Selective dopamine-1 receptor agonist augments regional myocardial blood flow: comparison of fenoldopam and dopamine.

A new class of vasodilators exhibiting selective dopamine-1 receptor agonist activity is being introduced into clinical practice. Inasmuch as various vasodilators either augment or decrease myocardial blood flow ("coronary steal") depending on their pharmacologic action, the goal of this study was to assess the effects of fenoldopam (selective dopamine-1 receptor agonist) and dopamine (nonselective dopamine-1 receptor agonist) on regional myocardial blood flow in the presence of coronary occlusion. Accordingly, in 16 dogs anesthetized with pentobarbital, the left anterior descending coronary artery was occluded. Cardiovascular and renal hemodynamic effects were measured before and after intravenous infusion of renal equipotent doses of either fenoldopam (n = 9, 0.1 micrograms/kg/min) or dopamine (n = 7, 1 micrograms/kg/min). Both fenoldopam and dopamine caused a significant and comparable increase in renal blood flow. Fenoldopam but not dopamine significantly decreased the calculated peripheral vascular resistance and subsequently increased cardiac output. Dopamine had no effect on regional myocardial blood flow. In contrast, fenoldopam augmented transmural myocardial blood flow in normal (from 114 +/- 10 to 188 +/- 27 ml/100 gm/min, p less than 0.02) and ischemic border myocardium (from 45 +/- 5 to 68 +/- 11 ml/100 gm/min, p less than 0.03 and p less than 0.02 vs dopamine). There was a significant increase in blood flow to both the endocardial and epicardial layers of normal and ischemic border myocardium. These changes were accompanied by a significant reduction in coronary vascular resistance in the normal myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction in myocardial hemorrhage and the extent of necrosis by gallopamil (D600) in dogs with coronary artery reperfusion.

To determine whether gallopamil (D600), a methoxy derivative of verapamil, administered immediately before coronary artery reperfusion reduces the extent of myocardial hemorrhage and necrosis, the left anterior descending coronary artery was occluded for 3 h and reperfused for 3 h in anesthetized, open-chest dogs. To quantify the extent of the hypoperfused zone (HZ), 99mTc-labeled albumin microspheres were injected into the left atrium 1 min after occlusion. Five minutes before reperfusion, dogs were randomly assigned to a control group or a gallopamil-treated group that immediately after assignment received 0.08 mg/kg gallopamil followed by a continuous infusion of 0.2 mg/kg/h for 3 h. Three hours after reperfusion, the left ventricle was cut into slices for triphenyltetrazolium chloride staining and autoradiography. There were no differences in the extent of the HZ between the two groups. Gallopamil significantly reduced the extent of myocardial necrosis from 81.3 +/- 4.2% (n = 8) of the HZ in the control to 46.1 +/- 13.1% (n = 9, p less than 0.05) in the treated group. The extent of gross hemorrhage was significantly smaller in the gallopamil-treated group (1.3 +/- 0.9% of the left ventricle or 3.1 +/- 1.8% of the HZ, p less than 0.01) as compared with the control group (6.2 +/- 1.4% of the left ventricle or 20.0 +/- 4.6% of the HZ). Thus, gallopamil administered immediately before coronary artery reperfusion limited infarct size and reduced the extent of myocardial hemorrhage.

Sustained beneficial effects of gallopamil (D600) on size of myocardial infarction 24 hours after coronary artery occlusion in dogs.

To examine whether gallopamil (D600), a methoxy derivative of verapamil, has sustained beneficial effects on the ischemic myocardium, its effects on the size of myocardial infarction determined 6 hours (protocol 1) and 24 hours (protocol 2) after left anterior descending coronary artery occlusion were compared in anesthetized, open-chest dogs. To quantify the extent of the hypoperfused zone, Tc-99m- or In-111-albumin microspheres were injected into the left atrium 1 minute after occlusion. Fifteen minutes after occlusion, dogs were randomly assigned to a control group or a gallopamil-treated group that received immediately after assignment 0.08 mg/kg of gallopamil followed by a continuous infusion of 0.2 mg/kg/hr for 6 hours. Six or 24 hours after occlusion, the left ventricle was cut into 3 mm thick slices for triphenyltetrazolium chloride staining and autoradiography. There were no differences in the extent of the hypoperfused zone among the four groups. In both protocols 1 and 2 the ratio of the extent of myocardial necrosis to the extent of the hypoperfused zone was significantly smaller in the treated groups (56.7 +/- 6.7% [n = 8], p less than 0.01 and 72.3 +/- 5.3% [n = 6], p less than 0.05 for protocols 1 and 2, respectively) than in the control groups (100.7 +/- 6.0% [n = 7] and 95.2 +/- 4.3% [n = 5] for protocols I and II, respectively). Thus gallopamil administered early after coronary artery occlusion had beneficial effects on the ischemic myocardium, which were sustained for at least 24 hours after the onset of infarction.

Three-dimensional analysis of infarct size reduction after administration of gallopamil in dogs.

Several interventions have been shown to protect the ischemic myocardium from evolving to necrosis. However, three-dimensional evaluation of infarct size reduction using anatomical measurements is lacking. Therefore, Tc-99m labeled albumin microspheres were injected into the left atrium of 16 dogs, 1 min after coronary artery occlusion, to assess the hypoperfused zone. After 15 min, 8 dogs received, intravenously, gallopamil (Procorum) (Ga: 0.08 mg/k as a bolus + 0.2 mg/k/h for 6 h) and the remaining 8 dogs served as controls. At sacrifice (6 h), the left ventricle was cut into 3 mm slices, stained with triphenyltetrazolium chloride to delineate the size of infarction and autoradiographed to delineate the hypoperfused zone. Lateral reduction was calculated by the difference distance between hypoperfused zone and infarct size on the endocardium, mid-myocardium and epicardium; radial reduction was calculated by the difference of the transmural distance taken at mid-infarction and mid-hypoperfusion and the longitudinal reduction was calculated by the distance of the hypoperfused slices that did not infarct. With this technique it could be demonstrated that gallopamil reduced the size of infarction in all three dimensions.

Myocardial salvage after regional beta-adrenergic blockade.

UNLABELLED: The aim of the study was to determine whether regional beta-adrenergic blockade via the coronary sinus limited myocardial damage after coronary artery occlusion in the canine model. Accordingly, open-chest anesthetized dogs were randomly allocated to one of three groups: a control group and groups treated with propranolol (in doses of 0.02, 0.2, and 2.0 mg/kg) given either intravenously or via the coronary sinus. The hypoperfused zone (i.e., risk area) and the extent of myocardial damage were assessed by autoradiography and triphenyltetrazolium chloride staining, respectively. Myocardial damage expressed as a percent of the hypoperfused zone was 84 +/- 5% in the control group (n = 9) and 78 +/- 7% (0.02 mg/kg, n = 7, NS), 63 +/- 6% (0.2 mg/kg, n = 7, p less than 0.05), and 62 +/- 7% (2.0 mg/kg, n = 9, p less than 0.02) in the groups receiving intravenous propranolol and 73 +/- 6% (0.02 mg/kg, n = 7, NS), 58 +/- 7% (0.2 mg/kg, n = 7, p less than 0.01), and 44 +/- 9% (2.0 mg/kg, n = 9, p less than 0.001) in groups receiving propranolol via the cardiac veins. There was a significant enhancement of myocardial salvage with increasing doses of propranolol delivered via the cardiac veins (linear regression trend, p less than 0.05). In contrast, myocardial damage expressed as a percent of the hypoperfused zone remained comparable with propranolol doses of 0.2 and 2.0 mg/kg administered intravenously (linear regression trend, NS). IN CONCLUSION: (1) regional beta-adrenergic blockade via the cardiac veins afforded significant myocardial salvage and (2) the regional administration of propranolol resulted in significant reduction of myocardial damage in a dose-dependent fashion.

Antihypertensive effectiveness of very low doses of hydrochlorothiazide: results of the PHICOG Trial.

A large, multicenter, randomized, placebo-controlled, double-blind trial was carried out to determine the effects of the lowest dose of commercially available hydrochlorothiazide. Thus, Dyazide (which contains 25 mg of hydrochlorothiazide and 50 mg of triamterene in an approximately 50% bioavailable form), one capsule, was given daily to patients with either mild or moderate hypertension (supine diastolic blood pressure of 95 to 115 mmHg) for eight weeks. At the end of this eight-week period, supine diastolic blood pressure (SDBP) fell by 11.3 +/- 6.7 mmHg (mean +/- SD) in the Dyazide-treated compared to 4.6 +/- 6.9 mmHg in the placebo-treated group (P less than 0.001). In two thirds of the patients receiving active treatment the fall in SDBP was more than 10 mmHg, and in over half SDBP was completely normalized (ie, SDBP less than 90 mmHg). Supine systolic blood pressure fell by 14.7 +/- 12.3 mmHg in the Dyazide-treated group compared to 5.3 +/- 11.6 mmHg in the placebo-treated group (P less than 0.001). Approximately 80% of the antihypertensive effect occurred within two weeks and after four weeks there was no further significant reduction. Mildly (SDBP = 95 to 104 mmHg) and moderately (SDBP = 105 to 115 mmHg) hypertensive patients responded similarly to treatment. All studied subpopulations responded to treatment with a reduction of SDBP of at least an average of 10 mmHg; the best responders were blacks, women, the elderly (greater than 65 years old), and patients weighing less than 170 lbs. Side effects were mild and infrequent. In conclusion, by examining the effects of Dyazide (one capsule/day), this investigation demonstrated the effectiveness of low-dose hydrochlorothiazide in antihypertensive therapy and quantified it both in the general population and in clinically relevant subpopulations.

The effects of phospholipase A2 inhibition on experimental infarct size, left ventricular hemodynamics and regional myocardial blood flow.

It has been reported that activation of phospholipase A2 and the subsequent degradation of membrane phospholipids are responsible for irreversible myocardial injury. Thus, we examined whether a phospholipase A2 inhibitor 1-(benzylmethyl-amino)-3-[(alpha, alpha, alpha-trifluoro-m-tolyl)oxy]-2- propanol hydrochloride, can reduce myocardial necrosis after coronary artery occlusion. In 14 anesthetized dogs, 1 minute after coronary occlusion, 99mTc-labeled albumin microspheres (8 mCi) were injected into the left atrium for future assessment of the hypoperfused zone. After 15 minutes, the dogs were randomized to a control group (n = 7) and a treated group (n = 7, 2 mg/kg i.v.). After 6 hours, infarct size and hypoperfused zones were measured using triphenyltetrazolium chloride staining and autoradiography, respectively. The hypoperfused zone, as a percentage of the left ventricle, was 26 +/- 3% and 23 +/- 1% in the control and the treated groups (NS), respectively. The percentage of the hypoperfused zone that evolved to necrosis was 98 +/- 4% in the control group and 45 +/- 10% in the treated group (P less than 0.001) showing a reduction of 54%. By weight, in the control group, necrosis involved 26 +/- 4 g of the left ventricle while in the treated group it was 9 +/- 2 g (P less than 0.005). In 6 additional dogs, left ventricular hemodynamics and regional myocardial blood flow were studied before and after treatment i.e., 15 and 30 minutes after coronary occlusion, respectively. Phospholipase A2 inhibitor did not acutely change heart rate, aortic pressure, left ventricular end-diastolic and systolic pressures, left ventricular dP/dt and regional myocardial blood flow. Thus, phospholipase A2 inhibitor salvaged the acutely ischemic myocardium, reducing necrosis by over 50% in the canine model. It is postulated that since this effect was not related to the studied hemodynamic parameters and regional myocardial blood flow, it may be related to the preservation of membrane integrity.

Efficacy of platelet depletion in counteracting the detrimental effect of acute hypercholesterolemia on infarct size and the no-reflow phenomenon in rabbits undergoing coronary artery occlusion-reperfusion.

It has recently been demonstrated that acute hypercholesterolemia per se, independently of its atherogenic effect, increases the extent of myocardial injury in rabbits undergoing coronary artery occlusion-reperfusion. Estimation of myocardial blood flow after reperfusion indicated that this deleterious effect was due to a vascular obstruction that limited the efficacy of reperfusion. The goal of this study was to evaluate the role played by platelets in contributing to the occurrence of this deleterious effect. Accordingly, New Zealand White rabbits were fed a standard laboratory chow diet (plasma cholesterol 67 +/- 12 mg/dl) or a 2% cholesterol-enriched diet for 3 days (plasma cholesterol 329 +/- 70 mg/dl). In a first series of experiments autologous platelets were labeled with 111In-oxine. After labeling, platelets were reinjected in the same animal and 30 min later coronary artery occlusion (CAO) was induced. CAO was maintained for 30 min followed by 5.5 hr of reperfusion. The animals were then killed, their hearts were excised, and each left ventricle was divided into ischemic and normally perfused samples. Myocardial samples were then counted in a gamma counter. Platelet accumulation ratio, i.e., 111In activity in the ischemic myocardium per gram of tissue divided by 111In activity in the normal myocardium per gram of tissue, was calculated. The ratio was 2.4 +/- 0.2 (mean +/- SEM) in controls (n = 7) and 10.3 +/- 1.0 in the cholesterol-fed group (n = 6, p less than .001), indicating that a marked accumulation of platelets occurs in the ischemic myocardium of hypercholesterolemic rabbits. To evaluate the importance of this phenomenon, another series of experiments was performed.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of acute hypercholesterolemia on myocardial infarct size and the no-reflow phenomenon during coronary occlusion-reperfusion.

The goal of this study was to determine the effects of acute hypercholesterolemia on the evolution of myocardial infarction in a preparation of coronary occlusion-reperfusion. New Zealand white rabbits were fed a 2% cholesterol-enriched diet for 3 days (plasma cholesterol 329 +/- 70 mg/dl), or maintained on the control diet (plasma cholesterol 67 +/- 12 mg/dl). Temporary (30 min) coronary artery occlusion was performed in open-chest rabbits with a suture snare. The snare was released to permit reperfusion. When the animals were killed 5.5 hr later, left ventricles were cut into 3 mm slices. Infarct size was determined by planimetry of tetrazolium-stained slices while the area at risk of infarction (hypoperfused zone) was determined by planimetry of the "cold spots" on autoradiograms of the slices that contained 99m Tc-labeled microspheres that had been injected 1 min after occlusion. Infarct size, expressed as percent of the hypoperfused zone, was 42.8 +/- 1.3% (n = 10) in the control group and was increased by approximately 100% in cholesterol-fed animals to 83.7 +/- 2.0% (n = 10, p less than .001). To test the hypothesis that vascular obstruction (no reflow) might account for the larger infarct size, thioflavin S was injected immediately before the animals were killed to demarcate perfused myocardium in three additional groups of animals: standard chow-fed rabbits (n = 5), cholesterol-fed rabbits (n = 5), and standard chow-fed rabbits that, in addition, received an infusion of isoproterenol (0.1 microgram/kg/min, n = 6), an intervention believed to increase infarct size through a mechanism not dependent on the no-reflow phenomenon.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of cytochrome C on the extent of myocardial infarction and regional function of the ischemic myocardium.

The effects of cytochrome C, an electron carrier in the process of oxidative phosphorylation, on infarct size and regional left ventricular function after a coronary artery occlusion were investigated. Thus, in 30 dogs, 1 minute after left anterior descending coronary artery occlusion, 99mTc-labeled albumin microspheres (8 mCi) were injected into the left atrium for subsequent assessment of the hypoperfused zone, that is, the area at risk of infarction. Fifteen minutes after coronary artery occlusion, dogs were randomized into a control group (n = 15) and a cytochrome C-treated group (n = 15). The latter immediately received cytochrome C, 2.5 mg/kg intravenously. Six hours after coronary artery occlusion the dogs were sacrificed and their left ventricles were cut into 3 mm thick slices. Infarct size was determined by triphenyltetrazolium chloride staining and measured by planimetry. The same slices were then submitted to autoradiography and the hypoperfused zone was then measured by planimetry. The hypoperfused zone was 22 +/- 2% and 23 +/- 2% of the left ventricle in the control and treated groups, respectively (NS), indicating that the extent of myocardium at risk before treatment was similar. The extent of the hypoperfused zone which evolved to necrosis was 90 +/- 3% in the control group but only 50 +/- 7% in the treated group (p less than 0.001). Myocardial salvage in the treated group was paralleled by improvement in systolic wall thickness of the ischemic segment as measured by two-dimensional echocardiography. Thus, cytochrome C reduced the extent of myocardial necrosis by 44% and improved systolic function of the ischemic myocardium.

Thoracic epidural anesthesia reduces myocardial infarct size after coronary artery occlusion in dogs.

The effect of thoracic epidural anesthesia (TEA) with lidocaine on regional myocardial blood flow (RMBF), hemodynamic performance, and myocardial infarct size after coronary artery occlusion was assessed in 21 dogs. In seven dogs, the left anterior descending coronary artery (LAD) was temporarily occluded twice: once before TEA (control) and once during TEA. Systemic hemodynamic parameters, RMBF (using radionuclide-labeled microspheres), and epicardial electrocardiographic maps (15 sites) were obtained before and 15 min after each temporary LAD occlusion. Compared with the ischemic period before TEA, the following were decreased during ischemia with TEA: heart rate, ST segment elevation, cardiac index, the peak first time derivative of left ventricular (LV) pressure, LV tension-time index, the rate-pressure product, and LV stroke-work index. Ischemic zone endocardial RMBF was increased from a control value of 26 +/- 6% to 36 +/- 6% of normal during TEA (P less than 0.05). An additional 14 dogs randomly received either TEA (1% lidocaine, 10 ml/hr) or epidural saline plus 1% lidocaine (10 ml/hr, intramuscularly), beginning 1 hr after LAD occlusion. After 6 hr, the heart was removed and the left ventricle was sectioned parallel to the atrioventricular groove. The infarcts (tetrazolium-stained) were 46% smaller with TEA than with saline, 15.4 +/- 1.8% vs 28.7 +/- 2.3% of the left ventricle (P less than 0.05). Thus TEA reduced hemodynamic correlates of myocardial O2 consumption, improved regional (ischemic zone) endocardial perfusion, and reduced the extent of myocardial infarction.

Limitation of myocardial infarct size by metabolic interventions that reduce accumulation of fatty acid metabolites in ischemic myocardium.

The effects on myocardial damage of metabolic interventions by nicotinic acid, oxfenicine, or a combination of the two were assessed in open-chest dogs exposed to coronary artery occlusion for 6 hours. The accumulation of metabolites of free fatty acids (FFAs) was studied in tissue samples of the left ventricle taken 60 minutes after coronary occlusion in separate animals. The percentage of the hypoperfused zone that evolved to infarction was 96 +/- 3% (mean +/- SEM) in control dogs, 74 +/- 4% in dogs treated with nicotinic acid (p less than 0.05 vs control dogs), 72 +/- 2% in dogs treated with oxfenicine (p less than 0.05 vs control dogs), and 54 +/- 5% in dogs with combined nicotinic acid and oxfenicine (p less than 0.05 vs control dogs, p less than 0.05 vs nicotinic acid and oxfenicine). Arterial FFA concentration was markedly reduced in dogs treated with nicotinic acid and those treated with combination nicotinic acid and oxfenicine. The accumulation of long-chain acyl carnitine was substantially reduced in the ischemic myocardium after nicotinic acid, oxfenicine, and a combination of the two, whereas the lowering of long-chain acyl CoA was less pronounced. Thus, nicotinic acid and oxfenicine, which depress myocardial FFA metabolism by different mechanisms, both reduce myocardial infarct size and their effects are additive.

Myocardial protection during transient coronary artery occlusion in man: beneficial effects of regional beta-adrenergic blockade.

The goal of this study was to verify whether myocardial protection could be achieved via the intracoronary administration of propranolol in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). Accordingly, 21 patients undergoing PTCA were randomly assigned to receive either intracoronary placebo (group A, n = 10) or intracoronary propranolol (group B, n = 11). Three balloon inflations (i.e., coronary artery occlusions) were performed in each patient. Inflations I and II (maximum duration 60 sec) served as control occlusions. Inflation III (maximum duration 120 sec) was performed either after intracoronary administration of saline (2 ml) or propranolol (1.1 +/- 0.2 mg). The following electrocardiographic index of myocardial ischemic injury were measured: (1) time to development of ST segment elevation equal to 0.1 mV and (2) magnitude of ST segment elevation after 60 sec of coronary artery occlusion. Both indexes did not differ significantly between the groups during inflations I and II. In group A the time to development of ST segment elevation of 0.1 mV remained unchanged between the second and third occlusions (25 +/- 5 and 26 +/- 4 sec during inflations II and III, respectively). In group B subselective injection of propranolol into the affected coronary artery significantly prolonged the time to ST segment elevation of 0.1 mV from 19 +/- 4 sec (inflation II) to 53 +/- 9 sec (inflation III; p less than .001). Administration of placebo did not change the magnitude of ST segment elevation 60 sec after coronary artery occlusion between the second and third occlusion in group A (0.16 +/- 0.02 and 0.18 +/- 0.03 mV, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Relation of myocardial salvage to size of myocardium at risk in dogs.

Infarct size varies in untreated animals subjected to coronary artery occlusion at the same anatomic site. The relation between the hypoperfused zone and the magnitude of myocardial salvage when different pharmacologic interventions are used remains to be established. Thus, in 95 anesthetized dogs, 1 minute after left anterior descending coronary occlusion, technetium-99m-labeled albumin microspheres (8 mCi) were injected into left atrium for the assessment of the hypoperfused zone. Fifteen minutes after coronary occlusion 42 dogs were randomized into a control group and 53 into a treated group. In the treated group, 6 dogs received nifedipine, 0.35 micrograms/kg followed by 2.4 micrograms/kg/hour; 7 received diltiazem, 0.2 mg/kg followed by 0.9 mg/kg/hour; 13 received bepridil, 2.5 mg/kg; 9 received cytochrome C, 2.5 mg/kg; 8 received rutosides, 200 mg/kg; and 10 received nifedipine plus cytochrome C. All drugs were administered intravenously. At 6 hours the dogs were killed and their hearts were cut into 3-mm-thick slices. Infarct size was determined by triphenyltetrazolium chloride staining; the hypoperfused zone was delineated by autoradiography. The dogs were retrospectively subgrouped as follows: those with small hypoperfused zones, i.e., less than 15% of the left ventricle (controls n = 8, treated n = 7) and those with large hypoperfused zones, i.e., more than 15% of the left ventricle (controls n = 34, treated n = 46). In dogs with large hypoperfused zones, treatment salvaged 42 +/- 3% of the myocardium destined to undergo necrosis, whereas in those with small hypoperfused zones 78 +/- 10% of myocardium was salvaged (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative effects of dobutamine and corwin, a beta 1-adrenergic partial agonist, in experimental left ventricular failure.

Corwin is a new, long-acting beta 1-adrenergic partial agonist for oral and intravenous (i.v.) use. The effects of corwin were compared with those of dobutamine in acute ischemic left ventricular failure in dogs. Failure was produced by embolization of the left main coronary artery with 50 micron plastic microspheres. This induced severe depression in left ventricular function, as evidenced by a marked increase in left ventricular end-diastolic pressure, reduction in left ventricular dP/dtmax, and cardiac output. After 45 min was allowed for stabilization, the 27 dogs were randomly assigned to three groups: control (n = 9), dobutamine-treated (5-10 micrograms/kg/min i.v., n = 9), and corwin-treated (0.025-0.10 mg/kg i.v., n = 9). The doses of dobutamine and corwin were adjusted to give an increase in left ventricular dP/dtmax of 50%. Both drugs similarly increased cardiac output (p less than 0.01), lowered left ventricular end-diastolic pressure (p less than 0.01) and total peripheral vascular resistance (p less than 0.01), but did not affect the heart rate. Only dobutamine increased the mean arterial pressure (p less than 0.01). Both drugs also increased the arterial concentrations and myocardial uptake of fatty acids (p less than 0.05) but caused only a small and nonsignificant increase in myocardial oxygen consumption. Our findings indicate that the hemodynamic and metabolic profiles of corwin and dobutamine are similar, and both drugs should be of special value in the treatment of congestive heart failure. Since corwin can be given orally and has a longer duration of action, it is potentially useful in the long-term treatment of heart failure.

Myocardial protection via coronary sinus interventions: superior effects of arterialization compared with intermittent occlusion.

It has been reported that infarct size can be reduced by several interventions, by which arterial blood is delivered retrogradely to the ischemic myocardium through the cardiac veins or alternatively the cardiac venous system is intermittently occluded. Accordingly, we studied several modalities of myocardial protection that used the cardiac venous system and compared them by means of a quantitative technique for measuring infarct size. Thus 73 anesthetized dogs with coronary arterial occlusion were randomized into the following groups: group I (n = 9), 6 hr of occlusion without any intervention; group II (n = 11), venovenous shunt (60 ml/min) to the great cardiac vein; group III (n = 11), arteriovenous shunt to the anterior interventricular vein; group IV (n = 12), high flow arteriovenous shunt to the anterior interventricular vein (60 ml/min); group V (n = 11), arteriovenous shunt to the great cardiac vein (60 ml/min); group VI (n = 10), arteriovenous shunt to the great cardiac vein (60 ml/min) combined with diastolic occlusion of the great cardiac vein; group VII (n = 9), intermittent pressure-controlled occlusion of the great cardiac vein without arterialization. The arteriovenous shunt (groups III to VI) or venovenous shunt (group II) was done by selective catheterization of the anterior interventricular vein or the great cardiac vein, advancing a catheter from the jugular vein through the right atrium and coronary sinus under fluoroscopic control. This catheter was then connected to a cannula located either in the carotid artery (groups III to VI) or in the right atrium (group II). One minute after occlusion, 99mTc-labeled albumin microspheres (8 mCi) were injected into the left atrium for the subsequent assessment of the hypoperfused zone, which is the area at risk for infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional myocardial lidocaine concentration determines the antidysrhythmic effect in dogs after coronary artery occlusion.

Ischemic ventricular dysrhythmias were produced in 40 of 47 anesthetized mongrel dogs by high ligation of the left anterior descending coronary artery. Dysrhythmias were treated with a single iv bolus of 20, 40, 80, or 120 mg of lidocaine (L) in order to determine the dose at which approximately 50% of animals had an antidysrhythmic response. Cardiac output and regional myocardial blood flow (RMBF) were measured by using radionuclide labeled microspheres. Lidocaine concentration [( L]) was measured from samples of arterial and venous blood and normal and ischemic myocardium. All dogs treated with 40, 80, or 120 mg of L had an antidysrhythmic effect. However, with 20 mg of L the dysrhythmia persisted in 12 and resolved in 14. With 20 mg of L, ischemic myocardial [L] was greater in dogs with an antidysrhythmic effect than in those with persistent dysrhythmias (1.14 +/- 0.12 vs. 0.76 +/- 0.04 micrograms X g-1), but no difference was seen for arterial, venous, and normal myocardial [L]. Ischemic RMBF was higher in the dogs that had an antidysrhythmic effect than in those that did not, 9.8 +/- 1.5 versus 6.9 +/- 1.3% of normal. With 20 mg of L, [L] in ischemic myocardium correlated well with ischemic RMBF. The antidysrhythmic response to L had a threshold at a tissue concentration of greater than or equal to 1.0 microgram X g-1 (chi-square = 8.55, P less than 0.005). For this model, the [L] in ischemic myocardium during acute ischemia correlates with the antidysrhythmic response to L, while the concentration in normal myocardium or blood does not.

Comparative effects of propranolol, timolol and metoprolol on myocardial infarct size after experimental coronary artery occlusion.

The effects of equiblocking doses of three beta-adrenergic blocking agents, propranolol, timolol and metoprolol, on myocardial infarct size were evaluated in 28 dogs after acute experimental coronary artery occlusion. Heart rate, arterial pressure and arterial free fatty acid concentration were measured in an attempt to evaluate their effects on the extent of myocardial injury. The zone at risk of infarction in each dog 1 minute after left anterior coronary artery occlusion was assessed by injecting highly radioactive albumin microspheres into the left atrium, and the hypoperfused zone was determined by autoradiography. After 15 minutes, the dogs were randomized into four groups: control dogs (n = 7), propranolol-treated dogs (1.2 mg/kg intravenously, n = 7), timolol-treated dogs (0.2 mg/kg intravenously, n = 7) and metoprolol-treated dogs (1.2 mg/kg intravenously, n = 7). After 6 hours, the dogs were killed. The left ventricle was sliced and stained with triphenyl-tetrazolium chloride for measurement on infarct size. The same slices were then autoradiographed for measurement of the hypoperfused zone. The percent of hypoperfused zone that evolved to infarction (the ratio of infarct size to hypoperfused zone) was 90.4 +/- 1.9% in the control group, 72.4 +/- 2.4% in the propranolol-treated dogs (p less than 0.05 versus control group); 57.9 +/- 4.4% in the timolol-treated dogs (p less than 0.01 versus control group; p less than 0.05 versus propranolol) and 54.4 +/- 3.7% in the metoprolol-treated dogs (p less than 0.01 versus control group; p less than 0.05 versus propranolol). Thus, propranolol, timolol and metoprolol reduced myocardial infarct size in dogs by 20, 36 and 40%, respectively, after experimental coronary artery occlusion. Metoprolol and timolol protected the ischemic myocardium more effectively than did propranolol.

The effect of halothane anesthesia on myocardial necrosis, hemodynamic performance, and regional myocardial blood flow in dogs following coronary artery occlusion.

The effect of halothane anesthesia on myocardial necrosis resulting from coronary artery ligation was examined in 28 anesthetized mongrel dogs. In 18 dogs, the left anterior descending coronary artery (LAD) was ligated immediately proximal to the first apical diagonal branch, and 1 h later the dogs were assigned randomly either to receive halothane, 0.5-1.0% inspired in room air for 12 h (n = 10) or to awaken without further intervention (control, n = 8). Infarct size was measured by staining the myocardium with triphenyl tetrazolium chloride 24 h after LAD ligation. Infarct size in halothane-treated dogs was 17.8 +/- 2.0% of the left ventricle, compared with 27.3 +/- 3.3% in control dogs (P less than 0.05). Myocardial salvage was present transmurally but was greatest in epicardial regions. In 10 additional dogs, hemodynamic variables (heart rate, arterial pressure, left ventricular end-diastolic pressure, peak left ventricular dP/dt, tension-time index, and rate-pressure product) were measured or calculated, and radionuclide-labeled microspheres were injected for measurement of cardiac output and regional myocardial blood flow (RMBF). Thirty minutes after LAD ligation and after initial hemodynamic measurements and microsphere injection, these dogs were assigned randomly to receive either halothane, 1.0%, inspired in room air (n = 5) or no intervention (control, n = 5). After 15 min of halothane inhalation (45 min after LAD ligation in control dogs), measurements were repeated. Halothane inhalation reduced heart rate, arterial pressure, and indexes of left ventricular contractile and pump performance. During halothane treatment, RMBF declined in normal myocardium but not in ischemic regions, while neither normal nor ischemic zone RMBF changed in control dogs. Systemic vascular resistance was unchanged in either group. Thus, halothane was associated with a 35% smaller myocardial infarct, transmural myocardial salvage, reduced heart rate, reduced left ventricular contractile and pump performance, reduced RMBF to nonischemic regions, and unchanged RMBF in the ischemic myocardium.

Dissociation of the site of origin from the site of cryo-termination of ventricular tachycardia.

We performed conventional electrogram mapping and cryomapping in dogs with one-week-old experimentally-induced myocardial infarctions and programmed stimulation-induced sustained ventricular tachycardias to assess whether there is a correlation between the "site of origin" and site of cryo-termination of ventricular tachycardia (VT). Electrogram maps showed that 4 of 8 induced sustained VTs were due to macro- and 4 of 8 to microre-entry. Local cooling of the site of origin terminated 4 of 4 microre-entrant VTs, but only 1 of 4 macrore-entrant VTs. In the other 3 macrore-entrant VTs, the sites of cryo-termination were 2, 2.5, and 4 cm distant from the sites of origin. In contrast, cooling of the mid-to-late diastolic portions of the re-entry loops terminated all 8 VTs. These data demonstrate a dissociation of the site of origin from the site of cryo-termination of macrore-entrant VT.