Lair G.T. Ribeiro

Increased survival in rats with congestive heart failure treated with enalapril.

Summary: Vasodilating drugs such as angiotensin converting enzyme (ACE) inhibitors may extend life expectancy in patients with congestive heart failure (CHF). The purpose of this study was to evaluate whether long-term therapy (365 days) with enalapril (ENAL, an ACE inhibitor), would prolong life in rats with a healed myocardial infarction (MI), an experimental model with hemodynamic characteristics of CHF. Seven days after sham or coronary ligation, when the healing phase of MI was well underway. 132 rats (75 sham. 57 Ml) were randomized to receive either enalapril in the drinking water (17–25 mg/L, approximately 1.0 mg/kg/day) or tap water. The date of spontaneous death was recorded, and heart weight and MI size (by planimetry) were determined. Serum ENAL. total ACE concentration, and angiotensin and methoxamine pressor responses were quantified in 12 survivors. Long-term enalapril prolonged survival (p = 0.014) with a median 50% survival of 164 (164–165) days, compared to 84 (64–104) days in rats receiving tap water. There were twice as many MI rats alive at the end of one year on angiotensin converting enzyme inhibition (ACEI) therapy as compared to the untreated group. The average MI size (39–40%) was not different between groups, and there was a significant inverse correlation between date of death and MI size (r = 0.7–0.8) in both treatment groups. Cardiac hypertrophy was evident in all MI rats. Serum ENAL levels, after one year, were at the clinically relevant concentration (2.3 ng/ml) and total serum ACE (inhibitor removed) doubled to 4,300 nmol/h/ ml. The depressor response to bradykinin was enhanced, and the ratio of the pressor responses to angiotensin I/an-giotensin II were reduced, reflecting chronic ACE inhibition. This study demonstrates that long-term ACEI therapy prolongs survival in rats with chronic congestive heart failure

Relationship between the extent of the hypoperfused zone of the myocardium and the occurrence of ventricular fibrillation

Ventricular fibrillation and subsequent death frequently occur so soon after coronary artery occlusion that infarct size cannot be determined; thus the systematic study of their relationship is impossible. Recently, however, a technique has been developed that permits the assessment, in vivo, of the extent of the myocardial hypoperfused zone (HZ). Accordingly, in 55 open-chest dogs, 99mTc-labeled (8 mCi) albumin microspheres (15 microns in diameter) were injected into the left atrium 1 minute after coronary artery occlusion. The zone of hypoperfusion was analyzed in 28 dogs that had ventricular fibrillation (group A) and 27 dogs that had no ventricular fibrillation (group B). In group B, the HZ was 26.3 +/- 1.7% of the left ventricle vs 31.6 +/- 1.3% of the left ventricle in group A (p less than 0.05), showing that ventricular fibrillation occurred in dogs with larger zones of hypoperfusion.

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.

Early augmentation of R wave voltage after coronary artery occlusion: A useful index of myocardial injury

Summary The goal of this investigation was to determine whether increases in R wave voltage shortly after coronary artery occlusion can be used to assess the severity of myocardial ischemic injury. Accordingly, the left anterior descending coronary artery was occluded in 16 open-chest, anesthetized dogs. Epicardial electrograms were recorded from 8–12 sites on the anterior surface of the left ventricle before and 15 minutes after coronary artery occlusion. Regional myocardial blood flow was determined 15 minutes after occlusion (RMBF 15min ) by the microsphere technique. After 24 hours, the dogs were sacrificed, the hearts excised, and 6–8 transmural specimens obtained for determination of RMBF 15min and creatine kinase activity (CK 24h ). In all dogs, the increase in R wave voltage from before to 15 min after occlusion (ΔR 15min ) correlated well with RMBF 15min [ΔR 15min (mV)=17.0–0.2 RMBF (% normal): n=79 specimens from 16 dogs, r=−0.79]. Twenty minutes after coronary artery occlusion, the dogs were randomized to untreated and hyaluronidase-treated groups. To establish the predictive value of ΔR 15min on myocardial necrosis, the relationship between ΔR 15min in the ischemic sites and CK 24h was evaluated in the untreated group (8 dogs). It was: [CK 24h (IU/mg prot) = 19.3−0.54 ΔR 15min (mV); n=30 specimens from 8 dogs, r=−0.75]. In the hyaluronidase-treated group (which received 500 N.F. units/kg intravenously as a bolus 20 min after occlusion) the same degree of increase in R wave voltage 15 minutes after occlusion (and, therefore, prior to hyaluronidase administration) resulted in less CK depression 24 hours later (p

Effects of lidocaine and droxicainide on myocardial necrosis: A comparative study

Lidocaine has been shown to protect ischemic myocardium, but the degree of its effectiveness is not yet well established. Therefore, in this study, the effects of this drug on ultimate infarct size were examined quantitatively. Another member of the same class of drugs, droxicainide (ALS1249), DL-N-(2-hydroxyethyl)-pipecolinyl-2,6-dimethylanilide hydrochloride, is a new antiarrhythmic agent that has shown a good therapeutic index in the initial experimental studies. Accordingly, the effects of this drug on ultimate infarct size were examined and compared with those of lidocaine. Coronary artery occlusion was performed on 29 dogs. One minute later, technetium-99m labeled microspheres were injected into the left atrium for assessment of the hypoperfused zone (the zone at risk of infarction). Fifteen minutes after occlusion, the dogs were randomized into three groups: 9 dogs served as a control group, 10 were given lidocaine and 10 were given the same dosage of droxicainide. Six hours after occlusion, the dogs were sacrificed and the hearts cut into 3 mm thick slices and incubated in triphenyltetrazolium chloride to delineate the area of myocardial damage. Autoradiography of the same slices provided images of the areas of myocardial hypoperfusion. Thereafter, in each dog, the percent of hypoperfused area that evolved to necrosis was calculated. In control dogs, it was 85.6 +/- 2.0%; in lidocaine-treated dogs, 68.1 +/- 4.1% (p less than 0.01), a reduction of 20%; and in droxicainide-treated dogs, 50.1 +/- 5.3%, a reduction of 41% (p less than 0.001 versus control and p less than 0.005 versus lidocaine).

Comparative effects of dobutamine and corwin, a β1-adrenergic partial agonist, in experimental left ventricular failure

Corwin is a new, long-acting β1-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 μm 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 μg/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 < 0.01), lowered left ventricular end-diastolic pressure (p < 0.01) and total peripheral vascular resistance (p < 0.01), but did not affect the heart rate. Only dobutamine increased the mean arterial pressure (p < 0.01). Both drugs also increased the arterial concentrations and myocardial uptake of fatty acids (p < 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.

Importance of the source of hyaluronidase preparations in determining protective effect on ischemic heart muscle in acute myocardial infarction

Using a very sensitive new technique, the effectiveness of hyaluronidase (HYL) in reducing infarct size (IS) was compared employing HYL obtained from bovine testicles and from fungi. One minute after coronary artery occlusion in dogs, highly radioactive microspheres were injected for autoradiographic assessment. The animals were then randomized into a control group and several HYL-treated groups. Six hours later all hearts were divided into 20 to 25, 3 mm-thick slices which were incubated in TTC to measure IS and thereafter autoradiographed to delineate the hypoperfused zone (HZ). The percent of HZ that evolved to necrosis (IS/HZ) was determined in each animal. In the control group, IS/HZ was 89.9 +/- 4.2% and was reduced by 17% (p less than 0.05) in the group treated with 500 units/kg of bovine HYL. With 500 units/kg of fungal HYL, IS/HZ was not reduced, but the higher dose of 5000 units/kg reduced IS/HZ by 26% (p less than 0.01). Thus dependence of HYL source is documented relative to the effectiveness of this salutary intervention for protecting ischemic heart muscle and limiting necrosis in acute myocardial infarction.

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 μg · 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 μg · g−1 (chisquare = 8.55, P < 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.