Effects of selective cyclooxygenase-2 inhibition on vascular responses and thrombosis in canine coronary arteries.

BACKGROUND: Prostanoid synthesis via the action of cyclooxygenase-2 (COX-2) is a component of the inflammatory response. Prostacyclin, a product of COX-2 in vascular endothelium, has important physiological roles, such as increasing blood flow to injured tissues, reducing leukocyte adherence, and inhibiting platelet aggregation. We examined the possibility that selective COX-2 inhibition could suppress the protective effects of prostacyclin, resulting in an alteration of the hemostatic balance and vascular tone. METHODS AND RESULTS: Circumflex coronary artery thrombosis was induced in dogs by vascular electrolytic injury. Orally administered celecoxib (COX-2 inhibition) or high-dose aspirin (HDA) (COX-1 and COX-2 inhibition) did not alter time to occlusive thrombus formation compared with controls (celecoxib 77.7+/-7.2 minutes, HDA 72.0+/-18.5 minutes, control 93.0+/-21.8 minutes). Oral HDA with an endothelial recovery period (HDA-ER) (COX-1 inhibition) produced a significant increase in time to vessel occlusion (257.0+/-41.6 minutes). The observed increase in time to occlusion was abolished when celecoxib was administered to animals dosed with HDA-ER (80.7+/-20.6 minutes). The vasomotor effect of endothelium-derived prostacyclin was examined by monitoring coronary flow during intracoronary administration of arachidonic acid or acetylcholine. In celecoxib-treated animals, vasodilation in response to arachidonic acid was reduced significantly compared with controls. CONCLUSIONS: The results indicate important physiological roles for COX-2-derived prostacyclin and raise concerns regarding an increased risk of acute vascular events in patients receiving COX-2 inhibitors. The risk may be increased in individuals with underlying inflammatory disorders, including coronary artery disease.

Tedisamil and dofetilide-induced torsades de pointes, rate and potassium dependence.

1. Tedisamil is a bradycardiac agent that prolongs the QT interval of the ECG and prevents cardiac arrhythmias. Given this profile, tedisamil might be expected to have proarrhythmic actions similar to Class III antiarrhythmic drugs. To address this question, the actions of dofetilide and tedisamil were examined in rabbit isolated hearts in which bradycardia was induced by AV ablation. 2. The QT interval was prolonged in a reverse rate-dependent fashion by dofetilide (3 and 30 nM) and tedisamil (0.3 and 3 microM). 3. Torsades de pointes was observed in 1/7 hearts treated with 3 nM dofetilide and 0/7 hearts treated with 0.3 microM tedisamil. The incidence of torsades de pointes was increased to 5/7 in hearts treated with 30 nM dofetilide and to 7/7 in hearts treated with 3 microM tedisamil (both P < 0.05 vs control). 4. The actions of 30 nM dofetilide and 3 microM tedisamil were also examined in hearts paced at 50, 100, 200 and 50 beats min(-1) successively. Both drugs caused torsades de pointes in 5/5 hearts paced at 50 beats min(-1); however, the incidence was reduced to 0/5 during pacing at 200 beats min(-1). Thus, drug-induced proarrhythmia was bradycardia-dependent. 5. Drug-induced prolongation of the interval between the peak and end of the T-wave (QTa-e) was reverse rate-dependent and was associated with the occurrence of torsades de pointes (r = 0.91, P < 0.01). 6. The results suggest that tedisamil, like dofetilide, presents a risk for development of torsades de pointes.

Prevention of arterial thrombosis by intravenously administered platelet P2T receptor antagonist AR-C69931MX in a canine model.

P2Y1, P2X1, and P2T receptors mediate ADP-induced platelet aggregation. The antithrombotic effects of AR-C69931MX (N6-[2-methylthio)ethyl]-2-[3,3,3-trifluoropropylthio]-5'-adenylic acid, monoanhydride with dichloromethylenebiphosphonic acid), a selective P2T platelet receptor antagonist, was assessed in a canine model of arterial thrombosis. Placebo or AR-C69931MX (4.0 microg/kg/min for 6 h) pretreatment was administered as an intravenous infusion beginning 15 min before inducing vessel wall injury. A 300-microA anodal current was applied to the intima of the carotid artery for 180 min or discontinued 30 min after cessation of blood flow due to thrombus formation. Each of five control animals developed occlusive thrombi within 3 h after induction of vessel wall injury. In contrast, carotid artery blood flow in five of six AR-C69931MX-treated animals was maintained for the duration of the protocol. Ex vivo platelet aggregation in response to adenosine diphosphate was inhibited at the first measurement time point of 75 min after the start of drug infusion and remained inhibited during drug administration. Bleeding time values were increased in the drug-treated group. Values for both the ex vivo platelet aggregation and the bleeding times returned to control values shortly after discontinuation of AR-C69931MX. The results indicate that AR-C69931MX antagonizes the ex vivo and in vivo aggregatory actions of ADP, and displays a rapid onset and offset of action with the ability to prevent occlusive arterial thrombus formation. AR-C69931MX may be suitable for the management of patients who require short-term modulation of platelet function.

Effect of ramiprilat or captopril on myocardial infarct size: assessment in canine models of ischemia alone and ischemia with reperfusion.

Cardioprotective effects of the angiotensin-converting enzyme inhibitors captopril and ramiprilat were studied in two in vivo canine models of myocardial ischemic injury: 90 min of regional ischemia with 18 h reperfusion (protocol I) and 6 h of continuous ischemia without reperfusion (protocol II). In protocol I, neither ramiprilat (50 micrograms/kg) nor captopril (5 mg/kg + 0.25 mg/kg/h) reduced infarct size after 18 h of reperfusion (vs. controls). In protocol II, drugs were administered directly into both left anterior descending coronary artery and left circumflex branch. Compared to controls, continuous intracoronary administration of ramiprilat (40 ng/kg/min) or captopril (400 ng/kg/min) did not reduce infarct size. Thus neither captopril nor ramiprilat protected the heart from injury under conditions of ischemia with reperfusion or ischemia without reperfusion.

Antifibrillatory efficacy of long-term tedisamil administration in a postinfarcted canine model of ischemic ventricular fibrillation.

The electrophysiologic and antifibrillatory properties of tedisamil (KC-8857) were studied in vivo in a conscious canine model of sudden cardiac death. Male mongrel dogs were anesthetized, and surgical anterior myocardial infarction was induced by a 2-h occlusion, with reperfusion of the left anterior descending coronary artery. Three to five days after infarction, dogs were subjected to programmed electrical stimulation (PES) to identify those at risk for ischemia-induced ventricular fibrillation. Previous studies documented that dogs with a significant anterior-wall infarction develop ventricular tachycardia in response to PES and are at an increased risk for sudden cardiac death on imposition of a transient ischemic event in a region remote from the infarct-related artery. PES-inducible animals were randomized to either oral placebo or oral tedisamil treatment (3 mg/kg, b.i.d for 4 days, Group 1, n = 8). Control animals received empty gelatin capsules (Group 2, n = 8). The effective refractory period and QTc interval were unchanged after 3 days of oral placebo or tedisamil dosing. Arrhythmic activity after drug administration was not observed in dogs treated with tedisamil. PES induction of ventricular tachycardia was reduced significantly in the tedisamil-treated group (100% inducible before drug vs. 9% inducible after drug; p < 0.05). In the sudden-cardiac-death protocol, tedisamil reduced the incidence of lethal ischemic arrhythmias developing in response to acute posterolateral myocardial ischemia. Tedisamil-treated animals exhibited a 100% compared with a 25% survival rate in the control group (p < 0.05). Anterior-wall infarct size, expressed as a percentage of the left ventricle, did not differ between groups: Group 1 = 20 +/- 1%; Group 2 = 22 +/- 1%. Our findings suggest that tedisamil might be useful in the prevention of malignant ventricular arrhythmias in myocardial ischemic injury.

TP-9201, a glycoprotein IIb/IIIa platelet receptor antagonist, prevents rethrombosis after successful arterial thrombolysis in the dog.

BACKGROUND AND PURPOSE: We examined the ability of TP-9201, a platelet glycoprotein IIb/IIIa receptor antagonist, to prevent carotid artery rethrombosis in the anesthetized dog. METHODS: Occlusive thrombosis was induced by electrolytic injury of the left carotid artery. Thirty minutes later, 0.05 U/kg of anisoylated plasminogen streptokinase activator complex (APSAC) was infused locally to achieve clot lysis. Carotid artery recanalization was followed immediately by the infusion of either saline (10 mL/h, 240 minutes; n = 9), low-dose TP-9201 (120 micrograms/kg plus 3 micrograms.kg-1.min-1, 240 minutes; n = 7), or high-dose TP-9201 (185 micrograms/kg plus 5 micrograms.kg-1.min-1, 240 minutes; n = 7). Ex vivo platelet aggregation responses to ADP or arachidonic acid were determined. RESULTS: TP-9201 produced complete inhibition of platelet aggregation in citrated platelet-rich plasma but a partial and dose-dependent inhibition in heparinized platelet-rich plasma. A twofold and eightfold increase in the template bleeding time was associated with the infusion of low-dose and high-dose TP-9201, respectively. There were frequent cyclic flow reductions in both the saline and low-dose TP-9201-treated groups after thrombolysis. However, the high-dose TP-9201-treated group exhibited a sustained flow with minimal evidence of cyclic flow reductions. At the conclusion of the protocol, patent vessels were found more frequently in the high-dose TP-9201 (5/7; P = .0048) than in the low-dose TP-9201 treatment group (2/7; P = .17) when compared with the saline group (0/9). Infusion of high-dose TP-9201 was associated with a significant reduction in the thrombus mass as compared with the control vessels. CONCLUSIONS: Administration of TP-9201 in conjunction with successful thrombolysis inhibited ex vivo platelet aggregation and prevented rethrombosis of the canine carotid artery. This study demonstrates that TP-9201, an inhibitor of the platelet GPIIb/IIIa receptor, can inhibit platelet-vessel wall interaction and thus prevent rethrombosis.

Cardioprotective effects of heparin or N-acetylheparin in an in vivo model of myocardial ischaemic and reperfusion injury.

OBJECTIVE: The aim was to determine if either heparin or N-acetylheparin could reduce the extent of myocardial injury resulting from 90 min of coronary artery occlusion and 6 h of reperfusion in the anaesthetised dog. METHODS: Heparin or N-acetylheparin was given in three repeated intravenous doses of 2 mg.kg-1. Drug or vehicle (0.9% saline) was given 75 min after onset of ischaemia and 90 and 180 min after reperfusion. To ensure an equal degree of myocardial ischaemia induced by left circumflex coronary artery occlusion among the three groups of animals studied, only animals with ischaemic zone blood flow of < or = 0.16 ml.min-1.g-1 were included in the final analysis. RESULTS: Ischaemic zone blood flow was 0.068(SEM 0.0016) ml.min-1.g-1 in control animals (n = 13), 0.083(0.017) ml.min-1.g-1 in heparin treated animals (n = 10), and 0.094(0.010) ml.min-1.g-1 in N-acetylheparin treated animals (n = 10). Baseline haemodynamic variables did not differ among the three groups studied. Heparin treatment alone significantly increased bleeding time and activated partial thromboplastin time. Electrocardiographic ST segment elevation, an indicator of regional ischaemia at the onset of coronary occlusion, was not different among control, heparin, or N-acetylheparin groups. The area of the left ventricle at risk of infarct was 39.8(1.5)%, 38.6(0.7)%, and 37.3(2.0)% in control, heparin, and N-acetylheparin treated groups, respectively. Myocardial infarct size, as a percentage of area at risk, was 43.0(3.7)%, 30.7(3.9)%, and 24.5(3.7)% in control, heparin, and N-acetylheparin treated animals, respectively (P < 0.05, control v heparin and N-acetylheparin). CONCLUSIONS: The glycosaminoglycans, heparin or N-acetylheparin, can reduce the extent of myocardial injury associated with regional ischaemia and reperfusion in the canine heart. The mechanism of cytoprotection is unrelated to alterations in the coagulation cascade and may involve inhibition of complement activation in response to tissue injury.

Effects of BMY21190, an inhibitor of cAMP phosphodiesterase, on infarct size and myeloperoxidase activity in the ischemic myocardium of a canine occlusion-reperfusion model.

This study was performed to assess the effect of BMY21190, an inhibitor of cAMP phosphodiesterase, on infarct size using a canine ischemic model that underwent a 90-min occlusion and a 6-hour reperfusion of the left coronary artery. The infarct zone/area at risk of the BMY21190 group was significantly smaller than that of the vehicle group (36.1 +/- 7.8%; 62.4 +/- 4.3%, respectively; p < 0.05). Myeloperoxidase activity, an indicator of neutrophil infiltration, was significantly correlated to infarct size (r = 0.6893, p < 0.02). Myeloperoxidase activity (0.14 +/- 0.07 U/100 mg tissues) measured in the area at risk from hearts of the BMY21190-treated group was significantly lower than that of the vehicle-treated tissue (0.40 +/- 0.08 U/100 mg tissue, p < 0.05). It is suggested that BMY21190 reduces infarct size through the inhibition of neutrophil infiltration in the canine model.

Effect of ranolazine on infarct size in a canine model of regional myocardial ischemia/reperfusion.

We assessed ranolazine's potential to reduce myocardial injury resulting from 90-min occlusion and 18-h reperfusion of left circumflex coronary artery (LCX) in anesthetized dogs. Ranolazine, a putative antianginal agent, has exhibited positive results in a variety of experimental models associated with the ischemic myocardium. Previous studies demonstrated that ranolazine possesses a mechanism of action involving increases in the amount of active pyruvate dehydrogenase during ischemia, suggesting that the compound may act to promote glucose utilization. Ranolazine was administered as a bolus of 3.3 mg/kg, followed by a constant infusion of 7.2 mg/kg/h for 20 h. The loading dose was administered 30 min before LCX occlusion. Control animals received appropriate volumes of vehicles (loading and infusion). Hemodynamics were unchanged between ranolazine and vehicle groups. Three animals in each group were excluded because of ventricular fibrillation (VF). There was no difference in degree of ST segment change between control and ranolazine-treated groups at any time during LCX occlusion. The area at risk (AAR) of infarct was 40.1 +/- 1.7 and 38.9 +/- 1.3% in control-treated (n = 13) and randolazine-treated (n = 8) animals, respectively (p = 0.631). Myocardial infarct size (IS) was 31.7 +/- 5.2 and 36.6 +/- 8.5% in control and ranolazine-treated animals, respectively (p = 0.603). No significant changes were observed in plasma content of enzymatic markers at 0.5, 2.0, and 18.0 h of reperfusion. The results of this in vivo study indicate that ranolazine did not provide protection from injury to regionally ischemic and reperfused myocardium despite its reported antiischemic activity.

Prevention of thrombosis and rethrombosis and enhancement of the thrombolytic actions of recombinant tissue-type plasminogen activator in the canine heart by DMP728, a glycoprotein IIb/IIIa antagonist.

1. We studied DMP728, a non-peptide glycoprotein (GP) IIb/IIIa receptor antagonist, for prevention of coronary artery thrombosis or rethrombosis in a chronic canine model subjected to arterial injury. 2. In protocol I, DMP728 (1.0 mg kg-1, i.v., n = 8) or saline (n = 8) was administered and a 150 microA anodal current was applied to the intimal surface of the left circumflex coronary artery (LCX). Dogs were monitored for 6 h and again on each of 5 subsequent days. 3. Ex vivo platelet aggregation was inhibited but returned to baseline 1 day after drug administration. Thrombus weight was reduced (saline, 20.7 +/- 5.0 mg; DMP728 1.7 +/- 0.4 mg; P < 0.05), as was infarct size [saline, 27.5 +/- 4.3; DMP728, 1.6 +/- 0.7 (per cent left ventricle); P < 0.05]. All control animals died by day 3, while all but one of the treated dogs survived the entire protocol (P < 0.05). 4. In protocol II, an LCX thrombus was induced and thrombolytic therapy was initiated 30 min later. DMP728 (1.0 mg kg-1, i.v., n = 8) or saline (n = 8) was administered 5 min after recombinant tissue-type plasminogen activator infusion had begun. The incidence of reocclusion was reduced by DMP728 (saline, 4/8; DMP728, 1/8). One day after thrombolysis, 7/8 DMP728-treated animals were alive compared with 1/8 in the control group (P = 0.01). 5. DMP728 inhibited ex vivo platelet aggregation, prevented primary and secondary occlusive thrombus formation, reduced thrombus weight and infarct size and increased survival in a chronic canine model of coronary artery thrombus formation. DMP728 is an effective anti-platelet intervention when used as the singular adjunctive agent in association with thrombolytic therapy.

Inhibition of in vivo myocardial ischemic and reperfusion injury by a synthetic manganese-based superoxide dismutase mimetic.

We determined whether an organic superoxide dismutase mimetic could reduce myocardial injury resulting from a 90-min occlusion of the left circumflex coronary artery, followed by 18 hr of reperfusion in an anesthetized canine. The superoxide dismutase-mimetic studied (SC-52608) was a synthetic Mn-based macrocyclic compound. SC-52608 or the inactive analog SC-54385 was administered as four doses of 4 mg/kg i.v. Drug, inactive analog or vehicle was administered 30 and 15 min before ischemia and 15 min and immediately before reperfusion. To ensure parity of left circumflex coronary artery occlusion-induced ischemia, only animals with ischemic zone blood flow of less than 0.15 ml/min/g were included in the final analysis. Ischemic zone blood flow was 0.069 +/- 0.016 ml/min/g in control animals (n = 10), 0.072 +/- 0.010 ml/min/g in SC-52608-treated animals (n = 11) and 0.053 +/- 0.011 ml/min/g in SC-54385-treated (n = 9) animals. A transient hypotensive effect was observed upon SC-52608 administration. Hemodynamic parameters were otherwise unaffected by SC-52608 or SC-54385. The areas at risk of infarct were 39.6 +/- 1.9%, 38.7 +/- 1.1% and 39.4 +/- 1.1% in control, SC-52608-treated and SC-54385-treated animals, respectively. Myocardial infarct sizes (% of area at risk of infarct) were 44.2 +/- 5.6%, 25.7 +/- 4.3% and 35.1 +/- 4.9% in control, SC-52608-treated and SC-54385-treated animals, respectively (P < .05 control vs. SC-52608-treated). Therefore, the synthetic superoxide dismutase mimetic protected the regionally ischemic and reperfused myocardium from injury, implicating oxygen-derived radicals in the tissue-injury process.

Antithrombotic effects of BMY21190, an inhibitor of cAMP phosphodiesterase, in a canine model of coronary artery thrombosis.

BMY21190, an inhibitor of cyclic AMP phosphodiesterase, has a coronary vasodilating effect. BMY21190 was evaluated for its ability to modify the development of experimental thrombosis resulting from anodal current injury (100 microA for 6 h) of the intimal surface of the left circumflex coronary artery (LCX) in anesthetized dogs. Two groups of dogs were studied. One group received BMY21190 (1 mg/kg) and the other group received an equal volume of vehicle infused into the left jugular vein. After a 30 min administration of BMY21190, heart rate and mean coronary blood flow were increased significantly and mean arterial pressure was decreased. However, the myocardial tension of the left anterior descending coronary artery (LAD) and LCX areas did not increase significantly after BMY21190 infusion. During LCX stimulation, the first LCX occlusion and hyperemic reaction of the control group both occurred significantly earlier than those of the BMY21190 group. BMY21190 treatment reduced the development of the LCX thrombus mass, as compared to that in the controls. In ex vivo studies, platelet aggregation in response to arachidonic acid, ADP or collagen was inhibited by BMY21190. These results suggest that BMY21190 possesses anti-thrombotic and coronary vasodilating effects which may be mediated through the inhibition of cyclic AMP phosphodiesterase.

Inhibition of coronary artery reocclusion after thrombolysis with an RGD-containing peptide with no significant effect on bleeding time.

BACKGROUND: A synthetic RGD-containing cyclic peptide, TP9201, specific for the platelet alpha IIb beta 3 receptor complex, was tested for its ability to accelerate thrombolysis and prevent reocclusion in experimentally induced coronary artery thrombosis. METHODS: Anesthetized, open-chest dogs with occlusive thrombi received tissue plasminogen activator with TP9201 (113 micrograms/kg bolus; 2.7 micrograms/kg/min infusion, n = 7) or saline control (n = 9). RESULTS: A 2.8-fold increase in the duration of vessel patency from 52.7 +/- 63.7 min to 149.1 +/- 63.7 min (P < 0.05) was observed with TP9201 treatment. The mean duration of vessel occlusion was reduced 2.4-fold from 172.4 +/- 81.1 min to 71.7 +/- 63.7 min (P < 0.05). Administration of TP9201 reduced the mean time to lysis from 76.6 +/- 42.9 min to 54.4 +/- 42.9 min, but thrombolysis was not significantly accelerated. Persistent patency was observed in four out of seven of the treated dogs compared with none of the nine in the control group (P < 0.05). Administration of TP9201 inhibited ex-vivo platelet aggregation stimulated by ADP (30 microM) or collagen (10 micrograms/ml). No thrombocytopenia or changes in hemodynamic parameters were observed in the treated group compared with the control group. Peptide TP9201 had no effect on bleeding time and the inhibitory effect on ex-vivo platelet aggregation was rapid and reversible. The pharmacodynamic half-life of TP9201 was approximately 1 h with ex-vivo platelet activity returning to baseline within 2 h of discontinuation of treatment. CONCLUSIONS: TP9201 may be an effective therapy for the prevention of re-thrombosis after thrombolytic therapy without adversely affecting hemostasis.

Inhibition of platelet-activating factor fails to limit ischemia and reperfusion-induced myocardial damage.

To determine the role of platelet-activating factor (1-O-hexa-decyl-2-acetyl-sn-glyceryl-phosphoryl-choline, PAF) in myocardial ischemic and reperfusion-induced injury, the effects of a PAF receptor antagonist (WEB 2086) were studied in an anesthetized canine model of ischemia (90 min) and reperfusion (6 h). Thirty minutes after onset of ischemia, WEB 2086 was administered as a bolus (20 mg/kg intravenously, i.v.) followed by a continuous 6-h infusion (10 mg/kg/h i.v.). Controls received vehicle alone (0.9% saline). Platelet aggregation was studied at baseline and at 1, 2, 4, and 6 h of drug administration and at the end of the reperfusion period. WEB 2086 treatment did not significantly affect platelet aggregation stimulated by ADP or arachidonic acid (AA). After 1 h of drug infusion, the ex vivo aggregatory response to exogenous (200 nM) PAF was ablated in WEB 2086-treated animals. WEB 2086 administration did not affect heart rate (HR) or mean arterial blood pressure (MAP) during the occlusion or reperfusion phases. During reperfusion of the ischemic tissue, left circumflex coronary artery (LCX) blood flow of WEB 2086-treated animals increased (p < 0.05) above control value. The area of the left ventricle at risk of infarct was not different between control and WEB 2086-treated groups. Infarct size was not significantly reduced in WEB 2086-treated animals. The results of our investigation using a 90-min ischemic period followed by 6-h reperfusion show that pharmacologic antagonism of PAF by WEB 2086 does not protect the heart against ischemia and reperfusion-induced injury.

Antiarrhythmic and electrophysiologic actions of CK-3579 and sematilide in a conscious canine model of sudden coronary death.

The antiarrhythmic and antifibrillatory actions of the CK-3579 and sematilide, two new class III antiarrhythmic drugs, administered in a multiple-dose regimen were evaluated in conscious dogs 3-5 days after anterior myocardial infarction. The study population consisted of three groups of 10 dogs each, in which all animals entered into the final protocol developed nonsustained or sustained ventricular tachycardia in response to programmed electrical stimulation using one, two or three premature stimuli. Each drug was administered intravenously in a dose of 3.0 mg/kg every 3 h for a total of six doses. Sematilide significantly suppressed the induction of ventricular tachyarrhythmia by programmed electrical stimulation in six of 10 postinfarcted dogs, whereas CK-3579 suppressed the induction of tachyarrhythmia in only two of 10 animals. Despite its ineffectiveness in preventing electrical induction of tachycardia, CK-3579 produced a significant increase in the cycle length of the induced ventricular rhythm. The administration of each drug was associated with an increase in the ventricular refractoriness and in the paced QT interval, suggesting that class III electrophysiologic properties contribute to the antiarrhythmic action of each drug. In addition, CK-3579 was shown to have beta 1-adrenoceptor blocking properties. The subsequent induction of an acute ischemic event in a region remote from the infarct-related artery was associated with a high incidence (80%, eight of 10 postinfarcted dogs) of ventricular fibrillation within the first hour after the onset of myocardial ischemia in the vehicle-treated control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the positive inotropic agents milrinone and pimobendan on the development of lethal ischemic arrhythmias in conscious dogs with recent myocardial infarction.

The effects of milrinone and pimobendan upon the initiation of programmed ventricular stimulation-induced ventricular tachycardia (VT) and the incidence of lethal ischemic ventricular arrhythmias were assessed in conscious dogs with recent anterior myocardial infarctions. Based upon the results of previous studies, the animals which were entered into this investigation were nonresponsive to baseline programmed stimulation and, therefore, considered to be at "low risk" toward the development of subsequent lethal ischemic arrhythmias. Milrinone (200 micrograms/kg/h continuous i.v. infusion) and pimobendan (300 micrograms/kg i.v.) were administered in dosing regimens shown to produce equivalent and sustained increases in left ventricular (LV) + dP/dt. At the time of repeat electrophysiologic testing, 9 of 9 pimobendan-, 9 of 10 milrinone-, and 12 of 12 concurrent vehicle-treated animals remained nonresponsive to programmed ventricular stimulation. Compared to a total control population of 39 "low risk" postinfarction dogs; however, both milrinone and pimobendan administration increased the incidence of sudden ventricular fibrillation occurring in response to the development of acute posterolateral ischemia (milrinone 4 of 10 [40%] and pimobendan 4 of 10 [40%] versus "low risk" control population 4 of 39 [10.3%]; p = 0.038). The incidence of ischemic mortality at 24 h after the development of posterolateral myocardial ischemia was increased in the milrinone-treated group (6 of 10 [60%]) compared to the "low risk" control population (6 of 39 [15.2%]; p = 0.007), whereas the incidence of 24-h ischemic mortality in the pimobendan-treated group (4 of 10 [40%]) was only of borderline statistical significance when compared to that of the "low risk" control population (p = 0.083). Milrinone, but not pimobendan, delayed the onset of acute posterolateral myocardial ischemia in the postinfarction dogs. The predominant electrophysiologic effects of both milrinone and pimobendan were decreases in ventricular refractoriness in both non-infarct (NZ) and in infarct zones (IZ), as well as reductions in electrocardiographic QTc or QT intervals. These findings suggest that with both positive inotropic agents, including milrinone which may possess protective antithrombotic action, sudden death may be increased via a reduction in ventricular refractoriness in the ischemically injured heart. The enhanced susceptibility toward the development of ischemic ventricular arrhythmias in the presence of the inotropic interventions is not predicted by programmed ventricular stimulation testing prior to the ischemic event.

Alinidine reduces the incidence of ischemic ventricular fibrillation in a conscious canine model, a protective effect antagonized by overdrive atrial pacing.

The antiarrhythmic and antifibrillatory effects of the specific bradycardic agent alinidine were evaluated in a conscious canine model of myocardial infarction and sudden death, and by determination of ventricular fibrillation thresholds (VFT) in anesthetized dogs. Programmed electrical stimulation (PES) was performed in conscious animals, 3-5 days after a 2-h occlusion/reperfusion of the left anterior descending coronary artery (LAD). Dogs in which PES resulted in a reproducible nonsustained or sustained ventricular tachycardia (VT) were randomized to receive either intravenous alinidine (1 mg/kg, n = 11) or intravenous vehicle (n = 10). Programmed electrical stimulation and measurement of electrophysiologic parameters were repeated after 30 min, and the animals were entered into the sudden death protocol by introducing a 150 microA anodal current to the lumen of the left circumflex coronary artery (LCX) via a surgically implanted silver wire electrode. A second alinidine-treated group (n = 3) had heart rates controlled by atrial pacing during this period. Alinidine failed to prevent the programmed electrical induction of VT in 10 of 11 animals, but significantly reduced both sudden (less than 1 h ischemia) and 24-h mortality as compared to the ventricle group. Infarct sizes were similar in the two groups, but the ischemia-related increase in heart rate was attenuated (p less than 0.05) by alinidine and the onset of ischemia tended to be delayed. All of the atrial-paced animals died acutely. Heart rate decreased after alinidine (p less than 0.01), but apart from a single index of refractoriness, the drug was without electrocardiographic or electrophysiologic effects. Neither alinidine nor vehicle demonstrated any effect upon VFT in two groups of five animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Superoxide dismutase conjugated to polyethylene glycol provides sustained protection against myocardial ischemia/reperfusion injury in canine heart.

Disagreement regarding the cardioprotective role of superoxide dismutase may relate to the use of different durations for induction of ischemic injury and reperfusion. The present study employed superoxide dismutase conjugated to polyethylene glycol (PEG-SOD), which has a half-life greater than 30 hours. Two protocols differing in the mode of administration and the duration of the reperfusion interval were used. Dogs were subjected to occlusion of the circumflex coronary artery for 90 minutes, then reperfused for 6 hours (Protocol A) or 4 days (Protocol B). The dogs received either polyethylene glycol conjugated to albumin (PEG-ALB) or PEG-SOD (1,000 U/kg). In Protocol A, treatment was administered starting 15 minutes before coronary occlusion and continued for 2 hours, terminating 15 minutes after reperfusion. Infarct size was determined 6 hours later. In Protocol B, the conjugated proteins were given 15 minutes before reperfusion and ended simultaneously with reperfusion. Infarct size was measured after 4 days. Infarct size (percentage of area at risk) in control (n = 9) and treated (n = 9) dogs in Protocol A differed between groups: 46.7 +/- 3.5% versus 28.3 +/- 2.9%, respectively (p less than or equal to 0.005); risk regions did not differ: 42.8 +/- 1.5% versus 43.8 +/- 2.1%, respectively. Myocardial salvage also was observed in Protocol B. Infarct size in control (n = 13) and treated (n = 13) groups was 44.2 +/- 2.6% versus 29.2 +/- 1.6%, respectively (p less than or equal to 0.005), with risk regions being 44.4 +/- 1.4% versus 46.0 +/- 1.6% (p = NS). Hemodynamic variables did not differ during the period of coronary artery occlusion. The respective collateral blood flows to the inner two thirds of the ischemic myocardium determined 60 minutes after occlusion were 0.05 +/- 0.01 ml/min/g and 0.06 +/- 0.04 ml/min/g (p = 0.806) for the PEG-ALB and PEG-SOD treated groups, respectively. Infarct size was related inversely to collateral blood flow in the PEG-ALB treated group. This relation shifted downward (analysis of covariance, p = 0.017). Plasma SOD activity in Protocols A sustained for 6 hours. Significant enzymatic activity was present after 4 days in Protocol B. Previous negative studies with native SOD may be related to the short half-life of its free-radical scavenging capacity, which compromises the chances of observing a protective effect after 4 days of reperfusion. The present results support our previous observations, as well as those of other investigators, demonstrating that superoxide dismutase can reduce that component of myocardial injury associated with reperfusion.

Cardiac electrophysiologic and hemodynamic activity of pimobendan (UD-CG 115 BS), a new inotropic agent.

The hemodynamic and cardiac electrophysiologic properties of pimobendan, a new pyridazinone-benzimidazole type inotropic agent, were studied in urethane-anesthetized dogs. The cumulative i.v. administration of 0.1, 0.3, and 1.0 mg/kg pimobendan caused a dose-dependent decrease in mean arterial pressure and an increase in sinus heart rate. When heart rate was maintained constant by overdrive atrial pacing, hemodynamic changes in response to pimobendan consisted of dose-related increases in right ventricular isometric contractile force (P less than .05 at 0.3 and 1.0 mg/kg), left ventricular +dP/dt (P less than .05 at 0.3 and 1.0 mg/kg), and left circumflex coronary artery blood flow (P less than .05 at 1.0 mg/kg). Increases in each of the aforementioned hemodynamic parameters were sustained for up to 4 hr after the i.v. administration of 1.0 mg/kg pimobendan. The cardiac electrophysiologic changes associated with pimobendan administration included decreases in the atrial (P less than .05 at 1.0 mg/kg), ventricular (P less than .05 at 0.3 and 1.0 mg/kg), and atrioventricular nodal functional (P less than .05 at 0.3 and 1.0 mg/kg) and effective (P less than .05 at 1.0 mg/kg) refractory periods. Atrioventricular conduction velocity was enhanced after pimobendan, as indicated by a shortening of the AH (P less than .05 at 0.3 mg/kg and at 1.0 mg/kg) and PR intervals (P less than 0.05 at 1.0 mg/kg). Pretreatment with propranolol (0.5 mg/kg i.v.) attenuated the pimobendan-induced decrease in the ventricular refractory period and the increase in heart rate, whereas the decrease in arterial pressure was enhanced. These results indicate that the i.v. administration of pimobendan to anesthetized dogs produces a dose-related positive inotropic effect, coronary and peripheral vasodilation, and cardiac electrophysiologic effects that include decreases in atrial, atrioventricular, and ventricular refractoriness as well as a facilitation of atrioventricular conduction. The observed electrophysiologic changes may be mediated, in part, by a baroreceptor-mediated increase in sympathetic nervous system activity.

Antifibrillatory efficacy of concomitant beta adrenergic receptor blockade with dilevalol, the R,R-isomer of labetalol, and muscarinic receptor blockade with methylscopolamine.

The antiarrhythmic and antifibrillatory actions of dilevalol, the R,R-isomer of labetalol, were evaluated in conscious dogs 4 to 6 days after anterior myocardial infarction. The administration of dilevalol in a lower dose of 0.3 mg/kg i.v. q 8 hr or a higher dose of 3.0 mg/kg i.v. q 8 hr over a period of 24 hr failed to alter electrophysiologic parameters or significantly suppress the induction of ventricular tachycardia by programmed ventricular stimulation (incidence of ventricular tachycardia suppression: 4 of 25 [16%] dilevalol vs. 1 of 14 [7%] vehicle). Pretreatment with dilevalol failed to reduce arrhythmic death in response to the subsequent development of ischemia at a site distant to the area of previous infarction (mortality: 8 of 10 [80%] dilevalol vs. 14 of 14 [100%] vehicle), but did alter the nature of the lethal ischemic arrhythmia from ventricular fibrillation (incidence of ventricular fibrillation: 14 of 14 [100%] vehicle vs. 2 of 8 [25%] dilevalol, P less than .05) to bradyarrhythmia with eventual sinoatrial arrest (6 of 8 [75%] dilevalol). The administration of methylscopolamine, 0.01 mg/kg both i.v. and i.m., to postinfarction animals pretreated with dilevalol, 3.0 mg/kg i.v. q 8 hr for 24 hr, reduced significantly mortality in response to subsequent posterolateral ischemia (mortality: 4 of 10 [40%] dilevalol plus methylscopolamine vs. 14 of 14 [100%] vehicle, P less than .05). However, methylscopolamine alone failed to suppress the development of ischemic ventricular fibrillation in 5 of 6 (83%) postinfarction dogs.(ABSTRACT TRUNCATED AT 250 WORDS)