Yukio Hosoya

Role of ATP-sensitive K+ channel on ECG ST segment elevation during a bout of myocardial ischemia. A study on epicardial mapping in dogs.

BackgroundATP-sensitive K+ channels are activated when the myocardium becomes ischemic. However, the role of the ATP-sensitive K+ current in the emergence of ECG ST changes during ischemia remained unclarified. Methods and ResultsThe left anterior descending coronary artery (LAD) was cannulated and perfused with arterial blood from the carotid artery through a bypass tube in 8 anesthetized, open-chest dogs. An array of 60 unipolar electrodes mounted on a sock was used to record epicardial electrograms of the whole heart. Pinacidil (10 μg kg-1 min-1), an ATP-sensitive K+ channel opener, was infused into the bypass tube for 2 minutes, and the electrograms were recorded before and after the infusion. The elevation of the ST segment and the increase of QRST area were observed spatially over the LAD-perfused region. At the electrode showing the largest ST segment elevation, the activation recovery interval, an index of action potential duration, was shortened from 202±9 to 111±18 milliseconds (P<.001). These electrographic changes were similar to those noted in 2-minute coronary occlusion (n=8). The extent of ST segment elevation during coronary occlusion was attenuated after the intravenous pretreatment with glibenclamide (0.3 mg/kg), a blocker of the KATP channel (n=5) ConclusionsThe findings of this study suggest that the activation of ATP-sensitive K+ channels during a bout of acute myocardial ischemia plays an important role in the emergence of ECG ST elevation.

Ca2+ Elevation Evoked by Membrane Depolarization Regulates G Protein Cycle via RGS Proteins in the Heart

Regulators of G protein signaling (RGS), which act as GTPase activators, are a family of cytosolic proteins emerging rapidly as an important means of controlling G protein-mediated cell signals. The importance of RGS action has been verified in vitro for various kinds of cell function. Their in situ modes of action in intact cells are, however, poorly understood. Here we show that an increase in intracellular Ca2+ evoked by membrane depolarization controls the RGS action on G protein activation of muscarinic K+ (KG) channel in the heart. Acetylcholine-induced KG current exhibits a slow time-dependent increase during hyperpolarizing voltage steps, referred to as “relaxation.” This reflects the relief from the decrease in available KG channel number induced by cell depolarization. This phenomenon is abolished when an increase in intracellular Ca2+ is prevented. It is also abolished when a calmodulin inhibitor or a mutant RGS4 is applied that can bind to calmodulin but that does not accelerate GTPase activity. Therefore, an increase in intracellular Ca2+ and the resultant formation of Ca2+/calmodulin facilitate GTPase activity of RGS and thus decrease the available channel number on depolarization. These results indicate a novel and probably general pathway that Ca2+-dependent signaling regulates the G protein cycle via RGS proteins.

Acetylcholine and adenosine activate the G protein-gated muscarinic K+ channel in ferret ventricular myocytes

The properties of the K+ channel activated by acetylcholine (ACh) and adenosine (Ado) were examined in single ferret ventricular myocytes using patch-clamp techniques. In the whole-cell configuration, ACh and Ado induced an inwardly rectifying K+ current and shortened the action potential duration. The effect of ACh was blocked by atropine, while the Ado effect was interrupted by 8-cyclopenty1,1,2-dipropyl xanthine, a specific Ado A1 receptor antagonist. In cell-attached recordings, ACh and Ado added to the pipette solution activated a single population of inwardly rectifying K+ channels, distinct from the iK1 channel. The channel had a slope conductance of ∼ 40 pS in symmetrical 150 mM K+ solutions and a mean open time of 0.8 ms. Excision of the patch into the inside-out patch configuration in guanosine triphosphate (GTP)-free solution abolished the channel activity. The channel was reversibly reactivated by adding GTP to the intracellular side of the patch. GTPγS activated the channel irreversibly. When the inside-out patch was treated with the A protomer of pertussis toxin (PTX), intracellular GTP no longer activated the K+ channel. The results show that ferret ventricular myocytes possess a K+ channel activated by both muscarinic and Ado A1 receptors. Its electrophysiological properties and the gating by a PTX-sensitive G protein in a membrane-delimited fashion are identical with those of the muscarinic K+ channels in nodal and atrial tissues of other species. In conclusion, the G protein-gated muscarinic K+ channel is expressed in ferret ventricular myocardium and may underlie the direct negative inotropism of ACh and Ado in this tissue.

Relation between recovery sequence estimated from body surface potentials and T wave shape in patients with negative T waves and normal subjects.

BackgroundAdvances in analytical methods of the epicardial electrical potentials allowed us to demonstrate spatial distributions of local recovery. Because local recovery will be reflected in events on body surface ECG mapping, abnormalities in recovery sequence that may be responsible for the origin of negative T waves can be detected from body surface potentials. Methods and ResultsEighty-seven unipolar ECGs were recorded simultaneously from the entire thorax in patients having negative T waves on left anterior precordial leads and in normal subjects. These included 40 patients with anterior myocardial infarction (MI), 21 patients with left ventricular hypertrophy (LVH), and 44 male volunteers. We measured T., time, defined as the instant of maximal first derivative of the T wave as the index of local recovery (Wyatts method). Parameters related to T wave potentials were positive T wave amplitude, negative T wave amplitude, and T integral. Significant correlations were observed between the TMAX time and each of the T wave potentials. The T wave potentials were dependent on TMAX times. In the anterior MI, the late Tma times were located on the upper left anterior chest and early T.a. times on the lower right lateral chest. In the LVH, the area showing a delayed recovery was displaced in a left downward direction compared with anterior MI. ConclusionsBody surface TMAX time distributions clearly separate two negative T wave groups, i.e., anterior MI and LVH. Appearance of the negative T waves correlates well with the presence of the area with delayed TMAX time on the spatial distribution.

The clinical significance of exercise-induced ST segment changes in patients with previous inferior myocardial infarction.

To investigate the clinical significance of exercise-induced ST changes, we performed exercise body surface mapping (87 leads) in 52 patients (one-vessel disease [1 VD] n = 12, multivessel disease [MVD] n = 40) with previous inferior myocardial infarction (MI). ST isointegral maps were constructed and the locations of ST changes were compared with the findings of exercise thallium-201 (TI-201) myocardial scanning. Exercise-induced ST elevation was observed in 14 patients (27%) on the lower chest and on the back, corresponding to the infarcted area. Exercise-induced ST depression was observed more frequently in the MVD group (n = 30, 75%) than in the 1VD group (n = 2, 17%). Seventeen (77%) of 22 patients with ST depression had thallium-201 redistribution. There was a significant association between ST depression and TI-201 redistribution (chi2 = 13.1, p less than 0.001), but no association between ST depression and ST elevation. The body surface distribution of ST depression was shifted upward and rightward compared with its appearance in angina pectoris without MI. These findings suggest that exercise-induced ST depression reflects myocardial ischemia in patients with previous inferior MI.

Spectral analysis of 87-lead body surface signal-averaged ECGs in patients with previous anterior myocardial infarction as a marker of ventricular tachycardia.

BackgroundThere were few studies on the relation between the body surface distribution of high- and low-frequency components within the QRS complex and ventricular tachycardia (VT). Methods and ResultsEighty-seven signal-averaged ECGs were obtained from 30 normal subjects (N group) and 30 patients with previous anterior myocardial infarction (MI) with VT (MI-VT[+] group, n=10) or without VT (MI-VT[−] group, n=20). The onset and offset of the QRS complex were determined from 87-lead root mean square values computed from the averaged (but not filtered) ECG waveforms. Fast Fourier transform analysis was performed on signal-averaged ECG. The resulting Fourier coefficients were attenuated by use of the transfer function, and then inverse transform was done with five frequency ranges (0–25, 25–40, 40–80, 80–150, and 150–250 Hz). From the QRS onset to the QRS offset, the time integration of the absolute value of reconstructed waveforms was calculated for each of the five frequency ranges. The body surface distributions of these areas were expressed as QRS area maps. The maximal values of QRS area maps were compared among the three groups. In the frequency ranges of 0–25 and 150–250 Hz, there were no significant differences in the maximal values among these three groups. Both MI groups had significantly smaller maximal values of QRS area maps in the frequency ranges of 25–40 and 40–80 Hz compared with the N group. The MI-VT(+) group had significantly smaller maximal values in the frequency ranges of 40–80 and 80–150 Hz than the MI-VT(−) group. These three groups were clearly differentiated by the maximal values of the 40–80–Hz QRS area map. ConclusionsIt was suggested that the maximal value of the 40–80-Hz QRS area map was a new marker for VT after anterior MI.

Chapter 19 Functional Analyses of G-Protein Activation of Cardiac KG Channel

Publisher Summary This chapter discusses the models for functional analyses of G-protein activation of cardiac K G channel. By combining the Monod-Wyman-Changeux (MWC) allosteric model for G kβγ activation of muscarinic K + (K ACh ) channels and either the Thomsen or Mackay model for acetylcholine (Ach) activation of G proteins, the concentration-response relationships between guanosine triphosphate and K ACh channel activity in the presence of various ACh could be reasonably simulated. The models have clear limitations to explain the transient behavior of K ACh channel current. Therefore, they should be improved by further studies to explain not only the steady state but also activation and deactivation of K ACh channels on application and wash-out of ACh, respectively. The improved model may provide functional bases to further clarify the molecular mechanism underlying the functional interaction among the agonist, receptor, G protein, and K G channel.