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J J Lynch

Publications and source records attributed to J J Lynch.

At least 19 recordsLinked to original sources
PubMed1992

Echocardiography. Using its many capabilities to evaluate myocardial infarction.

How can the suspicion of myocardial ischemia be confirmed without putting the patient through an invasive procedure? In patients who have had myocardial infarction, how can those at risk for pump failure and other complications and future cardiac events be identified? How are such complications detected? The answer to all these questions is echocardiography. The authors review how to use the technique and provide illustrative images.

Echocardiography↗
PubMed1992

Visual effects of damage to P ganglion cells in macaques.

Four indices of visual performance were measured in control macaques and in macaques that had been exposed to monomeric acrylamide, a neurotoxicant that preferentially damages P retinal ganglion cells. Morphological examination of the retina and visual pathways of these monkeys showed virtually complete loss of P ganglion cells over a region extending to at least 40 deg from the fovea, and relative sparing of M ganglion cells. The four tests examined visual functions for which the visual pathway from P ganglion cells might be of great importance: visual acuity, contrast discrimination, hyperacuity, and shape discrimination. In the acrylamide-dosed monkeys, visual acuity was reduced slightly more than fourfold, a somewhat larger reduction than that seen previously after ibotenic-acid lesions of the P pathway in the geniculate. The residual acuity was in good agreement with the Nyquist frequency calculated from the density of ON or OFF M ganglion cells. Contrast increment thresholds were elevated for the dosed monkeys only in one of the two conditions tested. The elevation was found only under those spatiotemporal conditions for which we have previously shown that contrast thresholds are increased by acrylamide exposure, and was most marked at low background contrasts. Vernier acuity was elevated in one dosed monkey, but not affected in a second monkey that also had severe loss of P ganglion cells. Finally, we found no effect of acrylamide exposure on the number of training trials required to learn simple or complex shape discriminations. These results support previous findings in showing that the P pathway mediates visual acuity, and they show that several other important aspects of visual perception are not exclusively dependent on the P pathway.

Acrylamide↗
PubMed1992

Therapeutic potential of modulating potassium currents in the diseased myocardium.

Myocardial disease states are characterized by multiple electrophysiologic abnormalities, including alterations in potassium channel activities. During acute myocardial ischemia, activation of ATP-regulated K+ current (IK(ATP)) results in shortening of action potential duration and elevation of extracellular K+ concentration. In hypertrophied myocardium, increases in inward rectifier K+ current (IK1) and decreases in delayed rectifier K+ current (IK) are observed. Alterations in K+ channel activity in myocardial disease states suggest the potential to therapeutically modify cardiac rhythm and function with K+ channel modulators. Class III anti-arrhythmic agents, which prolong myocardial refractoriness predominantly via a blockade of IK, have demonstrated efficacy in suppressing reentrant atrial and ventricular arrhythmias in animal models as well as promising efficacy in initial clinical studies. Potassium channel openers (PCOs), which activate cardiac IK(ATP), have demonstrated both antiarrhythmic and proarrhythmic activities in various experimental settings, and also are being investigated as potential cardioprotective agents. Sulfonylureas, which block cardiac IK(ATP), also have been investigated as potential antiarrhythmic agents with equivocal results, and have displayed a propensity to exacerbate ischemic myocardial dysfunction in experimental studies. A more comprehensive understanding of K+ channel activity in various myocardial disease states, including concomitant disorders such as myocardial ischemia and hypertrophy, will facilitate the development of more useful potassium channel modulators, as well as a clearer recognition of the undesirable effects of such agents.

Animals↗
PubMed1992

Effect of E-4031, a class III antiarrhythmic agent, on experimental infarct size in a canine model of myocardial ischemia-reperfusion injury.

Class III antiarrhythmic agents such as E-4031 have demonstrated efficacy in preventing and/or terminating malignant ventricular arrhythmias in experimental models. It has recently been suggested that Class III agents might possess additional antiischemic properties that may translate into a reduction in the frequency or severity of arrhythmia. The potential for the Class III antiarrhythmic agent E-4031 to limit the extent of developing myocardial infarction was assessed in a barbiturate-anesthetized canine model of ischemic-reperfusion injury. Untreated control (n = 13) and E-4031-treated animals (n = 8, 300 micrograms/kg, i.v., immediately preceding myocardial ischemia) were subjected to a 90-min period of left circumflex coronary artery occlusion followed by a 5-h period of reperfusion. The predominant hemodynamic effect displayed by E-4031 was a reduction in heart rate throughout the period of coronary artery occlusion and early reperfusion. Areas at risk of infarction, expressed as percentages of left ventricle, were equivalent in the control and E-4031 treatment groups (38.5 +/- 1.0 and 34.6 +/- 1.9%, respectively). Posterolateral myocardial infarct sizes, expressed either as percentages of risk area or of total left ventricle, were reduced slightly but not significantly in the E-4031 treatment group compared to the control group (35.2 +/- 5.6 and 45.4 +/- 3.0% of risk area, respectively; 12.7 +/- 2.4 and 17.6 +/- 1.4% of left ventricle, respectively). Regional myocardial blood flows in nonischemic and central ischemic zones of myocardium did not differ significantly between the control and E-4031 treatment groups before and during the period of coronary artery occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Vampire bat salivary plasminogen activator promotes rapid and sustained reperfusion without concomitant systemic plasminogen activation in a canine model of arterial thrombosis.

The efficacy of recombinant vampire bat salivary plasminogen activator (bat-PA) as a thrombolytic agent was compared with that of human tissue-type plasminogen activator (t-PA) in a canine model of arterial thrombosis. An occlusive thrombus was formed in the femoral artery by insertion of a thrombogenic copper coil; femoral arterial blood flow was monitored with a Doppler flow meter. Bat-PA and t-PA, when administered by 5-minute intravenous infusion (14 nmol/kg), reperfused seven out of eight and four out of eight dogs, respectively. The median reperfusion times in the bat-PA and t-PA groups were 24 and greater than or equal to 131 minutes, respectively. The mean reperfusion times (+/- SEM) in the recanalized bat-PA- and t-PA-treated dogs were similar (20 +/- 5 and 11 +/- 2 minutes, respectively, p = NS). Maximal blood flow after reperfusion was greater with bat-PA than with t-PA (80 +/- 10% and 41 +/- 15% of control flow, respectively, p less than 0.05). Furthermore, the median reocclusion time was markedly delayed in the bat-PA group relative to the t-PA group (131 versus 34 minutes, respectively, p less than 0.05). Plasma fibrinogen and plasminogen were not significantly depleted by the administration of t-PA or bat-PA. However, plasma alpha 2-antiplasmin activity was moderately depressed in the t-PA group relative to the bat-PA group (p less than 0.05). The clearance profile for t-PA was monoexponential, with a half-life (t1/2) of 2.4 +/- 0.3 minutes and a mean residence time of 3.5 +/- 0.4 minutes. The clearance profile for bat-PA was biexponential, with a t1/2 alpha of 0.9 +/- 0.2 minutes, a t1/2 beta of 20.2 +/- 2.7 minutes, and a mean residence time of 21.3 +/- 4.3 minutes. The steady-state volume of distribution displayed by bat-PA was 16-fold greater than that of t-PA. Zymography of serial plasma samples from the bat-PA-treated dogs failed to demonstrate the apparent generation of a complex between bat-PA and plasminogen activator inhibitor-1; the corresponding complex with t-PA was observed in plasma samples from the t-PA-treated dogs. The sustained recanalization and improved blood flow in the bat-PA group relative to the t-PA group and the avoidance of fibrinogenolysis by bat-PA, despite its prolonged mean residence time, suggest that bat-PA may be superior to t-PA as a thrombolytic agent.

Animals↗
PubMed1992

Conjunctive enhancement of enzymatic thrombolysis and prevention of thrombotic reocclusion with the selective factor Xa inhibitor, tick anticoagulant peptide. Comparison to hirudin and heparin in a canine model of acute coronary artery thrombosis.

BACKGROUND: Effective thrombolytic recanalization of an occluded coronary vessel is often limited by acute thrombotic reocclusion, which has galvanized the search for effective adjunctive or conjunctive antithrombotic agents. METHODS AND RESULTS: Recombinant versions of tick anticoagulant peptide (rTAP) and hirudin (rHIR) are highly selective and potent polypeptide inhibitors of factor Xa and thrombin, respectively. The comparative antithrombotic efficacies of rTAP, rHIR, and heparin, administered conjunctively with recombinant tissue-type plasminogen activator (rt-PA), on thrombolytic reperfusion and reocclusion, were determined in a canine model of occlusive coronary artery thrombosis with a superimposed critical stenosis. In this model, a platelet-rich occlusive thrombus was formed after damage to the intimal surface of the left circumflex coronary artery induced by electrolytic injury. Fifteen minutes after occlusion, the dogs received a systemic intravenous administration of either saline (control), heparin (200 units/kg bolus + 2 units/kg/min, heparin (HEP) 200 or 100 units/kg bolus + 1 unit/kg/min, HEP 100), rHIR (50 or 100 micrograms/kg/min, rHIR 50 or 100, respectively), or rTAP (100 micrograms/kg/min, rTAP 100) followed 15 minutes later by rt-PA (100 micrograms/kg bolus + 10 micrograms/kg/min over 90 minutes). Infusions of the conjunctive agents were discontinued 60 minutes after termination of rt-PA. The incidence and time (mean +/- SEM) to thrombolytic reperfusion were determined for control (five of 12; 68.0 +/- 7.8 minutes), HEP 100 (six of eight; 40.1 +/- 8.3 minutes), HEP 200 (six of eight; 39.8 +/- 9.5 minutes), rHIR 50 (six of eight; 51.7 +/- 14.6 minutes), rHIR 100 (eight of eight; 19.5 +/- 4.2 minutes), and rTAP 100 (eight of eight; 22.8 +/- 10.0 minutes). The incidence and time to reocclusion after rt-PA were determined for control (four of five; 45.7 +/- 12.5 minutes), HEP 100 (four of six; 18.2 +/- 10.7 minutes), HEP 200 (five of six; 26.2 +/- 20.7 minutes), rHIR 50 (four of six; 47.3 +/- 21.6 minutes), rHIR 100 (six of eight; 89.8 +/- 5.9 minutes), and rTAP 100 (three of eight; 54.0 +/- 16.3 minutes). All of the dogs that reoccluded in the rHIR 100 group did so after termination of the inhibitor infusion, whereas two of the three dogs in the rTAP 100 group that reoccluded did so during the inhibitor infusion. Coronary artery blood flow was characterized by intermittent periods of reocclusion and recanalization in all groups except rTAP 100. CONCLUSIONS: The potent antithrombotic effects of rTAP in this model directly implicate de novo thrombin formation as a major source of thrombin activity within the highly thrombogenic residual thrombus. These findings suggest that direct inhibition of prothrombinase activity may be an effective strategy in the development of a new class of conjunctive agents.

Animals↗
PubMed1992

Acceleration of recombinant tissue-type plasminogen activator-induced reperfusion and prevention of reocclusion by recombinant antistasin, a selective factor Xa inhibitor, in a canine model of femoral arterial thrombosis.

Antistasin is a 119-amino acid protein initially isolated from salivary glands of the Mexican leech, Haementeria officinalis, that exhibits potent anticoagulant properties resulting from selective inhibition of blood coagulation factor Xa. The comparative antithrombotic efficacies of recombinant antistasin (rATS), standard heparin (Hep), and aspirin (ASA) administered adjunctly with recombinant tissue-type plasminogen activator (tPA) on thrombolytic reperfusion and reocclusion were determined in a canine model of femoral arterial thrombosis. An occlusive thrombus was formed by insertion of a thrombogenic copper coil into the femoral artery, and blood flow velocity was monitored directly and continuously by Doppler flowmetry. Sixty minutes after occlusion, dogs received an intravenous infusion of either saline (vehicle) or rATS (0.31, 1.25, or 2.5 micrograms/kg/min), intravenous boluses of Hep (100 units/kg + 50 units/kg/hr or 200 units/kg + 150 units/kg/hr), or a single intravenous bolus of ASA (2.0 mg/kg), followed 45 minutes later by tPA (0.8 mg/kg i.v. over 90 minutes). The saline and rATS infusions were discontinued 60 minutes after termination of tPA, and the last Hep boluses were given 105 minutes after termination of tPA. All dogs achieved reperfusion. The time to reperfusion in the ASA group was similar to that in the vehicle group (50 +/- 9 versus 50 +/- 6 minutes, respectively). Reperfusion times were slightly decreased by the low and high doses of Hep (34 +/- 6 and 31 +/- 4 minutes, respectively) and the rATS doses of 0.31 and 1.25 micrograms/kg/min (37 +/- 4 and 36 +/- 5 minutes, respectively). However, the time to reperfusion was dramatically reduced with the 2.5 micrograms/kg/min rATS dose (15 +/- 3 minutes, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Cardiovascular responses of patients with cardiac disease to talking and exercise stress testing.

The blood pressure (BP), heart rate (HR), and premature ventricular contraction responses of patients with cardiac disease during talking were compared with those during exercise stress testing (EST). BPs, HR, and heart rhythm were recorded in 52 patients with cardiac disease before and during talking about an intentionally neutral topic and compared with changes during EST. The systolic and diastolic BP and HR increased significantly during talking. Diastolic BP increased significantly more during talking than during EST stages 1 and 2. The increase in diastolic BP during EST stage 3 did not differ from the increase during talking. HR and systolic BP increased more during EST than during talking. Nine patients had premature ventricular contractions during both EST and talking, two during EST only, and one while talking only. The verbalization protocol provides information about changes in diastolic BP that are not seen with EST. It also may be of value for evaluating heart rhythm, HR, and systolic BP changes for patients whose disabilities preclude EST.

Adult↗
PubMed1991

Antiarrhythmic actions of tocainide in canine models of previous myocardial infarction.

The antiarrhythmic and antifibrillatory efficacies of the class IB antiarrhythmic agent tocainide were characterized in conscious dogs in the early subacute phase of anterior myocardial infarction (48 hours after infarction) and in anesthetized dogs with ventricular tachyarrhythmias that were inducible by programmed stimulation more chronically (10.8 +/- 1.0 days) after anterior myocardial infarction. The frequency of spontaneous premature ventricular complexes in the early subacute postinfarction phase was reduced significantly from 48.4% +/- 10.5% to 8.2% +/- 5.0% of total complexes (p less than 0.01) by the cumulative intravenous administration of 10 mg/kg tocainide. In the late postinfarction setting, the intravenous administration of tocainide (6 mg/kg intravenous loading dose + 100 micrograms/kg/min intravenous maintenance infusion) suppressed the initiation of ventricular tachyarrhythmias by programmed stimulation in 5 of 12 animals that were tested and slowed the rate of tachycardia in 3 additional animals. However, the incidence of ventricular fibrillation and of the total number of arrhythmia-related deaths that resulted from the occurrence of a secondary ischemic insult in the presence of previous infarction did not differ significantly between tocainide (75% [9 of 12] incidence of both ventricular fibrillation and of total number of arrhythmia-related deaths) and saline-vehicle control groups (80% [12 of 15] incidence of ventricular fibrillation; 93.3% [14 of 15] incidence of total number of arrhythmia-related deaths). These findings suggest that although class I agents such as tocainide may be efficacious in the suppression of spontaneous premature ventricular complexes and ventricular arrhythmias immediately after myocardial infarction, they may be of limited value in the prevention of malignant ischemic arrhythmias that occur later after myocardial infarction.

Animals↗
PubMed1991

Myocardial contractile behavior of a new sotalol derivative.

The effects of E4031, a new class III antiarrhythmic agent similar to sotalol, were tested in isometrically contracting rabbit papillary muscles and in anesthetized, open-chest dogs. In papillary muscles, E4031 caused a modest dose-dependent increase of 26 +/- 8% in developed tension and 38 +/- 8% in its maximal rate of rise. Since there was no significant change in the maximal rate of relaxation, the ratio between both maximal velocities increased from 0.92 +/- 0.03 to 1.19 +/- 0.10. Time to peak tension did not change significantly, whereas time to half relaxation increased from 72 +/- 3 to 85 +/- 4 ms. The effective refractory period in the rabbit papillary muscles increased from 179 +/- 10 to 414 +/- 45 ms. In the open-chest dog, the i.v. administration of E4031 did not induce significant changes in heart rate, mean arterial pressure, or left ventricular end diastolic pressure. +dP/dt increased from 1,839 +/- 162 to 2,470 +/- 247 mm Hg/s with no significant change in -dP/dt after 100 micrograms/kg of E4031. Consequently, (+dP/dt)/(-dP/dt) increased from 0.97 +/- 0.07 to 1.18 +/- 0.08. To further evaluate the effects of E4031 on myocardial relaxation, the time constant of isovolumic left ventricular pressure decay was measured by two different methods (tau 1 and tau 2) before and after administering 10 micrograms/kg E4031. Tau 1 increased from 27 +/- 1.8 to 33 +/- 1.6 ms and tau 2 increased from 30 +/- 2.3 to 41 +/- 3.3 ms.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Effects of new and potent methanesulfonanilide class III antiarrhythmic agents on myocardial refractoriness and contractility in isolated cardiac muscle.

The effects of the new and potent methanesulfonanilide class III antiarrhythmic agents (E-4031, UK-66,914, and UK-68,798) on myocardial refractoriness and contractility were compared to those of d-sotalol in ferret isometrically contracting right ventricular papillary muscle preparations. During 1 Hz pacing at 37 degrees C, the four class III agents elicited concentration-dependent increases in ventricular effective refractory period (ERP), with a relative order of potency of UK-68,798 greater than E-4031 greater than UK-66,914 much greater than d-sotalol. EC25 values (effective concentration required to increase ERP 25% above baseline) were (in microM) UK-68,798, 0.018; E-4031, 0.058; UK-66,914, 0.501; and d-sotalol, 43.76. Maximal increases in ERP relative to baseline (% of baseline value) for the class III agents at 37 degrees C (range of 44.5 +/- 4.5 to 63.0 +/- 3.1%) were greater than the maximal increases observed at 27 degrees C (range of 15.0 +/- 3.3 to 31.2 +/- 4.8%), whereas the maximal absolute (ms) increases in ERP above baseline were comparable for the class III agents at both temperatures. Increases in ERP produced by the four class III agents at 37 degrees C were significantly greater at a pacing frequency of 1 Hz (range of 70.0 +/- 7.6 to 102.0 +/- 2.3 ms) than at 3 Hz (range of 18.3 +/- 4.4 to 31.BBB/- 4.8 ms). During a temporary period of hypoxic perfusion at 37 degrees C, increases in ERP produced by the four class III agents were reversed, such that "hypoxic" ERP values approximated pretreatment, baseline values.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1991

Cardiac electrophysiologic and inotropic actions of new and potent methanesulfonanilide class III antiarrhythmic agents in anesthetized dogs.

The effects of cumulative intravenous (i.v.) administration of potent and selective methanesulfonanilide class III antiarrhythmic agents on cardiac electrophysiologic and hemodynamic parameters were compared with those of D-sotalol in chloralose-anesthetized dogs. The new class III agents tested were E-4031 [1-(2-(6-methyl-2-pyridyl)ethyl)-(4-methanesulfonamidobenzoyl)pipe ridine]; UK-66,914 [N-(4-(1-hydroxy-2-(4-(4-pyridinyl)-1-piperazinyl)ethyl)phenyl) methanesulfonamide], and UK-68,798 [1-(4-methanesulfonamidophenoxy)-2-(N- (4-methanesulfonamidophenethyl)-N-methylamino)ethane]. The class III agents produced significant and dose-dependent increases in ventricular refractoriness, with effective doses required to increase ventricular relative refractory period 20 ms above baseline (ED20, micrograms/kg i.v., with 95% confidence limits) of 5.2 (4.2-6.6) for UK-68,798, 17 (13-23) for E-4031, 75 (58-99) for UK-66,914, and 3,700 (2,600-5,800) for D-sotalol. Significant increases in the electrocardiographic QT and QTc intervals paralleled the increases in ventricular refractoriness for the four class III agents. Significant increases in left ventricular (LV) + dP/dt also paralleled increases in ventricular refractoriness and QT intervals for E-4031 (10-1,000 micrograms/kg i.v.), UK-66,914 (100-1,000 micrograms/kg i.v.), and UK-68,798 (30-1,000 micrograms/kg i.v.), but not for D-sotalol. No concomitant alterations in LV-dP/dt were observed for the new and potent methanesulfonanilide class III agents, resulting in significant increases in the ratio of LV + dP/dt/-dP/dt for E-4031, UK-66,914, and UK-68,798. Potent and selective methanesulfonanilide class III agents therefore may augment cardiac contractility in addition to prolonging ventricular refractoriness.

Animals↗
PubMed1991

Hypothyroidism renders protection against lethal ventricular arrhythmias in a conscious canine model of sudden death.

The protective effect of hypothyroidism against lethal ventricular tachyarrhythmias (VT) in the subacute phase of experimental myocardial infarction (MI) was investigated in 10 thyroidectomized dogs using a conscious model of sudden coronary death. Four weeks after surgical ablation of the thyroid, and having established biochemical hypothyroidism, anterior MI was produced by 120 min of occlusion-reperfusion of the left anterior descending coronary artery. In the subacute phase of MI, the inducibility of VT was investigated using programmed ventricular stimulation (PVS), and the effects on spontaneous development of ventricular fibrillation (VF) were studied by production of posterolateral ischemia at a site remote from the area of the previous infarction. Ischemia was produced by the passage of anodal direct current through a silver wire electrode implanted in the left circumflex coronary (LCX) artery. The results were compared to those from a cohort of 20 existing euthyroid controls that had undergone an identical experimental protocol. No differences were found in heart rate and other electrocardiographic parameters such as the PR, QRS, and QT (paced at 2.5 Hz) and the QTc interval between the hypo- and euthyroid groups. During PVS in the subacute phase of anterior MI, the measured threshold voltage and ventricular refractory periods were similar in both groups. The incidence of inducibility of VT was 100% in the euthyroid animals compared to 60% in the hypothyroid dogs, suggesting an antiarrhythmic effect of hypothyroidism. The incidence of sustained vs. nonsustained VT was similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Effective thrombolysis without marked plasminemia after bolus intravenous administration of vampire bat salivary plasminogen activator in rabbits.

BACKGROUND: The use of recombinant tissue-type plasminogen activator (t-PA) in thrombolytic therapy is frequently associated with significant fibrinogenolysis. In contrast, recombinant vampire bat salivary plasminogen activator (Bat-PA) displays strict fibrin specificity, an attribute that could be desirable in a fibrinolytic agent. METHODS AND RESULTS: The efficacy and fibrin selectivity of Bat-PA was evaluated and compared with that of t-PA using a rabbit model of femoral arterial thrombosis. Administration of 8.1, 14, and 42 nmol Bat-PA/kg by bolus intravenous injection restored flow in 50%, 75%, and 80% of the rabbits, respectively. The incidence of reperfusion after bolus intravenous injection of 14 and 42 nmol t-PA/kg was 15% and 78%, respectively. The maximal femoral artery reperfusion flows were equivalent after treatment with 42 nmol Bat-PA/kg or 42 nmol t-PA/kg, but the time to reach maximal flow for Bat-PA was approximately one half that of t-PA. Furthermore, the rapid restoration of flow by 42 nmol Bat-PA/kg, in contrast to equimolar t-PA, was accomplished without fibrinogenolysis and with only small decreases in the plasminogen and alpha 2-antiplasmin levels. Equipotent doses of Bat-PA and t-PA both resulted in approximate 2.5-fold increases in the template bleeding times of aspirin-pretreated rabbits. The clearance of Bat-PA from rabbits exhibited biexponential elimination kinetics; approximately 80% was cleared by the relatively slow beta phase (half-life of 17.1 minutes). Overall, Bat-PA was cleared approximately fourfold slower than t-PA. CONCLUSIONS: Bolus intravenous administration of Bat-PA would facilitate prompt initiation of thrombolytic therapy, and the avoidance of plasminemia could result in fewer and less severe bleeding complications.

Animals↗
PubMed1990

Negative lusitropic effect of DPI 201-106 and E4031. Possible role of prolonging action potential duration.

In open-chest anesthetized dogs, the time constant of isovolumic left ventricular pressure decay increased following the intravenous administration of either E4031, a class III antiarrhythmic agent which acts by K+ channel blockade, or DPI 201-106 (DPI), a cardiotonic agent which acts by delaying Na+ channel inactivation. In addition to prolonging cardiac refractoriness, both E4031 and DPI increased left ventricular +dP/dt but without significantly altering -dP/dt. Consequently, the value of the ratio (+dP/dt)/(-dP/dt) increased. There were no significant changes in heart rate, mean arterial pressure, or left ventricular end diastolic pressure. Since both E4031 and DPI prolonged the action potential duration (APD) and the refractory period, and slowed relaxation in vivo, the possibility of a causal link between these effects was further investigated under in vitro conditions. In isometrically contracting rabbit papillary muscles, E4031 and DPI increased peak developed tension (DT) and its maximal rate of rise (+T). Since the maximal rate of fall of DT (-T) did not increase by the same factor that +T increased, the value of the ratio +T/-T increased. Time to half relaxation increased, whereas time to peak tension was not significantly changed by either E4031 or DPI. These negative lusitropic effects produced by E4031 or DPI were not observed when equivalent increases in contractility were produced by increasing the extracellular Ca2+ concentration. The effective refractory period measured in the papillary muscles increased following superfusion with either of the two drugs, consistent with their known ability to increase APD. A causal link between the prolongation of APD and the negative lusitropic effects of E4031 and DPI is postulated as the possible mechanism.

Action Potentials↗
PubMed1990

Suppression of lethal ischemic ventricular arrhythmias by the class III agent E4031 in a canine model of previous myocardial infarction.

The antiarrhythmic efficacy of a new and potent class III agent E4031 [1-[2-(6-methyl-2-pyridyl)-ethyl]-4-(4- methylsulfonylaminobenzoyl)piperidine] was evaluated in several canine models of recent myocardial infarction. In anesthetized dogs with baseline inducible ventricular arrhythmias studied 4-10 days after anterior myocardial infarction, 30-300 micrograms/kg i.v. E4031 suppressed induction of ventricular tachyarrhythmias by programmed ventricular stimulation in 7 of 10 animals tested, while significantly prolonging refractoriness in both noninfarcted and infarcted ventricular myocardium. The incidence of lethal ischemic ventricular arrhythmias developing in response to acute posterolateral myocardial ischemia in the presence of previous anterior infarction was reduced from 10 of 10 (100%) in a vehicle pretreatment group to 3 of 10 (30%, p less than 0.01) in an E4031 (300 micrograms/kg intravenously, i.v.) pretreatment group. Neither the sizes of the underlying anterior myocardial infarctions (26.9 +/- 3.7 vs. 33.2 +/- 2.1% of left ventricle) nor the times to development of acute posterolateral myocardial ischemia (43 +/- 11 vs. 40 +/- 8 min) differed significantly between the vehicle and E4031 pretreatment groups, respectively, suggesting that the reduction in the incidence of lethal ischemic arrhythmias in the E4031 pretreatment group was not due to smaller underlying, electrically unstable myocardial substrates nor to a delay in onset of the acute ischemic insult. In conscious dogs with spontaneous ventricular ectopy at 48 h after myocardial infarction and in anesthetized dogs with no baseline inducible arrhythmias at 4-10 days after myocardial infarction, E4031 (30-3,000 micrograms/kg i.v.) produced no facilitation or aggravation of spontaneous or inducible ventricular arrhythmias. These findings suggest that pharmacologic agents such as E4031 that increase ventricular refractoriness (class III electrophysiologic activity) may provide significant protection against development of malignant ischemic ventricular arrhythmias in the setting of previous myocardial infarction.

Anesthesia↗
PubMed1990

Failure of lidocaine to suppress lethal ischemic ventricular arrhythmias in a canine model of previous myocardial infarction.

The antiarrhythmic actions of high-dose intravenous (i.v.) lidocaine infusions were assessed in conscious dogs with spontaneous ventricular ectopy subacutely (48 h) after anterior myocardial infarction and in anesthetized dogs with ventricular tachyarrhythmias inducible by programmed ventricular stimulation at 4-11 days after anterior myocardial infarction. In conscious dogs administered cumulative doses of lidocaine at 48 h after myocardial infarction, a significant reduction in the frequency of spontaneous ventricular ectopic complexes (from 61 +/- 12 to 11 +/- 9% of total complexes) occurred only after administration of 10 mg/kg i.v. lidocaine. In anesthetized postinfarction dogs responding to baseline programmed stimulation with ventricular tachyarrhythmias, lidocaine administration (6 mg/kg i.v. loading dose + 100 micrograms/kg/min i.v. maintenance infusion) resulted in a selective increase in infarct zone conduction time (53.0 +/- 5.6 to 60.5 +/- 6.2 msec; p less than 0.05), increases in infarct zone relative refractory periods (RRPs 182 +/- 5 to 193 +/- 5 ms; p less than 0.05), and effective refractory periods (ERPs 156 +/- 4 to 165 +/- 3 ms; p less than 0.05), and an increase in noninfarct zone ERP (154 +/- 5 to 166 +/- 8 ms; p less than 0.05). The induction of ventricular arrhythmias by programmed stimulation was suppressed by lidocaine (6 mg/kg + 100 micrograms/kg/min i.v.) in 5 of 10 postinfarction animals tested, with an additional 3 animals displaying favorable stabilizations of induced arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗