Endothelial driving factors pathophysiologically affect the regulation of coronary circulation.
To investigate the regulation of vascular function by endothelium-derived relaxing factor (EDRF) and endothelial cells, endothelium-dependent relaxation impairment was studied in acute ischemia-reperfusion injury in large coronary artery and coronary microvasculature. EDRF (NO) production and release were inhibited due to ischemia-reperfusion injury to the endothelium of large coronary arteries. There was an increased sensitivity selective to ET-1 in large coronary arteries exposed to ischemia and reperfusion. Reduced endothelium-dependent relaxation and augmented ET-1 sensitivity in large coronary arteries suggest the existence of spasmogeneity in reperfused blood vessels.
Ischemia and reperfusion also brought about various morphological and functional changes in the reperfused coronary microvasculature. Edema of perivascular interstitium and endothelial cells was the main observation and caused a decrease in the ability of the microvascular bed to dilate because of extravascular compression.
To examine the long-term suppression of NO synthesis accompanying endothelial dysfunction, the long-term reactions of coronary arteries and myocardium due to chronic inhibition of NO synthesis by continuously infused L-NAME was investigated. Endothelial cell impairment, proliferation and disarrangement of medial smooth muscle cells, microvascular injury due to platelet thrombi and increased perivascular fibrous tissue were found in rat coronary arteries. Myocardial fibrosis due to coronary microvascular injury was observed. These changes in coronary arterial and myocardial structure were suppressed by ACE inhibitors. Therefore, ACE inhibitors are useful in the treatment of coronary microvascular impairments.

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We analyzed the acute, direct effects of nitroglycerin (NTG) tape on the coronary arteries and hemodynamics in 38 patients who underwent coronary angiography. The diameters of the 3 main coronary arteries were compared among the angiograms obtained at baseline, 15 minutes following transdermal administration of 10mg (8 patients) or 25mg (30 patients) of NTG (Millisrol tape®), and after intracoronary injection of 2.5mg isosorbide dinitrate (ISDN). Only the left main trunk and proximal portion of the left anterior descending artery dilated after 10mg of transdermal NTG administration (p<0.05). However, every measured coronary segment (segments 1-8, 11, and 13) dilated (p<0.05) after 25mg of NTG. Systemic blood pressure decreased slightly but significantly from 150±22 to 147±21mmHg during the study, with no change in heart rate. Left ventricular end-diastolic pressure decreased significantly from 16±7 to 14±5mmHg. We conclude that 25mg of transdermal NTG tape dilates coronary arteries and is applicable for acute coronary syndrome, with few complications.

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The effect of injecting ethanol directly into the myocardium to control aconitine-induced ventricular tachycardia (VT) was evaluated in anesthetized dogs. In 17 dogs, VT was induced by injecting aconitine (1.0μg, median dose) directly into the epicardium. After inducing persistent VT for up to 3min, 0.6 ml (median volume) of 96% ethanol was injected into the same epicardial region. Regular sinus rhythm reappeared in 15 dogs with no change in systolic blood pressure; the other 2 dogs died of ventricular fibrillation (VF). In another 13 dogs, VT was induced by injecting aconitine directly into the endocardium using a Variocath needle catheter. After persistent VT for up to 3min, a regular sinus rhythm was restored in 7 dogs by injecting 2.0ml (median volume) of 96% ethanol; the remaining 6 dogs died of VF. Histology showed no transmural necrosis and the subendocardial necrotic areas were essentially the same in the dogs that recovered from VT as in those that died. There was no statistically significant relationship between doses of ethanol and VT duration. These preliminary results suggest that the injection of ethanol into the myocardium may efficiently terminate VT when other techniques fail.

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The inward rectification of the inward rectifier K⁺ channels has been reported to be caused by both the block of the outward current by cytoplasmic Mg²⁺ and by intrinsic channel gating. Recently it was uncovered that the apparent intrinsic gating is mostly due to a block by cytoplasmic polyamines which is actually extrinsic to the channel. Furthermore, negatively charged amino-acid residues in the center of the M2 region and in the C-terminal hydrophilic domain were identified to be involved in the binding of these blockers to the channels, The inward rectifier shows consistent inward rectification at various extracellular K⁺ concentrations ([K⁺]o). To explain the dependency of the channel activity on K⁺o, the hypothesis that K⁺o interacts with the inward rectifier K⁺ channel and thereby activates it (K⁺-activated K⁺ channel model) has been postulated. In this manuscript, the history and recent progresses of the study of the inward rectification mechanism, especially the effect of the cytoplasmic blockers and K⁺o, is reviewed.

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The binding sites of three typical calcium channel antagonists, 1, 4-dihydropyridines, benzothiazepines and phenylalkylamines, were successfully identified within the primary structures of calcium channels using a photoaffinity labeling technique. The results confirm pharmacological observations of the three antagonists that had been proposed to interact allosterically with each other. We briefly review the results and discuss the future prospects.

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A PCR-based cloning strategy was used to identify novel subunits of the two-transmembrane domain inward rectifier potassium channel family from rat brain, heart, and skeletal muscle. When expressed in Xenopus oocytes, two of these clones (Kir4.1 and Kir2.3) gave rise to inwardly rectifying potassium currents. Two-electrode voltage clamp commands to potentials negative to E_K evoked inward potassium-selective currents which rapidly reached a peak amplitude and then relaxed to a steady-state level. Differences in the extent of current relaxation, the degree of rectification, and the voltage-dependent block by external cesium were detected. Two other members of this family (Kir5.1 and Kir3.4) did not produce macroscopic currents, when expressed by themselves, yet both subunits modified the currents when coexpressed with other specific members of the Kir family. Expression of chimeric subunits between Kir4.1 and either Kir5.1 or Kir3.4 suggested that the transmembrane domains determine the specificity of subunit heteropolymerization, while the C-terminal domains contribute to alterations in activation kinetics and rectification. Expression of covalently linked subunits demonstrated that the relative subunit positions, as well as stoichiometry, affect heteromeric channel activity.

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The chloride conductance that arises from the stimulation of β-adrenoceptors has been shown to be carried by a cardiac isoform of cystic fibrosis transmembrane conductance regulator (CFTR) Cl^- channels. This brief review will focus first upon the cellular signal transduction system for the activation of this type of Cl^- channels and then its regulation by catecholamines, muscarinic agonists, endothelin-1 and angiotensin-II. Both in physiological and pathological conditions, the complex interaction of these agonists modulates the Cl^- conductance, which is potentially arrhythmogenie by shortening the action potential duration and inducing the depolarization.

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The experimental evidence so far described in the literature is reviewed to explain the ionic mechanisms underlying the cardiac pacemaker potential in the sinoatrial node cell. Following gating mechanisms underlie the slow diastolic depolarization of the SA node cells.¹²⁾ The delayed rectifier K⁺ channels (mainly the rapidly activated component of the delayed rectifier K⁺ currents, which is blocked by E-4031) activated during the preceding action potential are deactivated during diastole. The inactivation of the L-type Ca²⁺ channel is removed during the early diastolic period and results in an increasing inward current, provided that the amplitude of the window component is of significant amplitude. Because of its sustained nature, the removal of inactivation of the sustained inward current Ist, also generates inward current. The negative membrane potential near the maximum diastolic potential activates the hyperpolarization-activated non-selective cation current, If. Finally, the L-type Ca²+ channel is activated at the late phase of diastole depolarization, resulting in the maximum rate of rise of the action potential. These time- and voltage-dependent changes in membrane conductance occur in the presence of a significant background conductance. During the slow diastolic depolarization, Ist and IK may be the major component in the inward and outward currents, respectively.

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Study of TTX and STX toxins and their interaction with cloned Na channels has led to a molecular model of the toxins' binding site. This model is able to explain isoform differences in binding affinity, allowing prediction of the structures of toxin-resistant channels. It provides an example of a detailed drug binding site that could serve as an example for drug engineering to improve affinity and specificity. The model has also suggested important molecular characteristics of the channel's permeation path, providing a wealth of ideas for study of this fundamental biophysical process at the molecular level. The model of the TTX and STX binding site outlines an approach to resolution of molecular structure and of certain structure-function relationships, and experimentation provoked by the model will assist in improving it.

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Using the patch clamp technique, normal and abnormal functions of cardiac ion channels were studied. The transient outward K⁺ current contributes to the early repolarization phase of the action potential as well as to the plateau height and total duration. The latter role is observed in at premature excitations due to slow recovery from inactivation of this current compared to that of the Ca²⁺ current. Early and delayed afterdepolarizations are produced by multiple components of ionic currents, especially in the former case. Transient inward current is mainly involved in the formation of delayed afterdepolarizations, but the activities can be produced by a different ionic mechanism in rare occasions. Barium-induced automaticity can be brought about by blocking and unblocking of the inward rectifier K⁺ channels. The ATP-sensitive K⁺ channels are assumed to play important roles in myocardial ischemia and related conditions. The channels are a target of the K⁺ channel openers and their functions are modulated by various intracellular factors. While the channel activity is strongly inhibited by intracellular ATP, ATP is necessary for the channel in an operative state. The former effect by ATP is produced by its ligand action, but the latter may be brought about by hydrolysis of MgATP, which may be regulated by the assembly and disassembly of the actin cytoskeleton.

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The effects of antiarrhythmic agents, including Classes I and IV and 3-10mM Mg²⁺ on aconitine-induced arrhythmias were examined using a conventional microelectrode and patch clamp method in Langendorff-perfused rabbit hearts and isolated guinea-pig ventricular myocytes. Intracoronary application of 0.1μM aconitine induced polymorphic ventricular tachycardia (PVT) which continued for more than 60 minutes. Application of aconitine to ventricular myocytes caused a prolonged action potential duration (APD) and the appearance of early afterdepolarization (EAD) together with the occurrence of an inward hump of the I-V curve around -60 to -40mV and increased outward current at positive voltages. Application of 10μM TTX and 5mM or higher Mg²⁺ restored aconitine-induced PVT to sinus rhythm in Langendorffperfused preparations and also shortened the prolonged APD, demonstrating the abolishment of EAD by aconitine in ventricular myocytes. However, antiarrhythmic agents did not exert such effects. In conclusion, the antiarrhythmic actions of Mg²⁺ and TTX in aconitine-induced arrhythmia are to abolish EAD and shorten the prolonged APD by suppression of the inward Na⁺ current around -60 to -40mV.

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This article reviews experimental studies on the electrophysiological effects of amiodarone on mammalian hearts. Acute application of amiodarone (0.1-10μM) to papillary muscles or single ventricular cells isolated from rabbits or guinea pigs caused a significant decrease in action potential duration (APD) as well as a marked use-dependent inhibition of the maximum upstroke velocity (Vmax) of action potential with fast recovery kinetics. Acute amiodarone also caused a concentration-dependent decrease in the calcium current (I_Ca) and the delayed-rectifier potassium current (I_K). Action potentials recorded from papillary muscles or single ventricular cells isolated from the rabbits treated with oral amiodarone (100mg/kg daily, 4 weeks) were characterized by a moderate frequency-independent prolongation of APD. There was no use-dependent Vmax inhibition. The ventricular cells treated with chronic amiodarone showed a significant decrease in the current density of IC_a, I_K and It_o. The amount of mRNA for Kv1.5, a Shaker-related potassium channel from the rats treated with chronic oral amiodarone was significantly lower than that from control rats, These results suggest that the major and consistent effects of chronic amiodarone is repolarization delay (Class III action) through a decrease in I_K and I_to density, probably due to a modulation of gene expression of potassium channels. When amiodarone above a certain concentration is present in the extracellular space, fast kinetic Class I and Class IV actions would be added as acute effects.

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The heart Na channel, although resembling other voltage-gated Na channels, has important functional and structural differences. For heart channels expressed in oocytcs, the midpoint of the inactivation relationship was 13mV negative to that of rat skeletal muscle Na channels, and sensitivity to tonic lidocaine block was approximately 5 times more sensitive for heart. Co-expression with the β subunit increased the difference in inactivation midpoint to 24mV, largely by changing the midpoint of the rat skeletal muscle channel by 10mV in the positive direction. Co-expression with β1 decreased lidocaine sensitivity for heart but not for skeletal muscle Na channels, and decreased but did not eliminate the greater heart sensitivity to lidocaine block. The differences in inactivation are likely to account for some, but not all, of the differences in lidocaine sensitivity. This cardiac phenotype is important for the role the channel plays in cardiac physiology and pathophysiology, and also may lead to elucidation of structure-function relationships

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Catheter ablation for septal accessory pathways is occasionally associated with complications, such as atrioventricular block, since the septal region is a complex anatomical structure containing the atrioventricular conduction system. Therefore, we designed a signal separator composed of an inductancecapacitance network with which the local electrogram at the ablation site could be continuously monitored during the delivery of radiofrequency (RF) energy. We tested the safety and efficacy of RF catheter ablation using a signal separator in 17 patients with septal accessory pathways (10 anteroseptal and 7 midseptal cases). RF energy (520KHz) was applied at an output of 20-40W for 30-120sec. to the atrioventricular annulus where the shortest atrioventricular interval or accessory pathway potential was recorded on the electrogram using a large tip ablation electrode. In ablation for the anteroseptal or midseptal accessory pathways, the atrial to ventricular amplitude ratio on the local electrogram was maintained at 1 or less during the delivery of RF energy. In all 17 cases, the interruption of accessory pathways was successful without atrioventricular block. In one patient, accessory pathway conduction recurred which could be treated by the second session. There were no late complications during the 4 to 46 month follow-up period.
In conclusion, RF catheter ablation using a signal separator is a safe and reliable method for treating patients with septal accessory pathways.

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Radiofrequency (RF) catheter ablation of the slow AV nodal pathway was attempted in 34 patients with common type of AV nodal reentrant tachycardia (AVNRT). Radiofrequency energy of 18-32 watts was applied for 30-60 seconds at sites exhibiting atrial-slow pathway potentials or slow potentials. These potentials were recorded at the mid or posterior septum, anterior to the coronary sinus ostium. A mean of two radiofrequency applications successfully eliminated AVNRT in all patients. The incidence of junctional ectopy was significantly higher during 34 effective applications of radiofrequency energy than during 36 ineffective applications (100% versus 17%). Thus, the recording of atrial-slow pathway potentials or slow potentials, and the development of junctional ectopy can be used as a marker for successful ablation. Slow AV nodal conduction was eliminated in 22 patients and persisted without inducible AVNRT in 12. None of the patients had recurrences of AVNRT over a mean follow-up interval of 12 months, and all had preserved AV conduction. Longterm follow-up studies with an electrophysiological method confirmed that the ablation was effective. Transient AV block was observed in only 1 patient, and no major complications were noted.
Thus, radiofrequency catheter ablation of the slow AV nodal pathway is highly effective and safe, with a low rate of complication, for the treatment of common type of AVNRT.

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The utility of selective radiofrequency catheter ablation of the slow pathway for the treatment of common and uncommon atrioventricular nodal reentrant tachycardia (AVNRT) was studied in 110 consecutive patients, 94 with slow-fast form common AVNRT, and 11 and 5, respectively, with the fast-slow and slow-slow forms of uncommon AVNRT. Ablation sites were determined by mapping a late and spiky "slow pathway potential" in the posterior right atrial septum in common AVNRT, and also the earliest retrograde atrial activation over the retrograde slow pathway in uncommon AVNRT. AVNRT was successfully eliminated in all patients with a mean number of radiofrequency pulses of 2.9±3.0 and a mean total energy applied of 3536±2996 joules. There were no early or late complications, except for transient AV block for 15 sec immediately after energy application in one common AVNRT patient, and no recurrence of AVNRT in a mean follow-up period of 24±13 months. There were no significant differences between common and uncommon AVNRT in success rate, mean application number and total energy applied. However, the AVN physiology post-ablation was different. Slow pathway conduction was eliminated in only 32% of the patients post-ablation in common AVNRT, while it was eliminated in 100% in uncommon AVNRT.
Selective radiofrequency catheter ablation of the slow pathway can cure common and uncommon AVNRT effectively and safely. Common AVNRT can be eliminated irrespective of the persistence of slow pathway conduction, while uncommon AVNRT can be eliminated by the eradication of slow pathway conduction.

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The most common mechanism of monomorphic sustained ventricular tachycardia (VT) is reentry with an excitable gap, but the electrophysiological properties and response to antiarrhythmic agents in the area of slow conduction are not yet fully known.
The conduction time through the area of slow conduction may show a frequency-dependent delay in some VT but in others, constant conduction time was observed as the paced cycle length was decreased while VT was entrained. VT with a so-called decremental property could be terminated more often with rapid pacing with less risk of acceleration of the VT rate.
When the excitable gap was estimated by the width of the zone of entrainment: defined as the difference between the cycle length of VT and the longest VT-interrupting paced cycle length during transient entrainment, there was no difference in the width of the zone of entrainment between the responders (VT induction was prevented with drugs) and the non-responders (VT remained inducible). The cycle length of VT was not a predictor of drugefficacy. However, when the drug-effect was assessed at the intermediate doses, VT of those with a significantly narrowed width of the zone of entrainment were subsequently suppressed when the same drug was added.
In conclusion, the electrophysiological properties of the area is diverse and it might affect pacing-induced terminability.
Whether an antiarrhythmic agent is able to prevent VT-induction or not can not be predicted from the basal electrophysiologic parameters, but a significant narrowing of the width of the zone of entrainment, and hence the excitable gap, can be a hallmark for drug-efficacy.

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During A-V nodal reentry the impulse is supposed to travel through two distinct pathways in the A-V nodal junction, called slow and fast pathways. Clinically, catheter ablation of these pathways has been very successful in abolishing A-V nodal reentrant tachycardias. So-called double potentials have been used as a marker for the slow pathway, and the occurrence of accelerated junctional rhythms (AJR) following ablation is an indicator of successful destruction of the slow pathway. In Langendorff, blood-perfused porcine and canine hearts, extensive mapping of extracellular potentials, combined with microelectrode recordings, was carried out to answer the following questions: 1) what is the origin of double extracellular potentials? 2) what causes postablation AJR? 3) what is the activation pattern of the AV junction during ventricular echoes?
1) Two types of double potentials were found: a low-frequency component followed by a high-frequency deflection, the LH potential was caused by asynchronous activation of the sinus septum above the coronary sinus and the region between the coronary sinus orifice and tricuspid annulus, where the L component is a far field potential. HL potentials (high-frequency deflection followed by a low frequency component) were caused by asynchronous activation of atrial cells and cells with AV nodal characteristics at the same location. These cells were present around the entire tricuspid annulus, and were not part of the compact node. The proximity of LH potentials to the slow pathway is probably serendipity, HL potentials could represent the slow pathway.
2) Two types of AJR could be initiated both by application of radiofrequency energy and by heat: a regular rhythm that progressively accelerated and an irregular rhythm. The discrete sites where heat application induced AJR did not correlate with areas showing double potentials, nor with exit regions during ventricular pacing. They were close to the compact node and the underlying mechanism was accelerated phase 4 depolarization in single ormultiple foci, the latter accounting for irregular AJR. The association between presence of AJR and successful slow pathway ablation is probably also serendipity.
3) During ventricular pacing, two separate areas of earliest atrial activity were found. When ventricular echoes were induced by premature stimulation, the retrograde impulse activated both atrial exit sites and still returned to the ventricles as an echo. Thus, no evidence was found that atrial tissue forms part of the reentrant circuit.

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