutes after occlusion. The drug had no hemodynamic effects. During the experiments 6 of 14 animals died of ventricular fibrillation (VF) in the placebo-vehicle controls (3 during occlusion and 3 during reperfusion); in the drug-treated group 5 of 13 dogs died of VF (all during occlusion none during reperfusion). This difference in total mortality and cause was not statistically significant. Reperfusion arrhythmias were largely suppressed by BAY-U3405: 201 +/- 43 versus 689 +/- 98 irregular beats during 30 minutes (p less than 0.001) in the experimental and control groups, respectively. Coronary collateral flow, obtained from a load-line analysis by measurement of retrograde coronary flow, and collateral index were similar in both groups. Therefore, BAY-U3405 did not alter collateral blood supply to the ischemic myocardium. Infarct size, determined with tetrazolium staining, was reduced by 65% (p less than 0.01) after its administration. These results suggest that thromboxane antagonism by BAY-U3405 may delay infarct expansion and reduce the frequency of ventricular arrhythmias during reperfusion of previously ischemic myocardium.     

Effect of nifedipine on regional O2 consumption in ischemic myocardial tissue

The effect of intravenous (i.v.) nifedipine (5 micrograms/kg/min) on regional O2 supply/consumption variables was determined in 14 anesthetized open-chest dogs subjected to left anterior descending coronary artery (LAD) stenosis sufficient to reduce blood flow 50%. Myocardial blood flow was measured using radioactive microspheres, and regional arterial and venous O2 saturations were determined using microspectrophotometry. During LAD occlusion, blood flow and O2 consumption were decreased in the ischemic region while O2 extraction was increased. With nifedipine treatment, LAD flow (flow probe) was increased 44% as compared with the initial occluded value, with most of this increase going to the subepicardium (microspheres). Flow to the ischemic subendocardium was not changed with nifedipine treatment. Ischemic subepicardial O2 consumption increased slightly in nifedipine-treated animals as compared with saline values, whereas O2 extraction decreased slightly. In the subendocardial region, nifedipine resulted in a significant decrease in O2 extraction, with a slight decrease in O2 consumption as compared with saline controls. The O2 supply/demand ratio was significantly improved with nifedipine only in the subendocardium of the ischemic region. This suggested that nifedipine could increase O2 consumption in the ischemic subepicardium through proportional increase in O2 supply while it decreased O2 consumption in the subendocardium relative to O2 supply.     

Effects of SEA0400, a novel inhibitor of the Na+/Ca2+ exchanger, on myocardial stunning in anesthetized dogs

Activation of the Na+/Ca2+ exchanger may contribute to Ca2+ overload during reperfusion after transient ischemia. We examined the effects of 2-[4-[(2,5-difluorophenyl) methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a selective inhibitor of Na+/Ca2+ exchange, on a canine model of ischemia/reperfusion injury (myocardial stunning). Myocardial stunning was induced by a 15-min occlusion of the left anterior descending coronary artery followed by a 4-h reperfusion in anesthetized open-chest dogs. Reperfusion gradually restored myocardial percent segment shortening but remained depressed during a 4-h reperfusion period. A bolus intravenous injection of SEA0400 (0.3 or 1.0 mg/kg), given 1 min before reperfusion, improved significantly the recovery of percent segment shortening in the ischemic/reperfused myocardium. SEA0400 did not affect the hemodynamics and electrocardiogram parameters. In addition, SEA0400 did not affect reperfusion-induced change in coronary blood flow. These results suggest that the Na+/Ca2+ exchanger is involved in the stunned myocardium of dogs after reperfusion, and that SEA0400 has a protective effect against myocardial stunning in dogs.     

Reduction of acute myocardial ischemia in rabbit hearts by nafazatrom

The effects of oral nafazatrom pretreatment (10 mg/kg, twice a day, for 10 days) on myocardial ischemia were studied in the rabbit heart during 6-h occlusion of the left anterior descending coronary artery (LAD). The tension-time index (TTI), hemodynamics, and ischemia size were determined (Evan's blue-triphenyltetrazolium chloride staining with planimetry). In drug-vehicle controls, left ventricular (LV) and peripheral pressures and LV dP/dtmax decreased, while heart rate, end-diastolic pressure, the TTI, and electrocardiographic ST segments increased. Hemodynamics were nearly unaltered in the nafazatrom-pretreated animals, except for a heart rate elevation during the initial phase of LAD occlusion. In drug-treated hearts, 45 +/- 6% of the LAD perfusion region at risk was ischemic, showing a patchy distribution. In vehicle controls, 82 +/- 4% (p less than 0.02 vs. nafazatrom pretreatment) of the LAD-perfused myocardial regions was transmurally ischemic, showing a uniform pattern. Thus, nafazatrom pretreatment prevented most hemodynamic changes following LAD occlusion in the rabbit heart. Significant amounts of the muscle remained normoxic within the nonperfused arterial regions. These results indicate that the inhibition of lipoxygenase enzymes by nafazatrom may delay the development of ischemic damage to the heart following acute coronary artery occlusion.     

Effect of alpha-tocopherol (vitamin E) in a porcine model of stunned myocardium

Oxygen free radicals have been suggested to cause the myocardial damage resulting in the prolonged contractile depression following brief periods of regional ischemia. In pigs, we infused the natural antioxidant alpha-tocopherol as its water-soluble acetate [0.3 g/kg intravenously (i.v.), n = 6] three times during 1 week, prior to thoracotomy, 8-min distal left anterior coronary artery (LAD) occlusion and 90-min reperfusion. Plasma levels of alpha-tocopherol [high-performance liquid chromatography (HPLC)] on the experimental day were 148.91 +/- 21.47 micrograms/ml as compared to preinfusion control of 0.51 +/- 0.14 micrograms/ml. Myocardial levels of alpha-tocopherol were elevated to 93.15 +/- 14.78 micrograms/g as compared to 4.08 +/- 0.60 microgram/g in the control group (n = 6). Malondialdehyde levels in ischemic-reperfused myocardium of the treatment group were insignificantly lower (441.96 +/- 59.55 nmol/g) as compared to the control group (500.9 +/- 72.72 nmol/g). Heart rate was significantly higher in the treatment group by the end of the experiments (135 +/- 10 vs. 105 +/- 4 beats/min, p less than 0.01). Regional segment shortening (SS, sonomicrometry) became normal within 1 min of reperfusion in both the treatment and the control group. During the following 10 min, SS decreased to 52 +/- 6% of preischemic control in the alpha-tocopherol group and to 54 +/- 7% in the control group (NS). SS remained at these depressed values throughout the reperfusion period. Pretreatment with the antioxidant alpha-tocopherol resulted in a tendency to lower lipid peroxidation products but did not prevent development of contractile depression in reversibly ischemic reperfused myocardium.     

Nifedipine prevents sympathetic vasoconstriction distal to severe coronary stenoses

Cardiac sympathetic nerve stimulation ( CSNS ) can induce vasoconstriction distal to severe coronary stenoses by activation of vascular alpha 2-adrenoceptors. Whether nifedipine can antagonize this CSNS -induced vasoconstriction was tested in 11 anesthetized, vagotomized dogs. CSNS decreased the end-diastolic resistance of intact coronary arteries from 0.76 +/- 0.07 to 0.56 +/- 0.05 mm Hg x min x 100 g/ml (p less than 0.05). In contrast, the resistance distal to severe stenoses, which were defined by a reduction of the postocclusive reactive hyperemia to almost zero, was increased during CSNS from 0.52 +/- 0.06 to 0.87 +/- 0.14 mm Hg x min x 100 g/ml (p less than 0.05). This increase in resistance was associated with severe ischemia, as indicated by a net lactate production of the circumflex-perfused myocardium and a decrease in systolic segment shortening from 8.4 +/- 0.7 to 7.0 +/- 0.7% (p less than 0.05). Both intracoronary (10 micrograms) and intravenous (10 micrograms/kg) administration of nifedipine did not change the poststenotic resistance at rest, but did prevent the CSNS -induced increase in resistance, the decrease in regional contraction, and the net lactate production. We conclude that nifedipine can prevent the deleterious role of alpha-adrenoceptor-mediated vasoconstriction in the genesis of myocardial ischemia.     

Adrenergic influences on ischemic and reperfusion arrhythmias in a canine model with diminished collateral blood flow

To examine the role of adrenergic influences on genesis of ischemic and reperfusion arrhythmias, the left anterior descending coronary artery (LAD) was cannulated and perfused by a shunt from the left carotid artery in 38 open-chest pentobarbital-anesthetized dogs. Ischemia was produced by shunt occlusion and retrograde diversion of collateral flow from the LAD. The diverted blood was collected and returned to the animal by intravenous (i.v.) injection. The shunt was opened and the ischemic myocardium reperfused after 30 min of ischemia. Microsphere injections in six dogs during shunt occlusion and retrograde bleeding showed that blood flow to the ischemic zone was less than 1.5% of normal zone flow. The remaining 32 dogs were randomized into four treatment groups. Dogs (n = 8) were treated before shunt occlusion with either saline, nadolol (1 mg/kg), prazosin (0.2 mg/kg), or bilateral stellate transection. As compared with saline treatment, nadolol and stellate transection significantly reduced heart rate (HR), and prazosin significantly reduced mean arterial blood pressure (MAP) (p less than 0.05). However, none of the antiadrenergic interventions significantly reduced the number or frequency of ectopic beats during either the 1a or 1b phases of ischemia. None of the 32 dogs developed ventricular fibrillation (VF) during ischemia, but all dogs fibrillated within 30 s of reperfusion. The size of the ischemic zone ranged from 21 to 38% of the left ventricle, and there were no differences among the four treatment groups. The results suggest that when ischemia is severe, the adrenergic nervous system does not play a significant role in genesis of ischemic-induced ectopy or reperfusion-induced VF.