Effects of metoprolol, alone and in combination with lidocaine, on ventricular fibrillation threshold: comparison with atenolol, propranolol, and pindolol

Metoprolol and other beta-adrenergic blocking drugs are known to exert cardioprotective effects that include significant reduction in occurrence of ventricular fibrillation (VF) following myocardial ischemia and infarction. To help determine the mechanism of these cardioprotective effects, this study evaluated the effect of equipotent beta-blocking doses of metoprolol and three other beta-blockers with differing ancillary properties on ventricular fibrillation threshold (VFT) in the normal canine heart. Metoprolol tartrate (1.0 mg/kg i.v.), atenolol (0.3 mg/kg i.v.), propranolol hydrochloride (0.3 mg/kg i.v.), pindolol (0.03 mg/kg i.v.), or saline control (0.9% NaCl solution; vehicle) was given, alone and in combination with lidocaine (L), to groups of six pentobarbital (32.5 mg/kg i.v.) anesthetized mongrel dogs after control VFT and control isoproterenol-induced (ISO) positive chronotropic effects had been determined. The D- (membrane stabilizing, non-beta blocking) and L- (beta blocking) isomers of propranolol also were administered to separate groups of six anesthetized dogs in a dose of 0.3 mg/kg i.v. Blood samples (venous) were taken before drug or vehicle administration, 10 min after drug/vehicle administration and at half-hour intervals thereafter during experimentation. ISO responses and VFT were determined 5 and 15 min, respectively, after drug/vehicle administration and at half-hour intervals for a total experimental period of 165 min. VF was induced with a train of pulses (5 s, 100 Hz, 3-ms duration, 250-omega resistance) applied by bipolar platinum electrodes to a paced heart (200 beats/min). Voltage (V) was increased every 60 sec (0.25-V increments between 0-3.5 V and 0.5-V increments greater than 3.5 V) until VF occurred. Metoprolol increased VFT significantly (p less than 0.05) and maximally (max delta V = 2.3 +/- 0.7 V) at 135 min postdrug when the ISO-induced increase in heart rate was inhibited (%I ISO) by less than 53%. Max delta V was not significantly increased following i.v. administration of atenolol (0.8 +/- 0.6 V), pindolol (0.1 +/- 0.1 V), or saline (0.1 +/- 0.1 V). Max delta V was 0.5 +/- 0.2 in the D-propranolol-treated group and 0.5 +/- 0.3 in the L-propranolol-treated group. These values did not differ from max delta V obtained in the propranolol-treated group (0.6 +/- 0.4 V). Changes in VFT for all groups were, over time, negatively correlated with %I ISO and were not dependent on membrane stabilizing effect (metoprolol, propranolol (D,DL), pindolol), intrinsic sympathomimetic activity (pindolol), or cardioselectivity (metoprolol, atenolol).(ABSTRACT TRUNCATED AT 400 WORDS)     

Relationship between an arrhythmogenic action of lidocaine and its effects on excitation patterns in acutely ischemic porcine myocardium

To investigate the relationship between the effects of lidocaine on excitation patterns and its effects on the incidence of arrhythmias, the left anterior descending coronary artery was occluded for 6-min periods separated by 30 min of reperfusion, under control conditions and after injection of lidocaine, at a dose of either 2.5, 5.0, or 10.0 mg/kg i.v., in 29 open-chest anesthetized pigs. Sixty-three unipolar electrograms and a surface lead electrocardiogram were continuously recorded during atrial pacing and spontaneous ventricular arrhythmias. Ventricular fibrillation (VF) occurred only in four of a total of 45 control occlusions. VF occurred in two of five pigs following injection of lidocaine 2.5 mg/kg, in 15 or 17 pigs following injection of a 5 mg/kg dose, and in all three preparations following injection of a 10 mg/kg dose. Just prior to VF during occlusions preceded by injections of lidocaine 5 mg/kg, activation time of ischemic myocardium in atrial-paced beats was delayed by only 30 +/- 17 ms beyond preocclusion values, compared with 18 +/- 11 ms at a similar time during control occlusions and 33 +/- 18 ms at the end of control occlusions (mean +/- SD; n = 8). As ventricular tachycardia (VT) developed in the presence of lidocaine, conduction was further slowed or blocked in ischemic areas, and slowed in nonischemic regions; at the transition from VT to VF, excitation patterns displayed circus movement involving nonischemic regions.     

The influence of vitamin K3 treatment on the pharmacokinetics and metabolism of (+)-propranolol in the rat.

The effects of vitamin K3 treatment on the pharmacokinetics and metabolism of (+)-propranolol and the consequences of hepatic injury associated with vitamin K3 treatment were examined in groups of male Sprague-Dawley rats. When vitamin K3 (20 mg/kg) in polyethylene glycol 300 (PEG 300) was coinfused with (+)-propranolol (2 mg/kg) into the pyloric vein (a tributary flowing directly into the hepatic portal vein), a significant decrease in the intrinsic clearance of total drug (CLint) from 94.1 +/- 50.1 to 32.9 +/- 11.5 ml/min/kg was observed (p less than 0.01 vs. vehicle control). However, a lower dose of vitamin K3 (2 mg/kg in PEG 300) had little effect on this parameter. Interestingly, the PEG 300 vehicle control group exhibited a significantly (p less than 0.05) higher CLint than that observed in a saline control group (94.1 +/- 50.1 vs. 45.9 +/- 13.7 ml/min/kg). This difference appeared to be due to an increase in the free fraction of propranolol caused by PEG 300, because in vitro addition of this solvent to serum (at estimated in vivo concentrations) with or without added vitamin K3 doubled propranolol free fraction. Furthermore, rats that received the high dose vitamin K3 (20 mg/kg) treatment exhibited a pronounced increase in the serum concentration of enzymes of hepatic origin (alanine aminotransferase and sorbitol dehydrogenase) and in the incidence of hepatic necrosis. It was also observed that high-dose vitamin K3 treatment caused only minor changes in the urinary recovery of propranolol metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of cariporide (HOE642) on myocardial infarct size and ventricular arrhythmias in a rat ischemia/reperfusion model: comparison with other drugs

The effects of pretreatment with cariporide on myocardial infarction and ventricular arrhythmias in a rat model of ischemia/reperfusion were compared with those of nicorandil, propranolol, and nifedipine. Each drug was administered intravenously before coronary occlusion. Cariporide at 0.1, 0.3, and 1 mg/kg significantly reduced the infarct size (infarct mass/risk mass) from 28 +/- 4% (vehicle control value) to 9 +/- 3, 9 +/- 3, and 5 +/- 2%, respectively. Propranolol at 2.5 mg/kg also significantly reduced the infarct size to 11 +/- 1%. Neither nicorandil nor nifedipine was effective when given at 0.1 mg/kg. Cariporide dose dependently decreased the number of ischemia-induced ventricular premature beats (VPB), incidence and duration of ventricular tachycardia, and the number of reperfusion-induced VPB. Nicorandil was effective against only VPB after reperfusion, and propranolol reduced only postischemic arrhythmias, but nifedipine had no effect on either type of arrhythmia. In summary, cariporide reduced the infarct size and dose dependently suppressed arrhythmias induced by ischemia/reperfusion in rats. In contrast, in the present rat model, the doses of the other three drugs used in this study did not show comparable effects.     

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

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

CK-2289 and milrinone in dogs with propranolol-induced heart failure: Effect of ouabain

We examined the interaction between ouabain and CK-2289, a new bivalent inodilator, and compared their effect with that of milrinone on the hemodynamic and myocardial energetic parameters of anesthetized dogs with propranolol-induced heart failure (PIHF). Mongrel dogs (13–19 kg) of either sex were anesthetized with pentobarbital sodium (35 mg/kg, i. v.) and instrumented for routine hemodynamic measurements using an open-chest, artificially ventilated preparation. PIHF was produced by decreasing left ventricular (LV) dP/dT_max by 50% from control values with an initial infusion of 0.5 mg/kg of propranolol followed by continuous infusion of 0.02 to 0.08 mg/kg of propranolol to maintain PIHF. This was followed by infusion of saline (2 ml, i. v., n = 12/group) or ouabain (25 μg/kg, i. v., n = 12/group). Thirty min later saline and ouabain-treated animals (4/group) were given 2 doses of saline (1 and 2 ml, i. v.), CK-2289 (0.01 and 0.03 mg/kg, i. v.) or milrinone (0.03 and 0.1 mg/kg, i. v.) 30 min apart. Hemodynamic parameters were monitored continuously. Myocardial oxygen consumption (MVO₂) was monitored 15 and 30 min after each dose of drug. CK-2289 increased LV dP/dT_max and LV dP/dT_min by 60 and 120% and 42 and 43%, respectively. Mean arterial pressure decreased by 12% after the high dose of CK-2289. CK-2289 did not affect heart rate, while LV end diastolic pressure decreased by 5 mmHg. CK-2289 increased LV work and did not affect or decrease LV contractile efficiency. Ouabain enhanced the myocardial energetic profile of CK-2289 by allowing CK-2289 to stimulate more work at a lower MVO₂, thereby increasing myocardial efficiency. Milrinone had a profile similar to CK-2289 but in ouabain-pretreated animals with PIHF milrinone stimulated less work at the same MVO₂, thus decreasing contractile efficiency. Thus, ouabain may enhance the myocardial energetic effects of CK-2289.     

Effect of glucagon-like peptide-1(7-36) and exendin-4 on the vascular reactivity in streptozotocin/nicotinamide-induced diabetic rats

We investigated the vascular effects of glucagon-like peptide-1 (GLP-1) and Exendin-4 in type 2 diabetic rat aortae. Studies were performed in a normal control group (NC) (0.2 ml i.p. saline, n = 10), streptozotocin (STZ)/nicotinamide diabetic control group (DC) (a single dose of 80 mg/kg STZ i.p. injection 15 min after administration of 230 mg/kg nicotinamide i.p.), GLP-1 (GLPC) control group (1 microg/kg twice daily i.p. for 1 month, n = 10), Exendin-4 control group (EXC) (0.1 microg/kg twice daily i.p. for 1 month, n = 10), GLP-1-treated diabetic group (GLPT) (1 microg/kg twice daily i.p. for 1 month, n = 10), and Exendin-4-treated diabetic group (EXT) (0.1 microg/kg twice daily i.p. for 1 month, n = 10). One month of GLP-1 and Exendin-4 treatment significantly decreased the blood glucose levels of diabetic rats (113 +/- 2 mg/dl, p < 0.001, and 117 +/- 1 mg/dl, p < 0.001, respectively versus 181 +/- 9 mg/dl in the DC group). Sensitivity (pD2) and maximum response (% Max. Relax) of acetylcholine-stimulated relaxations in the DC group (pD2: 6.73 +/- 0.12 and 55 +/- 6, respectively) were decreased compared with the non-diabetic NC group (pD2: 7.41 +/- 0.25, p < 0.05, and 87 +/- 4, p < 0.01). Treating diabetic rats with GLP-1, pD2 values and with Exendin-4, Max. Relax %values of aortic strips to acetylcholine returned to near non-diabetic NC values (pD2: 7.47 +/- 0.15, p < 0.05, and 87 +/- 3, p < 0.01, respectively). Maximal contractile responses (Emax) to noradrenaline in aortic strips from the diabetic DC group (341 +/- 27 mg tension/mg wet weight) were significantly decreased compared with the non-diabetic NC (540 +/- 66 mg tension/mg wet weight, p < 0.001) and the GLPT group (490 +/- 25 mg tension/mg wet weight, p < 0.05). There were no significant differences in pD2 values of aortic strips to noradrenaline from all groups. Emax to KCl in aortic strips from the DC group (247 +/- 10 mg tension/mg wet weight, p < 0.01) was significantly decreased compared with non-diabetic NC group (327 +/- 26 mg tension/mg wet weight). Treating diabetic rats with GLP-1 (GLPT), Emax values of aortic strips to KCl returned to near non-diabetic NC values (271 +/- 12 mg tension/mg wet weight). GLP-1 and (partially) Exendin-4 treatment could improve the increased blood glucose level and normalize the altered vascular tone in type 2 diabetic rats.     

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

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

Intravenous aspirin at reperfusion does not reduce infarct size in the dog with a residual critical stenosis.

Platelet-related events being associated with the increment of infarct size at reperfusion in the presence of a residual stenosis, we tested in dogs whether intravenous aspirin (ASA) could limit infarct size. The left anterior descending coronary artery was occluded for 90 min and reperfused for 6 h in the presence of a residual critical stenosis. Controls received saline, and treated groups were given 2, 6, or 12 mg/kg ASA, i.v., 5 min before reperfusion. Infarct size did not differ significantly between groups (control, 43.80+/-6.28%; ASA, 2 mg/kg: 41.07+/-7.78%; ASA, 6 mg/kg: 37.55+/-3.44%; ASA, 12 mg/kg: 29.40+/-5.41%), as well as transmural collateral blood flow and [111In]-platelet accumulation in the infarcted myocardium (2.5-3.6 x 10(5) platelets/g). However, myocardial neutrophil accumulation was significantly reduced (p < 0.05) in groups given 6 (15.0+/-2.6 x 10(6)/g tissue) and 12 mg/kg (18.4 +/-3.8) ASA, but not in the 2-mg/kg group (21.0+/-5.2), as compared with control group (32.0+/-7.2). Ex vivo platelet aggregation to collagen was abolished during reperfusion in all treated groups (p < 0.05). Transcardiac arteriovenous differences in 6-keto-PGF1alpha were reduced significantly 1 h after reperfusion in groups given 6 or 12 mg/kg ASA (94.7+/-13.1 and 71.7+/-19.2 pg/ml, respectively) but not in the 2-mg/kg group (178.3+/-78.2 pg/ml), as compared with control (405.4+/-171.6 pg/ml). ASA-insensitive platelet activation at the site of stenosis or inhibition by ASA of prostacyclin production by jeopardized myocardium may explain the observed lack of benefit of ASA.     

Effect of beta-adrenergic receptor antagonism on chloralose-induced hemodynamic changes in newborn lambs.

alpha-Chloralose is an anesthetic commonly used in cardiovascular research. Using a chronically instrumented neonatal lamb model, we previously determined that chloralose has important effects on basal hemodynamics and arterial oxygen tension as compared with those of paired conscious control lambs. We wished to determine whether beta-adrenergic receptor stimulation accounted for chloralose-induced hemodynamic effects and to investigate the influence of chloralose and beta-adrenergic receptor antagonism on oxygen metabolism. In paired studies, five lambs were given chloralose intravenously (30 mg/kg i.v.) after propranolol (1 mg/kg i.v.) or saline control. The group pretreated with propranolol had reduced heart rate (HR 206 +/- 12 vs. 244 +/- 10 beats/min, p = 0.04) and cardiac output (CO 253 +/- 29 vs. 302 +/- 40 ml/min/kg, p = 0.005) 30 min after chloralose as compared with control; pretreatment with propranolol also attenuated the systemic hypertensive response to chloralose (77 +/- 8 vs. 89 +/- 5 mm Hg, p = 0.055). No difference in the response of stroke volume (SV), atrial or pulmonary arterial pressures, or pulmonary and systemic vascular resistances (PVR, SVR) were observed between treatment groups. No differences between propranolol and saline treatment groups were observed in arterial and mixed venous oxygen contents, arteriovenous (A-V) oxygen difference, oxygen extraction, or oxygen consumption; a reduction in oxygen delivery observed after propranolol as compared with saline was not altered by chloralose. We conclude that tachycardia and increase in CO induced by chloralose in lambs probably are mediated by beta-adrenergic receptor stimulation, which may be direct or indirect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ouabain pretreatment does not compromise the hemodynamic and myocardial energetic effects of CK-3197, a selective positive inotropic agent,in dogs with propranolol-induced heart failure

We examined the interaction between ouabain and CK-3197, a new selective positive inotrope, on the hemodynamic and myocardial energetic parameters of anesthetized dogs with propranolol-induced heart failure (PIHF). Mongrel dogs (13–18kg) of either sex were anesthetized with pentobarbital sodium (35mg/kg, i.v.) and instrumented for routine hemodynamic measurements using an open-chest, artificially ventilated preparation. PIHF was produced by decreasing left ventricular (LV) dp/dt max by 50% from control values with an intial infusion of 0.5 mg/kg of propranolol followed by continuous infusion of 0.02 to 0.08 mg/kg of propranolol to maintain PIHF. This was followed by infusion of saline (2ml, i.v., n=8/group) or ouabain (25 μ/kg, i. v., n=8/group). Thirty minutes later one-half of the saline and ouabain treated animals (Groups I and II;n =4/group) were given two increasing doses of saline or CK-3197 (0.1 and 0.3 mg/kg, i. v.; n= Groups III and IV; n =4/group) 30 min apart. Hemodynamic paramters were monitored continuously, while myocardial oxygen consumption (MVO₂) was monitored 15 and 30 min after each dose of drug. CK-3197 increased LV DP/dT_max and LV dP/dT_min by 41 and 78%, respectively. Mean arterial pressure increased by 16 and 6%. Heart rate decreased by 6 and 8%, while LV end diastolic pressure (LVEDP) decreased by 3mmHg after CK-3197 (0.3 mg/Kg, i.v.). CK-3197 increased LV work and LV contractile efficiency. Ouabain did not affect the hemodynamic and myocardial energetic profile of CK-3197. These data support the conclusions that CK-3197 is a selective positive inotrope which increases myocardial contractile efficiency in the dog with PIHF without any significant interaction with ouabain.     

Effect of long-term oral nisoldipine on infarct size and collateral development in pigs undergoing gradual occlusion of the left circumflex artery.

We examined the effects of nisoldipine on infarct size and collateral development in pigs, whose coronary circulation is similar to that of humans, using an experimental protocol reproducing as closely as possible the usual clinical setting. Fifteen pigs undergoing left circumflex Ameroid-occlusion were randomized into a control group (n = 8) and a group (n = 7) treated with oral nisoldipine 0.03 mg/kg every 6 h for 1 month starting on the second postoperative day. Infarct size (tetrazolium red) was 37.2 +/- 9.2% of the circumflex distribution in the control group and 10 +/- 3.2% in the treated group (p less than 0.01). Endocardial and transmural blood flows (microspheres) in the circumflex distribution were significantly higher (p less than 0.05) in the treated group (control endocardial 1.25 +/- 0.1 mg/g/min, treated endocardial 1.77 +/- 0.26 ml/g/min; control transmural 1.39 +/- 0.08 ml/g/min; treated transmural 1.78 +/- 0.23 ml/g/min). Epicardial flow and the ratio of subendocardial to subepicardial blood flow (endo/epi) were nonsignificantly higher in treated pigs. No differences were observed in heart rate (HR) and aortic pressure (AP). We conclude that in pigs undergoing left circumflex Ameroid-occlusion, long-term oral nisoldipine reduces infarct size and enhances collateral circulation to the ischemic myocardium.     

Effects of lignocaine and propranolol on experimental cardiac arrhythmias

1. The effects of intravenous injection of lignocaine and propranolol were studied in dogs.2. Ventricular ectopic beats produced by intravenous injection of adrenaline in anaesthetized dogs respired with halothane were abolished in four out of six dogs by lignocaine. Propranolol was effective in all three dogs tested.3. Intravenous infusion of lignocaine at (0.2 and 1.0 mg/kg)/min to total doses of 3.0 +/- 1.0 and 2.2 +/- 0.5 mg/kg, respectively, abolished the ventricular tachycardia produced in anaesthetized dogs by ouabain. A similar effect was produced by infusion of propranolol at (0.2 mg/kg)/min to a total dose of 1.9 +/- 0.4 mg/kg. Intravenous injection of single doses of lignocaine (4.0-8.0 mg/kg) also abolished the arrhythmia.4. The frequency of the ventricular ectopic beats occurring in conscious dogs 20-44 h after ligation of the anterior descending branch of the left coronary artery was reduced, with an increase in the number of sinus beats, after intravenous injection of lignocaine (8.0 mg/kg). Larger doses produced excitement. Propranolol (4.0 mg/kg) had a greater effect than the same dose of lignocaine but after 8.0 mg/kg, three of the four dogs died.5. Propranolol was more effective than lignocaine in abolishing the three different types of arrhythmia.6. Dose-response curves showed that lignocaine was more active in abolishing the ouabain induced arrhythmia than the halothane-adrenaline arrhythmia and was least active on the arrhythmia caused by ligation of the coronary artery.     

Reduction in myocardial ischemic/reperfusion injury and neutrophil accumulation after therapeutic administration of streptokinase.

The benefit of thrombolytic agents to reduce myocardial infarct size, improve left ventricular (LV) function, and prolong survival in human subjects is generally recognized, although the precise mechanism is poorly defined. This study was designed to evaluate the cardioprotective effects of streptokinase (SK) in rats, a species less responsive to plasminogen activators, using a model of mechanical occlusion and release of the left coronary artery. Myocardial injury and polymorphonuclear leukocyte (PMN) infiltration were determined by measuring creatine phosphokinase (CPK) specific activity and myeloperoxidase (MPO) activity, respectively, in the LV free wall (LVFW). After coronary artery occlusion for 0.5 h and reperfusion for 24 h (myocardial ischemia, MI/R), CPK specific activity decreased from 7.0 +/- 0.3 U/mg protein in the sham + vehicle group to 5.6 +/- 0.5 U/mg protein in the MI/R + vehicle group (n = 19, p less than 0.01), while MPO activity increased from 0.14 +/- 0.03 U/g tissue in the sham + vehicle group to 2.8 +/- 0.7 U/g in the MI/R + vehicle group (p less than 0.001). Administration of SK (100,000 IU/kg + 50,000 IU/kg/h for 2 h beginning 15 min before coronary artery reperfusion) reduced the loss of CPK specific activity from reperfused myocardium (6.8 +/- 0.5 U/mg protein, n = 23, p less than 0.05 as compared with the MI/R + vehicle group) and attenuated the increase in MPO activity (1.3 +/- 0.4 U/g tissue, p less than 0.05 as compared with the MI/R + vehicle group). This dose of SK did not change plasma fibrinogen concentration, slightly reduced plasminogen activity (i.e., 20% from control value), and markedly reduced alpha 2-antiplasmin activity (i.e., 60% from control values). A lower dose of SK (i.e., 10,000 IU/kg + 5,000 IU/kg/h for 2 h) did not reduce myocardial injury, did not attenuate the increase in MPO activity, and had no effect on the measured hemostatic parameters. Survival in all MI/R groups ranged from 62 to 66%, and there were no differences in survival between any of the groups (p greater than 0.05). In a model of arachidonic acid-induced rat hindpaw inflammation, SK had no effect on the increase in MPO activity, suggesting that the increase in myocardial MPO activity was not due to a direct effect on inflammatory cell accumulation. In in vitro studies, SK (1-1,000 U/ml) did not scavenge superoxide anion produced by purine (10 mM) and xanthine oxidase (10 mU/ml), nor did it reduce superoxide release, beta-glucuronidase release, or neutrophil aggregation of rabbit peritoneal neutrophils activated with fMLP.(ABSTRACT TRUNCATED AT 400 WORDS)     

Experimental treatment of the acute cardiovascular toxicity of caffeine

STUDY DESIGN: The intravenous infusion of caffeine-sodium salicylate (15 mg/kg/min) into artificially ventilated and anesthetized rats caused a progressive fall in arterial blood pressure which was mainly due to a decrease in peripheral resistance. Cardiac output increased initially by 15% but then declined after 30 minutes. The electroencephalogram showed sinus tachycardia and ectopic beats mainly in the form of monomorphic ventricular bigeminy which began after 22.8 minutes. Fatal ventricular fibrillation occurred in all animals by 66.9 +/- 3.1 minutes. Treatment of cardiac arrhythmia by repeated intravenous injections of propranolol (1 mg/kg) or verapamil (1 mg/kg) was effective and prolonged survival time to 91.7 +/- 4.4 or 84.3 +/- 2.9 minutes, respectively (p < 0.05). Propranolol also prolonged survival time when administered in a single dose of 20 mg/kg i.v. 10 minutes before the initiation of caffeine infusions. Repeated administrations of quinidine sulfate (5 mg/kg), phenytoin (5 mg/kg), or lidocaine (1-5 mg/kg), on the other hand, exerted very short antiarrhythmic activity and did not prolong survival time at all. Fluid therapy with polygeline plasma expander (0.5 mL/kg/min) did not influence caffeine-induced cardiovascular failure in any way. CONCLUSIONS: Ventricular ectopia leading to fibrillation accounts for the lethal outcome of caffeine poisoning in anesthetized rats and can be antagonized by treatment with propranolol or verapamil.     

Cardiovascular effects and plasma levels of denopamine (TA-064), a new positive inotropic agent, in chronically instrumented dogs

Cardiovascular effects of denopamine (TA-064), a new positive inotropic agent, in chronically instrumented dogs were investigated following intravenous and oral administration. In the conscious state, denopamine (0.5-4 micrograms/kg/min, i.v. infusion) increased LV dp/dtmax, cardiac output, stroke volume in a dose-dependent manner, and it decreased left ventricular end-diastolic pressure, total peripheral resistance and PQ interval. Denopamine produced an increase in LV dp/dtmax by 90% at a rate of 4 micrograms/kg/min with slightly increasing systemic blood pressure and heart rate. In the same dogs after anesthetizing with pentobarbital, denopamine in the same dose range showed more marked positive inotropic effects and less changes in cardiac output and total peripheral resistance than in conscious dogs. Other cardiovascular effects of denopamine were qualitatively similar to conscious dogs. These effects of denopamine were diminished by treatment with propranolol. Oral administration of denopamine to conscious dogs (0.1-0.4 mg/kg) produced a rise in LV dp/dtmax dose-dependently, and denopamine at a dose of 0.4 mg/kg increased LV dp/dtmax by 66%, this effect lasting for 7 hr. Heart rate and blood pressure were not affected significantly. Effects on other cardiovascular parameters were changed in the same direction as intravenous administration. The increase in LV dp/dtmax corresponded well with the changes in plasma levels of denopamine in conscious dogs by both intravenous and oral administration. Denopamine showed a selective positive inotropic effect in chronically instrumented dogs, and its positive inotropic action was more marked in the myocardium depressed with an anesthetizing dose of pentobarbital than in the conscious state.     

Antiarrhythmic and electrophysiologic effects of MDL 11,939, a novel class III antiarrhythmic agent in anesthetized dogs.

MDL 11,939 (alpha-phenyl-1-[2-phenylethyl]-4-piperidine-methanol) is a new class III antiarrhythmic agent that was evaluated for antiarrhythmic activity in anesthetized dogs. Intravenous (i.v.) administration of MDL 11,939 (1, 3, and 10 mg/kg) increased left ventricular effective refractory periods. Q-T interval, and Q-Tc in a dose-related way. The effects of MDL 11,939 on ventricular refractoriness were similar to those observed with administration of identical doses of d-sotalol, with the exception that those produced by MDL 11,939 lasted longer. Intraduodenal administration of 10 mg/kg MDL 11,939 also increased left ventricular effective refractory period (LV ERP). The increase in left ventricular refractoriness produced by MDL 11,939 occurred without a significant increase in QRS duration. MDL 11,939 (10 mg/kg i.v.) also protected against induction of ventricular tachycardia (VT) and ventricular fibrillation (VF) induced with programmed electrical stimulation (PES) in anesthetized dogs with chronic 4- to 7-day myocardial infarctions. In comparison, antiarrhythmic effects of bretylium (10 mg/kg i.v.) against PES-induced ventricular arrhythmias were dependent on additional administration of propranolol (0.1 mg/kg i.v.), whereas propranolol alone (0.1 mg/kg i.v.) was ineffective. The results observed with MDL 11,939 are consistent with its in vitro class III antiarrhythmic action and suggest utility for this agent in treatment of VT and VF.     

Effect of vasodilator drugs on coronary occlusion and reperfusion arrhythmias in anesthetized dogs

The effect of vasodilator drugs on the incidence of ventricular arrhythmias induced during 30 min of occlusion and 15 min of reperfusion of the left anterior descending coronary artery (LAD) was studied in 65 pentobarbital-anesthetized open-chest dogs. Intravenous administration of captopril (0.5 mg/kg), enalapril (0.5 mg/kg), felodipine (4 micrograms/kg), or ketanserin (0.1 mg/kg) 30 min before LAD occlusion reduced mean arterial blood pressure by 15.5 +/- 0.6% (mean +/- SEM). Nifedipine (5 micrograms/kg bolus + 1 microgram/kg min-1) infusion reduced mean arterial blood pressure by 24.8 +/- 1.8%. In none of the dogs was the diastolic blood pressure reduced below 70 mm Hg. During LAD occlusion, reduction in arterial blood pressure by these drugs was associated with a reduced incidence of ventricular premature depolarizations, ventricular tachycardia, and ventricular fibrillation (VF). During LAD reperfusion, the incidence of VF in saline-treated animals was 6/9, whereas for captopril it was 6/9, enalapril 1/9, felodipine 7/9, nifedipine 3/8, and ketanserin 3/9 animals. Thus, only enalapril significantly lowered the incidence of VF (p less than 0.05). The mechanism responsible for this antifibrillatory effect of enalapril is unknown. The muscle mass of the left ventricle supplied by the LAD distal to the site of occlusion in dogs which survived was similar to that of dogs which developed ventricular fibrillation.     

Prevention of reocclusion following tissue type plasminogen activator-induced thrombolysis by the RGD-containing peptide, echistatin, in a canine model of coronary thrombosis

We evaluated the effect of the RGD-containing peptide, echistatin, on thrombolysis time and acute reocclusion in a canine model of coronary thrombosis/thrombolysis. Occlusive thrombus formation was induced by electrical injury, via a stimulating electrode, to the endothelial surface of the circumflex coronary artery in the open-chest, anesthetized dog in the presence of a critical stenosis. Fifteen minutes after occlusive thrombus formation, dogs received either an intravenous infusion of vehicle (saline at 0.1 ml/min) or echistatin (15 micrograms/kg/min i.v.). Heparin was given as an initial bolus (100 U/kg i.v.) 15 min after thrombus formation and repeated at hourly intervals (50 U/kg). This dose of heparin increased activated partial thromboplastin time to 1.5- to 2.5- fold over control. Thrombolysis was induced with recombinant tissue-type plasminogen activator (tPA) at a total dose of 1 mg/kg, intravenously administered over 90 min with 10% given as an initial bolus. The vehicle-treated animals reperfused at 48 +/- 9 min with a reperfusion incidence of 60% (3/5). The echistatin-treated animals reperfused at 46 +/- 5 min with a reperfusion incidence of 100% (5/5). After stopping the tPA infusion, acute reocclusion occurred in 100% (3/3) of the vehicle-treated dogs and in only 20% (1/5) of the echistatin-treated dogs. Echistatin caused a greater than 5-fold increase in buccal mucosa bleeding time and almost completely inhibited ex vivo platelet aggregation to ADP, collagen, and U-46619. Residual thrombus wet weight, determined at the end of the experiment, was significantly lower for the echistatin group (2.1 +/- 0.2 mg) compared to the vehicle group (5.8 +/- 0.7 mg).(ABSTRACT TRUNCATED AT 250 WORDS)