Chemical bonding and fermi level pinning at metal-semiconductor interfaces.

Since the time of Bardeen, Fermi level pinning at metal-semiconductor interfaces has traditionally been attributed to interface gap states. The present work shows that polarized chemical bonds at metal-semiconductor interfaces can lead to the apparent Fermi level pinning effect. Good agreement with various systematics of polycrystalline Schottky barrier height experiments has been found. These findings suggest that chemical bonding is a primary mechanism of the Schottky barrier height.

Safety of implantation of a cardioverter-defibrillator without general anesthesia in an electrophysiology laboratory.

Implantable cardioverter-defibrillators (ICDs) have conventionally been implanted in an operating room under general anesthesia. This study was performed to evaluate ICD implantation without general anesthesia by 2 electrophysiologists in an electrophysiology laboratory. Between February and September 1994, 27 consecutive patients (22 men and 5 women, mean age 59 +/- 15 years) who underwent ICD implantation by 2 electrophysiologists were included in this study. Fourteen patients received biphasic waveform ICDs, and the remaining 13 had monophasic waveform devices. All patients received local anesthesia and intravenous sedation for implantation. Implantation was successful in 23 of 27 patients at first attempt (11 of 11 with biphasic and 12 of 16 with monophasic waveform ICDs, respectively). Of 4 patients in whom implantation was initially unsuccessful, 3 subsequently received biphasic devices and 1 had improved defibrillation threshold ( < or = 26 J) on repeat testing after amiodarone withdrawal. Mean implantation time was 128 +/- 51 minutes, with 132 +/- 35 minutes under sedation. Patients who received biphasic versus monophasic waveform ICDs had no significant differences in mean sedation or implantation time. Minor complications occurred in 2 patients (7%): 1 minor abdominal pocket hematoma and 1 incision-site cellulitis. Mean time from implantation to discharge was 2.5 +/- 2.1 days. During late follow-up (n = 23; mean 12.4 +/- 5.8 weeks), all devices were functioning appropriately. In conclusion, this report demonstrates that ICD implantation can be successfully and safely performed by a team of 2 electrophysiologists using local anesthesia and intravenous sedation.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term survival after permanent pacemaker implantation for sick sinus syndrome.

In this population-based study, long-term survival and prognostic factors were examined in 148 patients, 55 men and 93 women, from Olmsted County, Minnesota, who had permanent pacemaker implantation for sick sinus syndrome between 1969 and 1991. The overall survival for patients who had received a permanent pacemaker for sick sinus syndrome was significantly worse than that of an age- and sex-matched control population (p < 0.0001). The increased mortality was attributable at least in part to the presence of structural heart disease in patients with sick sinus syndrome who had undergone permanent pacemaker implantation (82 of 148 patients, 55%). Survival of patients with isolated sick sinus syndrome was comparable (p = 0.6729), whereas in patients with structural heart disease it was significantly worse than expected (p < 0.0001). Symptoms were eliminated or improved in 116 patients (78%) after pacemaker implantation. Multivariate analysis identified congestive heart failure, valvular heart disease, history of stroke or transient ischemic attack, and age as independent risk factors for mortality. However, there was a trend toward decreased survival in patients who had received ventricular pacing compared with those who had received dual-chamber pacing, but this difference did not reach statistical significance (p = 0.0556). The mode of pacing was not an independent risk factor (p = 0.23). The observed survival of patients aged < 80 years was significantly worse than expected (p < 0.0001), whereas that of patients aged > or = 80 years was similar to the expected (p = 0.22).

Idiopathic ventricular fibrillation in out-of-hospital cardiac arrest survivors.

This study examined diagnostic and therapeutic roles of electrophysiological testing and long-term clinical outcome after out-of-hospital cardiac arrest due to idiopathic ventricular fibrillation. This is defined as ventricular fibrillation occurring in the absence of detectable underlying heart disease or metabolic or electrolyte disturbance. Out-of-hospital cardiac arrest resulting from idiopathic ventricular fibrillation is uncommon. Records of all patients who underwent electrophysiological testing between June 1979 and June 1992 were reviewed. Patients with out-of-hospital cardiac arrest due to idiopathic ventricular fibrillation were identified. Follow-up information was obtained by telephone interview in June 1992. Of 194 patients who underwent electrophysiological study after out-of-hospital cardiac arrest not associated with acute myocardial infarction, only six (4 male and 2 female) had idiopathic ventricular fibrillation. It was induced in only two patients by programmed ventricular stimulation. No sustained ventricular arrhythmias were induced in the remaining four patients. Four patients received implantable cardioverter defibrillators, one was treated with a beta-adrenergic blocker, and one received no treatment. All patients were alive at a mean follow-up of 50 months. Two of the four patients without inducible sustained ventricular arrhythmias had events during follow-up. Of the two patients with inducible ventricular fibrillation, one experienced a cardiac arrest and documented ventricular fibrillation at 41 months after the index event and the other had had no recurrence at 15-month follow-up. All four patients with implantable cardioverter defibrillators were alive at last follow-up, and two had device discharges.(ABSTRACT TRUNCATED AT 250 WORDS)

G proteins activate ATP-sensitive K+ channels by antagonizing ATP-dependent gating.

To determine whether G proteins activate cardiac ATP-sensitive K+ (KATP) channels by regulating intracellular ATP (ATPi)-dependent gating, currents were measured in inside-out patches. When ATPi closed KATP channels, activators of endogenous G proteins, GTP (plus adenosine or acetylcholine), GTP gamma S, or AlF-4 stimulated channels, an effect prevented by GDP beta S. In the absence of ATPi, G protein activators were ineffective. Intracellular nucleoside diphosphates restored KATP channel openings after the "rundown" of spontaneous activity. Only when ATPi suppressed nucleoside diphosphate-induced openings, GTP gamma S or AlF-4 enhanced KATP channel activity. Active forms of exogenous G protein subunits (G alpha i-1, G alpha i-2, or G alpha o) activated only KATP channels closed by ATPi. G proteins stimulate cardiac KATP channels apparently by antagonizing ATPi-dependent inhibitory gating. Regulation of ligand-dependent gating represents a distinct type of G protein modulation of ion channels.

On the mechanism of G protein beta gamma subunit activation of the muscarinic K+ channel in guinea pig atrial cell membrane. Comparison with the ATP-sensitive K+ channel.

The mechanism of G protein beta gamma subunit (G beta gamma)-induced activation of the muscarinic K+ channel (KACh) in the guinea pig atrial cell membrane was examined using the inside-out patch clamp technique. G beta gamma and GTP-gamma S-bound alpha subunits (G alpha *'s) of pertussis toxin (PT)-sensitive G proteins were purified from bovine brain. Either in the presence or absence of Mg2+, G beta gamma activated the KACh channel in a concentration-dependent fashion. 10 nM G beta gamma almost fully activated the channel in 132 of 134 patches (98.5%). The G beta gamma-induced maximal channel activity was equivalent to or sometimes larger than the GTP-gamma S-induced one. Half-maximal activation occurred at approximately 6 nM G beta gamma. Detergent (CHAPS) and boiled G beta gamma preparation could not activate the KACh channel. G beta gamma suspended by Lubrol PX instead of CHAPS also activated the channel. Even when G beta gamma was pretreated in Mg(2+)-free EDTA internal solution containing GDP analogues (24-48 h) to inactivate possibly contaminating G i alpha *'s, the G beta gamma activated the channel. Furthermore, G beta gamma preincubated with excessive GDP-bound G o alpha did not activate the channel. These results indicate that G beta gamma itself, but neither the detergent CHAPS nor contaminating G i alpha *, activates the KACh channel. Three different kinds of G i alpha * at 10 pM-10 nM could weakly activate the KACh channel. However, they were effective only in 40 of 124 patches (32.2%) and their maximal channel activation was approximately 20% of that induced by GTP-gamma S or G beta gamma. Thus, G i alpha * activation of the KACh channel may not be significant. On the other hand, G i alpha *'s effectively activated the ATP-sensitive K+ channel (KATP) in the ventricular cell membrane when the KATP channel was maintained phosphorylated by the internal solution containing 100 microM Mg.ATP. G beta gamma inhibited adenosine or mACh receptor-mediated, intracellular GTP-induced activation of the KATP channel. G i alpha *'s also activated the phosphorylated KATP channel in the atrial cell membrane, but did not affect the background KACh channel. G beta gamma subsequently applied to the same patch caused prominent KACh channel activation. The above results may indicate two distinct regulatory systems of cardiac K+ channels by PT-sensitive G proteins: G i alpha activation of the KATP channel and G beta gamma activation of the KACh channel.

Activation of the cardiac ATP-sensitive K+ channel by ER-001533, a newly synthesized vasorelaxant.

Effects of ER-001533 (ER), a newly synthesized vasorelaxant, on the membrane currents were examined in single ventricular cells of guinea pigs. The patch-clamp technique was used in the "whole-cell" and "inside-out" patch configurations. In the whole-cell clamp condition, ER induced a time-independent K(+)-dominant current, which was inhibited by glibenclamide (1-3 microM), suggesting that ER activated the cardiac ATP-sensitive K+ channel (KATP). To elucidate the mechanism of ER-mediated KATP channel activation, the drug was applied to the inside-out patches before and after channel "run-down." Since nucleotide diphosphates could induce the channel openings after complete run-down, effects of the drug on the nucleotide diphosphate-induced channel openings were also examined. Before run-down, ER activated the KATP channel only in the presence of ATP. ER shifted the relation between [ATP]i and the channel activity to the right in a concentration-dependent fashion without a significant alteration of the slope. After channel run-down, ER did not affect the channel openings either in the absence or in the presence of UDP. However, ER could relieve the ATP-gamma-S inhibition of the UDP-induced channel openings. Thus, we conclude that ER antagonizes the inhibitory effect of ATP on the KATP channel in a competitive manner, thereby enhancing the channel openings.

Essential role of nucleotide diphosphates in nicorandil-mediated activation of cardiac ATP-sensitive K+ channel. A comparison with pinacidil and lemakalim.

Vasorelaxant agents such as pinacidil, lemakalim, and nicorandil, known as K+ channel openers, can activate the ATP-sensitive K+ channel (KATP channel) in cardiac myocytes. The aim of this study was to elucidate the molecular mechanisms underlying the K+ channel opener-mediated cardiac KATP channel activation by using the inside-out patch-clamp technique in guinea pig ventricular myocytes. Effects of pinacidil, lemakalim, and nicorandil on the KATP channel were examined both before and after channel "run-down". Since nucleotide diphosphates (NDPs) could activate the channel after complete run-down, effects of the drugs on the NDP-induced channel openings were also examined. We made the following observations: 1) Pinacidil (10-100 microM) and lemakalim (300 microM) activated the KATP channel before run-down and after run-down when NDPs were present. 2) Nicorandil (30 microM-1 mM) activated the KATP channel only in the presence of NDPs regardless of the condition of the channel with respect to run-down. 3) None of these K+ channel openers activated the channel after run-down in the absence of NDPs. These observations suggest that NDP binding is essential for nicorandil-mediated activation of the KATP channel and indicate that the molecular mechanisms underlying nicorandil activation are distinct from those of pinacidil and lemakalim activation of the KATP channel. We discuss the possible interactions between the drugs and the KATP channel based on a functional channel model.

On the mechanism of nucleotide diphosphate activation of the ATP-sensitive K+ channel in ventricular cell of guinea-pig.

1. Effects of intracellular nucleotide diphosphates (NDPs) on the ATP-sensitive K+ channel (K+ATP channel) were examined in ventricular cells of guinea-pig heart, using the inside-out patch clamp technique. On formation of inside-out patches in the ATP-free internal solution, the K+ATP channel appeared and then ran down spontaneously. This run-down of the K+ATP channel activity was probably due to dephosphorylation. 2. Millimolar concentrations of various NDPs, e.g. UDP (uridine diphosphate), IDP (inosine diphosphate), CDP (cytidine diphosphate) and GDP (guanosine diphosphate), applied to the internal side of the patch membrane, induced openings of the K+ATP channel after run-down, i.e. in the dephosphorylated state. ADP opened the channel weakly at low concentrations (100 microM) but inhibited it at higher concentrations (1-10 mM). 3. NDP-induced openings of the channel were Mg2+ dependent and inhibited by ATP (100 microM) and glibenclamide (1 microM). None of nucleosides, nucleotide monophosphates nor nucleotide triphosphates induced openings of the channel. Thus, the K+ATP channel may have a Mg(2+)-dependent NDP-binding site, which induces openings of the dephosphorylated channel in ATP-free solution, in addition to the Mg(2+)-independent ATP-binding inactivation site and phosphorylation site. 4. In inside-out patches, pinacidil (a K+ATP channel opener) activated the K+ATP channel in the phosphorylated state but not in the dephosphorylated state. In the presence of NDPs (UDP, IDP, CDP, GDP), however, pinacidil (30 microM) enhanced openings of the dephosphorylated K+ATP channel prominently. 5. From the above results, we concluded that NDP-binding to the specific site has similar effects to channel phosphorylation, i.e. it keeps the K+ATP channel in an operative state in ATP-free solution and enhances the pinacidil-induced channel openings.