Toshihisa Miyazaki

Pericardial prostaglandin biosynthesis prevents the increased incidence of reperfusion-induced ventricular fibrillation produced by efferent sympathetic stimulation in dogs.

This study tested the hypothesis that sympathetic neural stimulation increases the prevalence of reperfusion-induced ventricular fibrillation and explored the mechanisms by which this occurs and how it may be prevented. In anesthetized, autonomically denervated dogs, we examined the effects of bilateral ansae subclaviae stimulation (SS) and of induction of pericardial biosynthesis of prostaglandins, an intervention that reduces SS effects by acting at presynaptic sites. A 5-minute occlusion of the left anterior descending coronary artery distal to the first or second diagonal branch was performed during SS. Heart rate was maintained constant by atrial pacing. In the absence of SS, one of 23 dogs developed ventricular fibrillation during occlusion, and three of the remaining 22 dogs developed ventricular fibrillation upon reperfusion. SS did not increase the prevalence of occlusion-induced ventricular fibrillation (four of 23 dogs) but increased the prevalence of reperfusion-induced ventricular fibrillation (12 of the remaining 19 dogs, p = 0.01). SS did not affect occlusion-induced decrease in local electrogram amplitude recorded from the ischemic myocardium or myocardial blood flow to the ischemic myocardium during occlusion or reperfusion. SS, however, prevented occlusion-induced increase in diastolic excitability threshold. Instillation into the pericardial cavity of arachidonic acid solution (3 micrograms/ml) resulted in release of prostacyclin, measured by radioimmunoassay as a stable metabolite 6-ketoprostaglandin F1 alpha (63.1 +/- 11.3 ng/ml, n = 11, mean +/- SEM), and of prostaglandin E2 (7.0 +/- 0.9 ng/ml, n = 11). This pericardial solution blunted SS-induced increase in mean arterial blood pressure and reduced the prevalence of ventricular fibrillation during reperfusion (six dogs to one dog, p less than 0.05). Blood flow to the ischemic myocardium remained unaffected. Indomethacin, when added to the solution (3 micrograms/ml), reversed the effects of prostaglandin release and arrhythmia development. These data indicate that efferent sympathetic stimulation during a coronary occlusion and reperfusion sequence increases the prevalence of reperfusion-induced ventricular fibrillation that is reduced by pericardial biosynthesis of prostaglandins. Pericardial prostaglandin synthesis may serve as a unique antiarrhythmic function by regulating efferent cardiac sympathetic nerve effects.

Blockade of ATP-sensitive potassium channels by 5-hydroxydecanoate suppresses monophasic action potential shortening during regional myocardial ischemia

SummaryWe tested 5-hydroxydecanoate (5-HD), a specific blocker of ATP-sensitive potassium channels (IK.ATP), to determine if it mitigates electrophysiologic changes produced by regional myocardial ischemiain vivo. A sequence of 5-minute occlusion of the distal LAD and 30-minute reperfusion was repeated while recording the monophasic action potential (MAP) and bipolar electrogram (EG) from the epicardial center of the ischemic myocardium in anesthetized dogs. 5-HD (30 mg/kg, IV) or glibenclamide (0.15 or 0.3 mg/kg, IV) was administered before the third occlusion, and the data were compared to the second occlusion data. 5-HD did not affect baseline MAP duration at 90% and 50% repolarization (APD90, APD50) before LAD occlusion but suppressed occlusion-induced shortening of APD90 (16 ± 2% during the second occlusion vs. 5 ± 3% during the third occlusion, n=8, p<0.01) and APD50 (16 ± 3% vs. 10 ± 3%, n=8, p<0.05). Pretreatment with glibenclamide also suppressed occlusion-induced MAP shortening and eliminated an additional effect of 5-HD (n = 3). 5-HD did not affect the occlusion-induced increase in duration and activation time of EG. 5-HD, as well as glibenclamide, suppressed regional ischemia-induced MAP shortening, probably by blocking activation of IK.ATP, without affecting conduction delay. These differential effects of 5-HD on repolarization and conduction during the early phase of regional ischemia might have the potential to suppress reentrant ventricular arrhythmias.

Nicorandil augments regional ischemia-induced monophasic action potential shortening and potassium accumulation without serious proarrhythmia

Nicorandil is a clinically used nitrovasodilator that has a property as an opener of ATP-sensitive potassium (KATP) channels in vitro. We examined whether nicorandil at a clinically used dose augmented regional ischemia-induced monophasic action potential (MAP) shortening and increase in extracellular potassium concentration ([K+]o), and how it affected arrhythmia occurrence. Five-minute occlusion of a distal site of the left anterior descending coronary artery (LAD) was repeated at 30-min intervals in anesthetized open-chest dogs while recording MAP or measuring [K+]o with a potassium-sensitive valinomycin electrode from the epicardial center of the ischemic myocardium. Nicorandil (0.2-0.5 mg/kg) was administered intravenously (i.v.) 5 min before the third occlusion, and the data were compared with those during the second occlusion (control). During the second occlusion, MAP duration at 90% repolarization (APD90) shortened (mean rate for 5 min, 13 +/- 3%, n = 11) and [K+]o increased from 3.7 +/- 0.1 to 6.2 +/- 0.8 mM at 5 min (n = 12). These changes were reversed < or = 3 min after reperfusion. Before the third occlusion, baseline APD90 and [K+]o were not altered by nicorandil; however, the extent of occlusion-induced shortening of APD90 (25 +/- 4%) and [K+]o increase (7.8 +/- 1.6 mM) was augmented by the pretreatment. The drug effect was attenuated by a concomitant pretreatment with 5-hydroxydecanoate, a specific blocker of KATP channels (n = 2). The prevalence of ventricular fibrillation (VF) during occlusion/reperfusion sequence was reduced after nicorandil (1 of 25 vs. 5 of 25) without de novo VF. These results suggest that nicorandil at a clinical dose facilitates regional ischemia-induced activation of myocardial KATP channels without causing serious proarrhythmia. Such a property might help protect the myocardium against ischemia/reperfusion damage.

Intractable heart failure, conduction disturbances and myocardial infarction by massive myocardial invasion of malignant lymphoma

A patient with malignant lymphoma who developed congestive heart failure, conduction disturbances and myocardial infarction is presented. Two-dimensional echocardiography revealed marked thickening of the left ventricular wall, where the gallium scan correspondingly showed an abnormal accumulation. Irradiation to the mediastinum resulted in a dramatic decrease in ventricular wall thickness and disappearance of the gallium accumulation. Postmortem examination confirmed previous lymphomatous involvement of the myocardium. Combined techniques, including echocardiography and gallium scan, can be valuable for noninvasive detection and follow-up of myocardial involvement in patients with malignant lymphoma.

Protection of hypoxic myocardium by intracoronary administration of verapamil in open-chest dogs.

Hypoxic perfusion of the regional myocardium was performed in 34 open-chest dogs. In eight dogs in which the myocardium was perfused with original hypoxic Krebs-Henseleit (K-H) solution for 5 min (group I) there was a marked decrease in adenosine triphosphate content (2.03 +/- 0.44 mumol/g) and an increase in lactate content (8.65 +/- 2.26 mumol/g). In myocardium of nine dogs (group II) perfused with verapamil-containing (1.3 mg/dl) K-H solution and in that of nine dogs (group III) receiving Ca2+-free solution, the degrees of reduction in adenosine triphosphate (2.99 +/- 0.73 and 3.25 +/- 0.48 mumol/g, respectively) and of lactate accumulation (5.16 +/- 0.59 and 4.79 +/- 1.02 mumol/g, respectively) at 5 min were significantly less than in group I. Absence of statistically significant differences in hemodynamic parameters among these three groups indicates that the metabolic preservation in group II probably resulted from a direct effect of verapamil on the regional myocardium related to Ca2+ metabolism. However, metabolic data in four dogs of group I and four dogs of group III killed at 40 sec of perfusion, in conjunction with results of the analysis of regional contraction, revealed that the time courses of segmental shortening in the three groups did not account for the metabolic differences among them.

Changes in left ventricular diastolic function after left ventriculography: A comparison with iopamidol and urografin

Changes in left ventricular (LV) diastolic indices after left ventriculography (LVG) with iopamidol or urografin were studied in 42 subjects. Increase in heart rate and decrease in LV systolic pressure were more significant with urografin than with iopamidol (p less than 0.05 to 0.001). LV end-diastolic pressure was elevated more with urografin than with iopamidol (p less than 0.005 to 0.05) 1 to 3 minutes after LVG. LV peak negative dP/dt decreased significantly with urografin immediately (10 to 15 seconds, -511 and 30 seconds, -376 mm Hg/sec; p less than 0.0005 to 0.02), but with iopamidol it did not decrease significantly after LVG. Time constant, T, was elongated with iopamidol (10 to 15 seconds, +13 and 30 seconds, +6 msec; p less than 0.0005), but this elongation was significantly less than urografin (10 to 15 seconds, +34; 30 seconds, +25; 1 minute, +15; and 2 minutes, +10 msec; p less than 0.05 to 0.0005). We conclude that iopamidol disturbed LV diastolic function to a lesser degree than did urografin.

Examination of the Direct Effects of Nicorandil, Verapamil, Propranolol, and Nitroglycerin on the Hypoxic Canine Myocardium

Effects of intracoronary administration of verapamil (VER), nitroglycerin (TNG), propranolol (PRO), and nicorandil (NIC) on regional hypoxia were examined in 39 open-chest dogs. Distal left anterior descending coronary artery was perfused for 5 min with deoxygenated Krebs-Henseleit solution (KHS) in group 1 (n = 9), VER-containing (1.3 mg/dl) KHS in group 2 (n = 9), TNG-containing (0.5 mg/dl) KHS in group 3 (n = 7), PRO-containing (0.4 or 0.8 mg/dl) KHS in group 4 (n = 7), and NIC-containing (0.5 or 2.5 mg/dl) KHS in group 5 (n = 7). Transmural biopsy at 5 min revealed a less severe metabolic deterioration in the hypoxic myocardium in groups 2, 4, and 5, as evidenced by higher ATP content (2.99 ± 0.73, 2.81 ± 0.35, and 3.14 ± 1.20 μmol/g in groups 2,4, and 5, respectively) and lower lactate accumulation (5.16 ± 0.59, 5.62 ± 1.44, and 5.05 ± 1.12 μmol/g in groups 2, 4, and 5, respectively) compared with those in group 1 (2.09 ± 0.45 μmol/g in ATP and 8.77 ± 2.34 μmol/g in lactate). Metabolic preservation by VER, PRO, and NIC were not mediated by changes in hemodynamics and regional myocardial contraction. On the other hand, any significant protective effects were not noted in group 3, despite a significant reduction in rate-pressure products. Under an aerobic condition these agents affected regional myocardial contraction in a different manner from each other.

Ectopic ventricular tachycardia sensitive to calcium antagonists in acute myocardial infarction in dogs.

The effects of antiarrhythmic agents on automatic ventricular tachycardia (VT), which emerged in the early stage of acute myocardial infarction (AMI), were examined in 30 closed-chest mongrel dogs. Antiarrhythmic agents were administered intravenously when the rate of VT became almost equal to sinus rate (5.6 +/- 1.4 hours). VT was slowed significantly by verapamil (0.15 or 0.3 mg/kg), diltiazem (0.2 or 0.4 mg/kg), propranolol (0.1 mg/kg) and amiodarone (5 mg/kg), but not by procainamide (20 mg/kg), lidocaine (2 or 4 mg/kg), nifedipine (0.01 mg/kg) and nicorandil (0.03 mg/kg). The number of ventricular premature complexes was reduced most effectively by verapamil. The significant suppressive effects of calcium antagonist drugs (verapamil and diltiazem) and propranolol indicate that an inward calcium current during diastole may play a critical role in the abnormal enhancement of ventricular automaticity in the early stage (4 to 8 hours) of AMI.

Epicardial mapping during induction of nonsustained polymorphic ventricular tachycardia in a 7-day-old canine myocardial infarction model

Programmed electrical stimulation and epicardial mapping were performed to study electrophysiologic mechanisms for induction of nonsustained polymorphic ventricular tachycardia in 29 dogs with 7-day-old myocardial infarction. Nine dogs had 15 different episodes of reproducible monomorphic ventricular tachycardia (11 sustained and 4 nonsustained) (group A). Seven episodes of polymorphic ventricular tachycardia (group B) were induced in six dogs, three of which degenerated into ventricular fibrillation. Epicardial activation time during premature stimulation at the time of tachycardia induction was more prolonged in group A than in group B (183 +/- 43 vs 123 +/- 35 msec, p less than 0.01). Furthermore, induction of ventricular tachycardia was preceded by the development of functional block in 13 of 15 group A tachycardias, but in only three of seven group B tachycardias. During polymorphic ventricular tachycardia, epicardial activation patterns were radial from the earliest epicardial activation site, similar to those observed during left ventricular endocardial pacing. QRS polymorphism was associated with a beat-to-beat variation in the earliest epicardial activation site. In conclusion, inducibility of nonsustained polymorphic ventricular tachycardia is less dependent on the epicardial activation sequence than on monomorphic ventricular tachycardia.

Comparative effects of intracoronary administration of propranolol with systemic administration on hypoxic canine myocardium

Myocardial protective effects of intracoronary administration of relatively small doses of propranolol were examined and compared with systemic administration in 20 open-chest dogs. In group 1 (n = 6) rate-pressure-product (R X P) did not change during 5-minute left anterior descending artery (LAD) perfusion with deoxygenated Krebs-Henseleit solutions (KHS). However, R X P decreased by the same degree in group 2 (n = 7), which received perfusion with KHS containing 0.4 or 0.8 mg/dl of propranolol, and in group 3 (n = 7) given LAD perfusion with original KHS and systemic administration of 0.02 to 0.04 mg/kg of propranolol. Total administered doses of propranolol were the same for groups 2 and 3. Transmural biopsy after 5 minutes of perfusion revealed less severe metabolic deterioration of hypoxic myocardium in group 2 when compared with that in group 1, as evidenced by higher ATP (adenosine triphosphate) (2.81 +/- 0.35 versus 2.23 +/- 0.45 mumol/g, p less than 0.05) and lower lactate content (5.62 +/- 1.44 versus 9.01 +/- 2.62 mumol/g, p less than 0.05). On the other hand, significant metabolic preservation was not noted in group 3. Sequential changes in regional myocardial contraction did not differ among the three groups. In conclusion, intracoronary administration of propranolol showed myocardial protective effects that were not mediated by the changes in hemodynamics and myocardial contraction.