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Abstract Strict monitoring of the heart rhythm in patients with COVID‐19 even nonsevere case and patient with low cardiovascular risk factors is very important to prevent fatal outcomes.

Three studies examined how the perception that one's attitudes are based in values affects attitude clarity and correctness. Specifically, perceiving that one's attitude is based in important values increases attitude clarity (the subjective sense that one knows one's attitude) but not attitude correctness (the subjective sense that the attitude is correct). To test this, participants read a counterattitudinal message and were given feedback about the basis of their attitude. Relative to participants who learned that their attitudes were weakly based in values, participants who were told that their attitudes were strongly based in values reported greater attitude clarity than correctness (Study 1). Similarly, increases in attitude clarity from having an attitude based in values increased the perception that participants effortfully processed the message (Studies 2 and 3), the belief that participants more successfully resisted the message, and participants' intentions to act on the attitude., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Blankenship, Kane and Machacek.)

The present research examines whether the perceived uniqueness of one's thoughts and salience of uniqueness motivations can influence attitude strength and resistance. Participants who rated their thoughts as relatively unique formed attitudes that showed greater correspondence with behavioral intentions to act on the attitude (Study 1). In Study 2, participants who recalled a previous purchase motivated by the desire to be unique (versus to fit in) after generating message counterarguments were less persuaded (more resistant) and reported greater willingness to act on their (negative) attitude. Moreover, attitudes mediated the effect of the purchase manipulation on intentions to act on the attitude., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Blankenship, Kane and Machacek.)

Context: This article focuses on whether, and the extent to which, the resources made available by Title X-the only federal policy aimed specifically at reproductive health care-are equitably accessible. Here, equitable means that barriers to accessing services are lowest for those people who need them most., Methods: The authors use geographic information systems (GIS) and statistical/spatial analysis (specifically the integrated two-step floating catchment area [I2SFCA] method) to study the spatial and nonspatial accessibility of Title X clinics in 2018., Findings: The authors find that contraception deserts vary across the states, with between 17% and 53% of the state population living in a desert. Furthermore, they find that low-income people and people of color are more likely to live in certain types of contraception deserts., Conclusions: The analyses reveal not only a wide range of sizes and shapes of contraception deserts across the US states but also a range of severity of inequity., (Copyright © 2021 by Duke University Press.)

Ag, Pt, and Rh monometallic colloids were produced via laser ablation. Separate Ag-Rh and Ag-Pt heterostructures were formed by mixing and resulted in groupings of Rh/Pt nanoparticles adsorbing to the concavities of the larger Ag nanostructures. The 400 nm Ag plasmonic absorption peak was slightly blue-shifted for Ag-Pt and red-shifted for Ag-Rh heterostructures. Catalytic activity for the reduction of 4-nitrophenol increased significantly for Ag-Pt and Ag-Rh compared to the monometallic constituents, and persisted at lower loading ratios and consecutive reduction cycles. The enhancement is attributed to the Rh and Pt nanoparticles forming antenna-reactor-type plasmonic catalysts with the Ag nanostructures., (Copyright © 2019, Kane and Bertino; licensee Beilstein-Institut.)

Shigella flexneri is a facultative intracellular pathogen that relies on a type III secretion system and its associated effector proteins to cause bacillary dysentery in humans. The genes that encode this virulence system are located on a 230-kbp plasmid and are transcribed in response to thermal, osmotic, and pH signals that are characteristic of the human lower gut. The virulence genes are organized within a regulatory cascade, and the nucleoid-associated protein H-NS represses each of the key promoters. Transcription derepression depends first on the VirF AraC-like transcription factor, a protein that antagonizes H-NS-mediated repression at the intermediate regulatory gene virB. The VirB protein in turn remodels the H-NS-DNA nucleoprotein complexes at the promoters of the genes encoding the type III secretion system and effector proteins, causing these genes to become derepressed. In this study, we show that the VirB protein also positively regulates the expression of its own gene (virB) via a cis-acting regulatory sequence. In addition, VirB positively regulates the gene coding for the VirF protein. This study reveals two hitherto uncharacterized feedback regulatory loops in the S. flexneri virulence cascade that provide a mechanism for the enhanced expression of the principal virulence regulatory genes.

Chronic β-adrenoceptor antagonist (β-blocker) treatment in patients is associated with a potentially anti-arrhythmic prolongation of the atrial action potential duration (APD), which may involve remodelling of repolarising K(+) currents. The aim of this study was to investigate the effects of chronic β-blockade on transient outward, sustained and inward rectifier K(+) currents (I(TO), I(KSUS) and I(K1)) in human atrial myocytes and on the expression of underlying ion channel subunits. Ion currents were recorded from human right atrial isolated myocytes using the whole-cell-patch clamp technique. Tissue mRNA and protein levels were measured using real time RT-PCR and Western blotting. Chronic β-blockade was associated with a 41% reduction in I(TO) density: 9.3 ± 0.8 (30 myocytes, 15 patients) vs 15.7 ± 1.1 pA/pF (32, 14), p < 0.05; without affecting its voltage-, time- or rate dependence. I(K1) was reduced by 34% at -120 mV (p < 0.05). Neither I(KSUS), nor its increase by acute β-stimulation with isoprenaline, was affected by chronic β-blockade. Mathematical modelling suggested that the combination of I(TO)- and I(K1)-decrease could result in a 28% increase in APD(90). Chronic β-blockade did not alter mRNA or protein expression of the I(TO) pore-forming subunit, Kv4.3, or mRNA expression of the accessory subunits KChIP2, KChAP, Kvβ1, Kvβ2 or frequenin. There was no reduction in mRNA expression of Kir2.1 or TWIK to account for the reduction in I(K1). A reduction in atrial I(TO) and I(K1) associated with chronic β-blocker treatment in patients may contribute to the associated action potential prolongation, and this cannot be explained by a reduction in expression of associated ion channel subunits.

The H-NS protein represses the transcription of hundreds of genes in Gram-negative bacteria. Derepression is achieved by a multitude of mechanisms, many of which involve the binding of a protein to DNA at the repressed promoter in a manner that compromises the maintenance of the H-NS-DNA nucleoprotein repression complex. The principal virulence gene promoters in Shigella flexneri, the cause of bacillary dysentery, are repressed by H-NS. VirB, a protein that closely resembles members of the ParB family of plasmid-partitioning proteins, derepresses the operons that encode the main structural components and the effector proteins of the S. flexneri type III secretion system. Bioinformatic analysis suggests that VirB has been co-opted into its current role as an H-NS antagonist in S. flexneri. To test this hypothesis, the potential for VirB to act as a positive regulator of proU, an operon that is repressed by H-NS, was assessed. Although VirB has no known relationship with the osmoregulated proU operon, it could relieve H-NS-mediated repression when the parS-like VirB binding site was placed appropriately upstream of the RpoD-dependent proU promoter. These results reveal the remarkable facility with which novel regulatory circuits can evolve, at least among those promoters that are repressed by H-NS.

Background and Purpose: Cannabidiol (CBD) is a phytocannabinoid, with anti-apoptotic, anti-inflammatory and antioxidant effects and has recently been shown to exert a tissue sparing effect during chronic myocardial ischaemia and reperfusion (I/R). However, it is not known whether CBD is cardioprotective in the acute phase of I/R injury and the present studies tested this hypothesis., Experimental Approach: Male Sprague-Dawley rats received either vehicle or CBD (10 or 50 microg kg(-1) i.v.) 10 min before 30 min coronary artery occlusion or CBD (50 microg kg(-1) i.v.) 10 min before reperfusion (2 h). The appearance of ventricular arrhythmias during the ischaemic and immediate post-reperfusion periods were recorded and the hearts excised for infarct size determination and assessment of mast cell degranulation. Arterial blood was withdrawn at the end of the reperfusion period to assess platelet aggregation in response to collagen., Key Results: CBD reduced both the total number of ischaemia-induced arrhythmias and infarct size when administered prior to ischaemia, an effect that was dose-dependent. Infarct size was also reduced when CBD was given prior to reperfusion. CBD (50 microg kg(-1) i.v.) given prior to ischaemia, but not at reperfusion, attenuated collagen-induced platelet aggregation compared with control, but had no effect on ischaemia-induced mast cell degranulation., Conclusions and Implications: This study demonstrates that CBD is cardioprotective in the acute phase of I/R by both reducing ventricular arrhythmias and attenuating infarct size. The anti-arrhythmic effect, but not the tissue sparing effect, may be mediated through an inhibitory effect on platelet activation.

Objective: To implement and assess the effectiveness of the Strathclyde Computerized Randomized Interactive Prescription Tutor (SCRIPT) in teaching a competency-based undergraduate pharmacy course., Design: Data on students' access to SCRIPT, collected by quantitative electronic data capture, were analyzed to determine student usage patterns and correlations between usage and grades in class assessments. Data on students' perceptions were collected by electronic questionnaire and semi-structured interviews. Teaching staff members also were interviewed., Assessment: Two hundred forty-three students accessed SCRIPT a median of 23 times each. Students accessed SCRIPT predominantly at times outside normal teaching hours and tended to access the tool more often in the 48 hours preceding class assessments. Feedback from students indicated overall satisfaction with the tool to compliment the timetabled teaching sessions but highlighted that more specific feedback on the examples was required. All staff comments were positive., Conclusions: Students and teaching staff members valued SCRIPT as a tool to compliment teaching of the competency-based pharmacy practice classes in the MPharm degree. Future developments of SCRIPT will include expanded feedback for students, the capability to link the release of each SCRIPT exercise with the date the content is taught in class, and additional tools to facilitate "just in time" teaching.

1 Mast cells have classically been regarded as the 'bad guys' in the setting of acute myocardial ischaemia, where their released contents are believed to contribute both to tissue injury and electrical disturbances resulting from ischaemia. Recent evidence suggests, however, that if mast cell degranulation occurs in advance of ischaemia onset, this may be cardioprotective by virtue of the depletion of mast cell contents that can no longer act as instruments of injury when the tissue becomes ischaemic. 2 Many peptides, such as ET-1, adrenomedullin, relaxin and atrial natriuretic peptide, have been demonstrated to be cardioprotective when given prior to the onset of myocardial ischaemia, although their physiological functions are varied and the mechanisms of their cardioprotective actions appear to be diverse and often ill defined. However, one common denominator that is emerging is the ability of these peptides to modulate mast cell degranulation, raising the possibility that peptide-induced mast cell degranulation or stabilization may hold the key to a common mechanism of their cardioprotection. 3 The aim of this review was to consolidate the evidence implying that mast cell degranulation could play both a detrimental and protective role in myocardial ischaemia, depending upon when it occurs, and that this may underlie the cardioprotective effects of a range of diverse peptides that exerts physiological effects within the cardiovascular system.

Horizontal DNA transfer plays a major role in the evolution of bacteria. It allows them to acquire new traits rapidly and these may confer fitness advantages as the bacteria compete with others in the environment. Historically, the mechanisms of horizontal DNA transfer, chiefly conjugation, transformation and transduction, have received a great deal of attention. Less attention has been focused on the regulatory problems that may accompany the acquisition of new genes by lateral routes. How are these genes integrated into the existing regulatory circuits of the cell? Does a process of 'plug-and-play' operate, or are the new genes silenced pending the evolution of regulatory mechanisms that make their expression not only safe but also beneficial to both the gene and its new host? Recent research shows that bacterial nucleoid-associated proteins such as H-NS, HU and Fis are important contributors to the processes of regulatory integration that accompany horizontal gene transfer. A key emerging theme is the antagonism that exists between the DNA-protein-DNA bridging activity of the H-NS repressor and the DNA-bending and DNA-wrapping activities of regulatory proteins that oppose H-NS.

Background: Left ventricular systolic dysfunction (LVSD) is a risk factor for atrial fibrillation (AF), but the atrial cellular electrophysiological mechanisms in humans are unclear., Objective: This study sought to investigate whether LVSD in patients who are in sinus rhythm (SR) is associated with atrial cellular electrophysiological changes that could predispose to AF., Methods: Right atrial myocytes were obtained from 214 consenting patients in SR who were undergoing cardiac surgery. Action potentials or ion currents were measured using the whole-cell-patch clamp technique., Results: The presence of moderate or severe LVSD was associated with a shortened atrial cellular effective refractory period (ERP) (209 +/- 8 ms; 52 cells, 18 patients vs 233 +/- 7 ms; 134 cells, 49 patients; P <0.05); confirmed by multiple linear regression analysis. The left ventricular ejection fraction (LVEF) was markedly lower in patients with moderate or severe LVSD (36% +/- 4%, n = 15) than in those without LVSD (62% +/- 2%, n = 31; P <0.05). In cells from patients with LVEF 45%, by 24% and 18%, respectively. The LVEF and ERP were positively correlated (r = 0.65, P <0.05). The L-type calcium ion current, inward rectifier potassium ion current, and sustained outward ion current were unaffected by LVSD. The transient outward potassium ion current was decreased by 34%, with a positive shift in its activation voltage, and no change in its decay kinetics., Conclusion: LVSD in patients in SR is independently associated with a shortening of the atrial cellular ERP, which may be expected to contribute to a predisposition to AF.

Sphingosine-1-phosphate (S1P) is a bioactive lysophospholipid generated by the sphingosine kinase (SK1 or SK2)-catalysed phosphorylation of sphingosine. Plasma S1P is carried in high-density lipoprotein (HDL) or bound to albumin and is reported to arise from activated platelets and erythrocytes. In addition, extracellular SK1 released from vascular endothelial cells may also contribute to plasma S1P levels. S1P exerts its effects through a family of five high affinity S1P-specific G protein-coupled receptors (GPCRs), S1P(1-5). Various S1P receptors are present in the cardiovascular system, including cardiac tissue. Additionally, intracellular S1P may have a second messenger action. Since S1P is recognised as a survival factor in many tissues, there has been much interest in S1P as a cardioprotective agent. Recent evidence indicates that S1P can pre-condition and post-condition the heart and that the cardioprotective effect of HDL may be because of its S1P content. In addition, evidence is emerging that the cardioprotective effects of cannabinoids and S1P may be linked.

Cannabinoids (CBs) are known to alter coronary vascular tone and cardiac performance. They also exhibit cardioprotective properties, particularly in their ability to limit the damage produced by ischaemia reperfusion injury. The mechanisms underlying these effects are unknown. Here we investigate the intracellular localisation of CB receptors in the heart and examine whether they may modulate localised nuclear Ca(2+) release. In isolated cardiac nuclear preparations, expression of both the inositol 1,4,5-trisphosphate receptor type 2 (IP(3)R) and CB receptors (CB(1)R and CB(2)R) was demonstrated by immunoblotting. Both receptors localised to the nucleus and purity of the nuclear preparations was confirmed by co-expression of the nuclear marker protein nucleolin but absence of cytoplasmic actin. To measure effects of IP(3)R and CBR agonists on nuclear Ca(2+) release, isolated nuclei were loaded with Fluo5N-AM. This dye accumulates in the nuclear envelope. Isolated nuclei responded to IP(3) with rapid and transient Ca(2+) release from the nuclear envelope. Anandamide inhibited this IP(3)-mediated release. Preincubation of nuclear preparations with either the CB(1)R antagonist (AM251) or the CB(2)R antagonist (AM630) reversed anandamide-mediated inhibition to 80% and 60% of control values respectively. When nuclei were pre-treated with both CBR antagonists, anandamide-mediated inhibition of IP(3)-induced Ca(2+) release was completely reversed. These results are the first to demonstrate the existence of cardiac nuclear CB receptors. They are also the first to show that anandamide can negatively modulate IP(3)-mediated nuclear Ca(2+) release. As such, this provides evidence for a novel key mechanism underlying the action of CBs and CBRs in the heart.

Background and Purpose: Torsade de pointes (TdP) can be induced in several species by a reduction in cardiac repolarizing capacity. The aim of this study was to assess whether combined I(Kr) and I(Ks) blockade could induce TdP in anaesthetized guinea pigs and whether short-term variability (STV) or triangulation of action potentials could predict TdP., Experimental Approach: Experiments were performed in open-chest, pentobarbital-anaesthetized, adrenaline-stimulated male Dunkin Hartley guinea pigs, which received three consecutive i.v. infusions of either vehicle, the I(Kr) blocker E-4031 (3, 10 and 30 nmol kg(-1) min(-1)), the I(Ks) blocker HMR1556 (75, 250, 750 nmol kg(-1) min(-1)) or E-4031 and HMR1556 combined. Phenylephrine-stimulated guinea pigs were also treated with the K(+) channel blockers in combination. Arterial blood pressure, ECGs and epicardial monophasic action potential (MAP) were recorded., Key Results: TdP was observed in 75% of adrenaline-stimulated guinea pigs given the K(+) channel blockers in combination, but was not observed in guinea pigs treated with either I(K) blocker alone, or in phenylephrine-stimulated guinea pigs. Salvos and ventricular tachycardia occurred with adrenaline but not with phenylephrine. No changes in STV or triangulation of the MAP signals were observed before TdP., Conclusions and Implications: Combined blockade of both I(Kr) and I(Ks) plus the addition of adrenaline were required to induce TdP in anaesthetized guinea pigs. This suggests that there must be sufficient depletion of repolarization reserve and an appropriate trigger for TdP to occur.

Atrial fibrillation (AF) causes substantial morbidity and mortality. It may be triggered and sustained by either reentrant or nonreentrant electrical activity. Human atrial cellular refractory period is shortened in chronic AF, likely aiding reentry. The ionic and molecular mechanisms are not fully understood and may include increased inward rectifier K(+) current and altered Ca(2+) handling. Heart failure, a major cause of AF, may involve arrhythmogenic atrial electrical remodeling, but the pattern is unclear in humans. Beta-blocker therapy prolongs atrial cell refractory period; a potentially antiarrhythmic influence, but the ionic and molecular mechanisms are unclear. The search for drugs to suppress AF without causing ventricular arrhythmias has been aided by basic studies of cellular mechanisms of AF. It remains to be seen whether such drugs will improve patient treatment.

Background and Purpose: Torsade de pointes (TdP) can be induced by a reduction in cardiac repolarizing capacity. The aim of this study was to assess whether IKs blockade or enhancement of INa could potentiate TdP induced by IKr blockade and to investigate whether short-term variability (STV) or triangulation of action potentials preceded TdP., Experimental Approach: Experiments were performed in open-chest, pentobarbital-anaesthetized, alpha 1-adrenoceptor-stimulated, male New Zealand White rabbits, which received three consecutive i.v. infusions of either the IKr blocker E-4031 (1, 3 and 10 nmol kg(-1) min(-1)), the IKs blocker HMR1556 (25, 75 and 250 nmol kg(-1) min(-1)) or E-4031 and HMR1556 combined. In a second study rabbits received either the same doses of E-4031, the INa enhancer, ATX-II (0.4, 1.2 and 4.0 nmol kg(-1)) or both of these drugs. ECGs and epicardial monophasic action potentials were recorded., Key Results: HMR1556 alone did not cause TdP but increased E-4031-induced TdP from 25 to 80%. ATX-II alone caused TdP in 38% of rabbits, as did E-4031; 75% of rabbits receiving both drugs had TdP. QT intervals were prolonged by all drugs but the extent of QT prolongation was not related to the occurrence of TdP. No changes in STV were detected and triangulation was only increased after TdP occurred., Conclusions and Implications: Giving modulators of ion channels in combination substantially increased TdP but, in this model, neither STV nor triangulation of action potentials could predict TdP.

5-Hydroxytryptamine (5-HT) is proarrhythmic in atrial cells from patients in sinus rhythm (SR) via activation of 5-HT(4) receptors, but its effects in atrial cells from patients with atrial fibrillation (AF) are unknown. The whole-cell perforated patch-clamp technique was used to record L-type Ca(2+) current (I(CaL)), action potential duration (APD) and arrhythmic activity at 37 degrees C in enzymatically isolated atrial cells obtained from patients undergoing cardiac surgery, in SR or with chronic AF. In the AF group, 5-HT (10microM) produced an increase in I(CaL) of 115+/-21% above control (n=10 cells, 6 patients) that was significantly smaller than that in the SR group (232+/-33%; p<0.05; n=27 cells, 12 patients). Subsequent co-application of isoproterenol (1microM) caused a further increase in I(CaL) in the AF group (by 256+/-94%) that was greater than that in the SR group (22+/-6%; p<0.05). The APD at 50% repolarisation (APD(50)) was prolonged by 14+/-3ms by 5-HT in the AF group (n=37 cells, 14 patients). This was less than that in the SR group (27+/-4ms; p<0.05; n=58 cells, 24 patients). Arrhythmic activity in response to 5-HT was observed in 22% of cells in the SR group, but none was observed in the AF group (p<0.05). Atrial fibrillation was associated with reduced effects of 5-HT, but not of isoproterenol, on I(CaL) in human atrial cells. This reduced effect on I(CaL) was associated with a reduced APD(50) and arrhythmic activity with 5-HT. Thus, the potentially arrhythmogenic influence of 5-HT may be suppressed in AF-remodelled human atrium.

Background and Purpose: Protease-activated receptor-2 (PAR-2) is expressed on lymphocytes and endothelial cells, and plays a significant role in inflammatory reactions. Since leukocyte-endothelial cell interaction and reactive oxygen species (ROS) generation are hallmarks of the development of inflammation, the effects of PAR-2 activation by trypsin on lymphocyte adhesion and ROS generation was examined utilising PAR-2 wild type and knockout (PAR-2-/-) mice., Experimental Approach: Lymphocyte adhesion to the luminal surface of mouse isolated aortae was measured using 51Cr-labelled leukocytes and ROS generation from isolated lymphocytes was quantified using chemiluminescence., Key Results: Trypsin induced adhesion of lymphocytes when added exogenously to the endothelial surface of the aorta for 30 min. Similarly, increased lymphocyte adhesion was also observed when mice were injected with trypsin intravenously 24 h prior to the adhesion assay, an effect which was partly ICAM-1 mediated. Trypsin also increased ROS generation from isolated mouse lymphocytes in a dose-dependent manner. The increase in lymphocyte adhesion and ROS production in response to trypsin were abolished in PAR-2-/- mice indicating a PAR-2 dependent mechanism. Superoxide dismutase had a greater inhibitory effect in PAR-2-/- mice compared to wild type mice when lymphocytes were stimulated with PMA but not trypsin., Conclusions and Implications: The present study indicates that activation of PAR-2 may be an important factor in modulating lymphocyte adhesion and ROS generation. The results have implications for developing anti-inflammatory strategies.

Introduction: We investigated whether post-cardiac surgery (CS) new-onset atrial fibrillation (AF) is predicted by pre-CS atrial cellular electrophysiology, and whether the antiarrhythmic effect of beta-blocker therapy may involve pre-CS pharmacological remodeling., Methods and Results: Atrial myocytes were obtained from consenting patients in sinus rhythm, just prior to CS. Action potentials and ion currents were recorded using whole-cell patch-clamp technique. Post-CS AF occurred in 53 of 212 patients (25%). Those with post-CS AF were older than those without (67 +/- 2 vs 62 +/- 1 years, P = 0.005). In cells from patients with post-CS AF, the action potential duration at 50% and 90% repolarization, maximum upstroke velocity, and effective refractory period (ERP) were 13 +/- 4 ms, 217 +/- 16 ms, 185 +/- 10 V/s, and 216 +/- 14 ms, respectively (n = 30 cells, 11 patients). Peak L-type Ca(2+) current, transient outward and inward rectifier K(+) currents, and the sustained outward current were -5.0 +/- 0.5, 12.9 +/- 2.4, -4.1 +/- 0.4, and 9.7 +/- 1.0 pA/pF, respectively (13-62 cells, 7-19 patients). None of these values were significantly different in cells from patients without post-CS AF (P > 0.05 for each, 60-279 cells, 29-86 patients), confirmed by multiple and logistic regression. In patients treated >7 days with a beta-blocker pre-CS, the incidence of post-CS AF was lower than in non-beta-blocked patients (13% vs 27%, P = 0.038). Pre-CS beta-blockade was associated with a prolonged pre-CS atrial cellular ERP (P = 0.001), by a similar degree (approximately 20%) in those with and without post-CS AF., Conclusion: Pre-CS human atrial cellular electrophysiology does not predict post-CS AF. Chronic beta-blocker therapy is associated with a reduced incidence of post-CS AF, unrelated to a pre-CS ERP-prolonging effect of this treatment.

1. The overall aim of this study was to determine if adrenomedullin (AM) protects against myocardial ischaemia (MI)-induced arrhythmias via nitric oxide (NO) and peroxynitrite. 2. In sham-operated rats, the effects of in vivo administration of a bolus dose of AM (1 nmol kg-1) was assessed on arterial blood pressure (BP), ex vivo leukocyte reactive oxygen species generation and nitrotyrosine deposition (a marker for peroxynitrite formation) in the coronary endothelium. 3. In pentobarbitone-anaesthetized rats subjected to ligation of the left main coronary artery for 30 min, the effects of a bolus dose of AM (1 nmol kg-1, i.v.; n=19) or saline (n=18) given 5 min pre-occlusion were assessed on the number and incidence of cardiac arrhythmias. In a further series of experiments, some animals received infusions of the NO synthase inhibitor N(G)-nitro-L-arginine (LNNA) (0.5 mg kg-1 min-1) or the peroxynitrite scavenger N-mercaptopropionyl-glycine (MPG) (20 mg kg-1 h-1) before AM. 4. AM treatment significantly reduced mean arterial blood pressure (MABP) and increased ex vivo chemiluminescence (CL) generation from leukocytes in sham-operated animals. AM also enhanced the staining for nitrotyrosine in the endothelium of coronary arteries. 5. AM significantly reduced the number of total ventricular ectopic beats that occurred during ischaemia (from 1185+/-101 to 520+/-74; P<0.05) and the incidences of ventricular fibrillation (from 61 to 26%; P<0.05). AM also induced a significant fall in MABP prior to occlusion. AM-induced cardioprotection was abrogated in animals treated with the NO synthase inhibitor LNNA and the peroxynitrite scavenger MPG. 6. This study has shown that AM exhibits an antiarrhythmic effect through a mechanism that may involve generation of NO and peroxynitrite.

Endothelin-1 (ET-1) is elevated in patients with atrial fibrillation (AF) and heart failure. We investigated effects of ET-1 on human atrial cellular electrophysiological measurements expected to influence the genesis and maintenance of AF. Action potential characteristics and L-type Ca(2+) current (I(CaL)) were recorded by whole cell patch clamp, in atrial isolated myocytes obtained from patients in sinus rhythm. Isoproterenol (ISO) at 0.05 muM prolonged the action potential duration at 50% repolarisation (APD(50): 54 +/- 10 vs. 28 +/- 5 ms; P < 0.05, N = 15 cells, 10 patients), but neither late repolarisation nor cellular effective refractory period (ERP) were affected. ET-1 (10 nM) reversed the effect of ISO on APD(50), and had no basal effect (in the absence of ISO) on repolarisation or ERP. During repetitive stimulation, ISO (0.05 microM) produced arrhythmic depolarisations (P < 0.05). Each was abolished by ET-1 at 10 nM (P < 0.05). ISO (0.05 microM) increased peak I(CaL) from -5.5 +/- 0.4 to -14.6 +/- 0.9 pA/pF (P < 0.05; N = 79 cells, 34 patients). ET-1 (10 nM) reversed this effect by 98 +/- 10% (P < 0.05), with no effect on basal I(CaL). Chronic treatment of patients with a beta-blocker did not significantly alter basal APD(50) or I(CaL), the increase in APD(50) or I(CaL) by 0.05 microM ISO, nor the subsequent reversal of this effect on APD(50) by 10 nM ET-1. The marked anti-adrenergic effects of ET-1 on human atrial cellular action potential plateau, arrhythmic depolarisations and I(CaL), without affecting ERP and independently of beta-blocker treatment, may be expected to contribute a potentially anti-arrhythmic influence in the atria of patients with AF and heart failure.

Soon after its identification as a powerful vasoconstrictor peptide, endothelin (ET-1) was implicated as a detrimental agent involved in determining the outcome of myocardial ischaemia and reperfusion. Early experimental studies demonstrated that ET(A) selective and mixed ET(A)/ET(B) receptor antagonists can reduce infarct size and prevent ischaemia-induced ventricular arrhythmias in models of ischaemia/reperfusion, implying that ET-1 acts through the ET(A) receptor to contribute to injury and arrhythmogenesis. However, as our understanding of the physiology of ET-1 has expanded, the role of ET-1 in the ischaemic heart appears ever more complex. Recent evidence suggests that ET-1 exerts actions on the heart that are not only detrimental (vasoconstriction, inhibition of NO production, activation of inflammatory cells), but which may also contribute to tissue repair, such as inhibition of cardiomyocyte apoptosis. In addition, ET-1-induced mast cell degranulation has been linked to a homeostatic mechanism that controls endogenous ET-1 levels, which may have important implications for the ischaemic heart. Furthermore the mechanism by which ET-1 promotes arrhythmogenesis remains controversial. Some studies imply a direct electrophysiological effect of ET-1, via ET(A) receptors, to increase monophasic action potential duration (MAPD) and induce early after-depolarisations (EADs), while other studies support the view that coronary constriction resulting in ischaemia is the basis for the generation of arrhythmias. Moreover, ET-1 can induce cardioprotection (precondition) against infarct size and ventricular arrhythmias, through as yet incompletely understood mechanisms. To enable us to identify the most appropriate means of targeting this system in a therapeutically meaningful way we need to continue to explore the physiology of ET-1, both in the normal and the ischaemic heart.

The aims of this study were to determine if endothelin-1 (ET-1) under normal and ischaemic conditions exhibits a direct arrhythmogenic effect that is independent of its ability to cause coronary vasoconstriction, and to determine the contribution of the ET(A) and ET(B) receptor subtype. ET(A/B) (with ET-1) and ET(A) (ET-1 in the presence of BQ-788) receptor activation resulted in a significant reduction in both epi- and endocardial monophasic action potential duration (MAPD(90)). ET(A) receptor activation reduced both epi- and endocardial effective refractory period (ERP). This MAPD(90) and ERP shortening were associated with a reduction in coronary flow, myocardial contractility and induction of ventricular fibrillation (VF) during ERP measurement. The ET(B) agonist sarafotoxin (S6c) had no marked, or concentration-dependent, effect on MAPD(90), ERP, myocardial contractility or induction of arrhythmias. Neither ET-1 nor S6c, given prior to coronary artery occlusion, significantly changed the ischaemia-induced dispersion of MAPD(90), ERP or the % incidence of VF. In conclusion, neither ET(A) nor ET(B) receptor stimulation has a direct arrhythmogenic effect in isolated rabbit hearts under normal or ischaemic conditions. The ET-1-induced arrhythmogenic effect observed in nonischaemic hearts is likely to be the result of the associated coronary vasoconstriction caused by ET(A) receptor stimulation resulting in myocardial ischaemia.

Prucalopride is a selective 5-hydroxytryptamine type 4 (5-HT4) receptor agonist developed for the treatment of gastrointestinal disorders. The endogenous agonist 5-HT acting via 5-HT4 receptors increases the L-type Ca2+ current (I(CaL)) with potentially proarrhythmic consequences (Pau et al., 2003). The aims of this study were to investigate the effects of prucalopride on I(CaL), action potentials, refractory period, and arrhythmic activity in human atrial myocytes, and to compare these with the effects of 5-HT, using the whole-cell perforated patch-clamp technique. Prucalopride (10(-9) to 10(-4) M) produced a concentration-dependent increase in I(CaL) amplitude, with a maximum response at 10 microM, from -5.3 +/- 0.6 to -10.9 +/- 1.5 pA/pF (p < 0.05; n = 22 cells, 10 patients), without affecting its voltage-dependence. Subsequent application of 10 microM 5-HT further increased I(CaL) to -17.7 +/- 2.8 pA/pF (p < 0.05; n = 16 cells, 9 patients). The increase in I(CaL) by prucalopride, 98 +/- 15%, was significantly smaller than that by 5-HT, 233 +/- 26% (p < 0.05). Prucalopride (10 microM) significantly increased the action potential duration at 50% repolarization (APD50) from 12 +/- 2 to 17 +/- 3 ms (p < 0.05; n = 22 cells, 9 patients). Following washout of prucalopride, 5-HT (10 microM) increased APD50, to a greater extent, from 14 +/- 3 to 32 +/- 7 ms (p < 0.05; n = 11 cells; 8 patients). The APD75, APD90, and effective refractory period were unaffected by prucalopride or 5-HT. Furthermore, 5-HT induced abnormal depolarizations in 27% of the cells studied, whereas prucalopride induced none (p < 0.05). In conclusion, in human atrial cells, prucalopride, at concentrations markedly above those used therapeutically, acted as partial agonist on I(CaL) and APD50, with no effect on late repolarization or refractory period, and was devoid of arrhythmic activity.

The aims of this study were to determine if the ETB receptor agonist, sarafotoxin 6c (S6c) reduces myocardial infarct size following myocardial ischemia and reperfusion and to investigate whether any changes in mRNA for endothelin receptors in the injured myocardium were modified by S6c pretreatment. Hypnorm/Hypnovel anesthetized rats were subjected to occlusion of the left main coronary artery for 30 minutes, followed by 120 minutes reperfusion. Animals were administered a bolus dose of S6c (0.24 nmol kg-1 i.v., n = 10) or saline (n = 15) 5 minutes prior to occlusion. At the end of reperfusion, hearts were stained with Evan's Blue dye to delineate area at risk. A 1.5- to 2.0-mm thick slice was cut transmurally 1 mm below the site of ligation for assessment of infarct size by triphenyltetrazolium chloride. A further transmural slice (2.5-3-mm thick) was cut for assessment of receptor mRNA levels by RTPCR. Administration of S6c caused a transient fall in mean arterial blood pressure (MABP) prior to occlusion and attenuated the fall in MABP induced by coronary occlusion. S6c significantly reduced infarct size (13 +/- 4% of area of slice at risk) compared with control hearts (35 +/- 5%; P < 0.05). In control hearts, there was a marked reduction in mRNA content for both ETA (50% reduction) and ETB (70% reduction) receptors in the ischemic zone, compared with non-ischemic tissue. In hearts pre-treated with S6c there was a reduction in ETA, but not ETB receptor mRNA in the ischemic zone. This study has shown that S6c reduces myocardial infarct size and results in preservation of ETB receptor mRNA in ischemic/reperfused tissue.

5-Hydroxytryptamine (5-HT) has been postulated to play a proarrhythmic role in the human atria via stimulation of 5-HT4 receptors. The aims of this study were to examine the effects of 5-HT on the L-type Ca2+ current (ICaL) action potential duration (APD), the effective refractory period (ERP) and arrhythmic activity in human atrial cells, and to assess the effects of prior treatment with beta-adrenoceptor antagonists. Isolated myocytes, from the right atrial appendage of 27 consenting patients undergoing cardiac surgery who were in sinus rhythm, were studied using the whole-cell perforated patch-clamp technique at 37 degrees C. 5-HT (1 nm-10 microm) caused a concentration-dependent increase in ICaL, which was potentiated in cells from beta-blocked (maximum response to 5-HT, Emax=299+/-12% increase above control) compared to non-beta-blocked patients (Emax=220+/-6%, P<0.05), but with no change in either the potency (log EC50: -7.09+/-0.07 vs -7.26+/-0.06) or Hill coefficient (nH: 1.5+/-0.6 vs 1.5+/-0.3) of the 5-HT concentration-response curve. 5-HT (10 microm) produced a greater increase in the APD at 50% repolarisation (APD50) in cells from beta-blocked patients (of 37+/-10 ms, i.e. 589+/-197%) vs non-beta-blocked patients (of 10+/-4 ms, i.e. 157+/-54%; P<0.05). Both the APD90 and the ERP were unaffected by 5-HT. Arrhythmic activity was observed in response to 5-HT in five of 17 cells (29%) studied from beta-blocked, compared to zero of 16 cells from the non-beta-blocked patients (P<0.05). In summary, the 5-HT-induced increase in calcium current was associated with a prolonged early plateau phase of repolarisation, but not late repolarisation or refractoriness, and the enhancement of these effects by chronic beta-adrenoceptor blockade was associated with arrhythmic potential.

Objective: To assess the contribution of the Na, K pump current (I(p)) to the action potential duration (APD) and effective refractory period (ERP) in human atrial cells, and to investigate whether I(p) contributes to the changes in APD and ERP associated with chronic atrial fibrillation (AF)., Methods: Action potentials and ion currents were recorded by whole-cell patch clamp in atrial myocytes isolated from consenting patients undergoing cardiac surgery, who were in sinus rhythm (SR) or AF (>3 months)., Results: In cells from patients in SR, the I(p) blocker, ouabain (10 microM) significantly depolarised the membrane potential, V(m), from -80+/-2 (mean+/-S.E.) to -73+/-2 mV, and lengthened both the APD (174+/-17 vs. 197+/-23 ms at 90% repolarisation) and ERP (198+/-22 vs. 266+/-14 ms; P<0.05 for each, Student's t-test, n=7 cells, 5 patients). With an elevated pipette [Na(+)] of 30 mM, I(p) was measured by increasing extracellular [K(+)] ([K(+)](o)) from 0 to 5.4 mM. This produced an outward shift in holding current at -40 mV, abolished by 10 microM ouabain. K(+)- and ouabain-sensitive current densities were similar, at 0.99+/-0.13 and 1.12+/-0.11 pA/pF, respectively (P>0.05; n=9 cells), confirming the K(+)-induced current as I(p). I(p) increased linearly with increasing V(m) between -120 and +60 mV (n=25 cells). Stepwise increments in [K(+)](o) (between 0 and 10 mM) increased I(p) in a concentration-dependent manner (maximum response, E(max)=1.19+/-0.09 pA/pF; EC(50)=1.71+/-0.15 mM; n=27 cells, 9 patients). In cells from patients in AF, the sensitivity of I(p) to both V(m) and [K(+)](o) (E(max)=1.02+/-0.05 pA/pF, EC(50)=1.54+/-0.11 mM; n=44 cells, 9 patients) was not significantly different from that in cells from patients in SR. Within the group of patients in AF, long-term digoxin therapy (n=5 patients) was associated with a small, but significant, reduction in E(max) (0.92+/-0.07 pA/pF) and EC(50) (1.35+/-0.15 mM) compared with non-treatment (E(max)=1.13+/-0.08 pA/pF, EC(50)=1.76+/-0.14 mM; P<0.05 for each, n=4 patients). In cells from non-digoxin-treated patients in AF, the voltage- and [K(+)](o)-sensitivity (E(max) and EC(50)) were similar to those in cells from patients in SR., Conclusions: The Na, K pump current contributes to the human atrial cell V(m), action potential shape and ERP. However, the similarity in I(p) sensitivity to both [K(+)](o) and V(m) between atrial cells from patients with and without chronic AF indicates that I(p) is not involved in AF-induced electrophysiological remodelling in patients.

Objective: Chronic beta-adrenoceptor antagonist (beta-blocker) treatment reduces the incidence of reversion to AF in patients, possibly via an adaptive myocardial response. However, the underlying electrophysiological mechanisms are presently unclear. We aimed to investigate electrophysiological changes in human atrial cells associated with chronic treatment with beta-blockers and other cardiovascular-acting drugs., Methods: Myocytes were isolated enzymatically from the right atrial appendage of 40 consenting patients who were in sinus rhythm. The cellular action potential duration (APD), effective refractory period (ERP), L-type Ca(2+) current (I(CaL)), transient (I(TO)) and sustained (I(KSUS)) outward K(+) currents, and input resistance (R(i)) were recorded using the whole cell patch clamp. Drug treatments and clinical characteristics were compared with electrophysiological measurements using simple and multiple regression analyses. P<0.05 was taken as statistically significant., Results: In atrial cells from patients treated chronically with beta-blockers, the APD(90) and ERP (75 beats/min stimulation) were significantly longer, at 213+/-11 and 233+/-11 ms, respectively (n=15 patients), than in cells from non-beta-blocked patients, at 176+/-12 and 184+/-12 ms (n=11). These cells also displayed a significantly reduced action potential phase 1 velocity (22+/-3 vs. 34+/-3 V/s). Chronic beta-blockade was also associated with a significant reduction in the heart rate (58+/-3 vs. 69+/-5 beats/min) and in the density of I(TO) (8.7+/-1.3 vs. 13.7+/-2.1 pA/pF), an increase in the R(i) (214+/-24 vs. 132+/-14 MOmega), but no significant change in I(CaL) or I(KSUS). The I(TO) blocker 4-aminopyridine largely mimicked the changes in phase 1 and ERP associated with chronic beta-blockade, in cells from non-beta-blocked patients. Chronic treatment of patients with calcium channel blockers or angiotensin converting enzyme inhibitors (n=11-13 patients) was not associated with any significant changes in atrial cell electrophysiology., Conclusion: The observed atrial cellular electrophysiological changes associated with chronic beta-blockade are consistent with a long-term adaptive response, a type of 'pharmacological remodelling', and provide mechanistic evidence supportive of the anti-arrhythmic actions of beta-blockade.

To study the relation between beta 2 microglobulin (beta 2M) and survival in AL amyloidosis, we measured the serum level of beta 2M in 80 patients with AL amyloidosis diagnosed within 1 year of evaluation, who had received no therapy. Patients had a median age of 61 years and 52% were male. Major clinical manifestations were renal disease in 25 patients (31%), cardiomyopathy in 23 patients (29%), and neuropathy or other organ involvement in 32 patients (41%). The beta 2M level, measured by an ELISA assay in serum samples collected at the time of evaluation, ranged from 1.69 to 10 mg/ml (mean = 4.57); in 56% of the patients beta 2M > 4 mg/ml. The patients with a beta 2M < or = 4 mg/ml had serum creatinine levels lower than those with beta 2M > 4 (1.43 vs 2.67 mg/dl; p = 0.02). Survival from study entry was analyzed overall by the level of beta 2M, adjusting for creatinine level and clinical stratum. We found the beta 2M level to be predictive of survival (median survival 16.1 months for beta 2M < or = 4 mg/ml vs 8.0 months for beta 2M > 4 mg/ml, p = 0.044). Thus a beta 2M level less than 4 mg/ml indicated a longer time of survival.

Apex-to-base differences in the density of potassium currents have been recently described in isolated rabbit myocytes. The significance of those findings for arrhythmogenesis in the whole heart is not known. We aimed to examine electrophysiological effects of hypokalaemia/hypomagnesaemia in isolated working rabbit hearts. Monophasic action potential duration (MAPD(90)), effective refractory period (ERP) and conduction delay were measured at 3 left ventricular sites (basal epicardium, apical epicardium, apical endocardium) in control (K(+) = 4mmol/L, Mg(2+) = 1mmol/L) and hypokalaemia/hypomagnesaemia (K(+) = 2mmol/L, Mg(2+) = 0.5mmol/L) groups. It was found that hypokalaemia/hypomagnesaemia shortened ERP in the apical epicardial region (by 22 +/- 6ms), without any significant effect in the basal area. Consequently, hypokalaemia/hypomagnesaemia increased transepicardial dispersion of refractoriness (from 10 +/- 3 to 25 +/- 7ms, P <.05) and increased inducibility of ventricular fibrillation (from 10% to 100%, P <.05). Similar effects were seen in hearts with left ventricular hypertrophy secondary to perinephritis-induced hypertension. These results suggest that hypokalaemia/hypomagnesaemia is pro-arrhythmic in normal or hypertrophied hearts due to an increase in apex-to-base dispersion of refractoriness.

The neural activity associated with conscious recollection and habit was examined using event-related brain potentials. In a training phase, participants learned A-B, A-C word associations in which the probability of specific responses was varied. Once a habit was established, participants studied and were tested on a series of short lists consisting of word pairs seen in training. The process-dissociation procedure was used to estimate the contribution of habit and recollection to memory performance. Habit estimates reflected the probability with which information was presented in training but recollection estimates did not show this effect. Recollection was associated with sustained negativity over the parieto-occipital region, which was opposite in polarity over the frontal regions. Indices of habit strength were associated with a sustained positivity over left fronto-temporal regions and a sustained negativity over right fronto-central regions. Partial-least squares analyses revealed two significant latent variables that distinguished recollection and habit, consistent with the distinction between consciously controlled and automatic influences of memory.

The effects of the endothelin ET(A), (BQ-123) and endothelin ET(A/B) (PD161721) receptor antagonists were investigated on ischaemia-induced arrhythmias and on the maximum following frequency. The study was carried out in Langendorff perfused rat hearts subjected to coronary artery occlusion in which the severity of arrhythmias, coronary perfusion pressure and heart rate were measured. The % incidence of ischaemia-induced irreversible ventricular fibrillation (ventricular fibrillation) was reduced significantly from 58%, in control rat hearts, to 0% (at 10(-7) and 10(-6) M PD161721 and 10(-6) M BQ-123 P<0.05). Maximum following frequency was measured in guinea-pig isolated atria. In the presence of normal extracellular [K(+)], BQ-123 and PD161721, at 10(-6) M, significantly decreased the maximum following frequency from 9.0+/-0.7 to 7.2+/-0.4 and from 8.3+/-0.4 to 6.7+/-0.3 Hz, respectively (P<0.05). These effects were not potentiated by raising the extracellular [K(+)] with the exception of 10(-9) M PD161721. In contrast, lignocaine's ability to reduce the maximum following frequency was greater in elevated (e.g. at 1.7x10(-4) M from 8.4+/-0.3 to 2.5+/-0.6 Hz) than in normal [K(+)] (from 9.0+/-0.3 to 4.9+/-0.5 Hz). In conclusion, both BQ-123 and PD161721 had an anti-fibrillatory effect in isolated rat hearts that may be due, at least in part, to an ability to reduce the maximum following frequency. This latter effect is unlikely to be due to Na(+) channel blockade since it was not markedly potentiated by elevation of extracellular [K(+)].

Objective: To investigate changes in human atrial single cell functional electrophysiological properties associated with chronic atrial fibrillation (AF), and the contribution to these of accompanying ion current changes., Methods: The whole cell patch clamp technique was used to record action potentials, the effective refractory period (ERP) and ion currents, in the absence and presence of drugs, in enzymatically isolated myocytes from 11 patients with chronic (>6 months) AF and 39 patients in sinus rhythm., Results: Stimulation at high rates (up to 600 beats/min) markedly shortened late repolarisation and the ERP in cells from patients in sinus rhythm, and depolarised the maximum diastolic potential (MDP). Chronic AF was associated with a reduction in the ERP at physiological rate (from 203+/-16 to 104+/-15 ms, P<0.05), and marked attenuation in rate effects on the ERP and repolarisation. The abbreviated terminal phase of repolarisation prevented fast rate-induced depolarisation of the MDP in cells from patients with AF. The density of L-type Ca(2+) (I(CaL)) and transient outward K(+) (I(TO)) currents was significantly reduced in cells from patients with AF (by 60-65%), whilst the inward rectifier K(+) current (I(K1)) was increased, and the sustained outward current (I(KSUS)) was unaltered. Superfusion of cells from patients in sinus rhythm with nifedipine (10 micromol/l) moderately shortened repolarisation, but had no effect on the ERP (228+/-12 vs. 225+/-11 ms). 4-Aminopyridine (2 mmol/l) markedly prolonged repolarisation and the ERP (by 35%, P<0.05). However, the combination of these drugs had no effect on late repolarisation or refractoriness., Conclusion: Chronic AF in humans is associated with attenuation in adaptation of the atrial single cell ERP and MDP to fast rates, which may not be explained fully by accompanying changes in I(CaL) and I(TO).

We have shown previously that a small bolus dose of endothelin-1, given intravenously before coronary occlusion, exerts a marked antiarrhythmic effect in anaesthetised rats. The aim of the current study was to determine whether or not this is due to a direct effect of endothelin-1 on the heart by assessing the antiarrhythmic effect of endothelin-1 against occlusion-induced arrhythmias in rat isolated hearts. Rat isolated hearts were perfused in Langendorff mode (constant flow) and subjected to coronary artery occlusion for 30 min. Coronary perfusion pressure and a surface electrocardiogram (ECG) were monitored throughout the experiment. In the first series of studies, the effects of three 5-min infusions of endothelin-1 (0.1-10 nM), given prior to coronary occlusion, were assessed. A second series of hearts was given a single bolus dose of endothelin-1 (10 pmol) 5 min prior to ischaemia. A third series of experiments was performed using a modified (low K+) Krebs Henseleit solution to increase the incidence of ischaemia-induced ventricular fibrillation (VF). In these hearts, endothelin-1 (0.1 or 2 pmol) was administered as a bolus injection 5 min before ischaemia. Infusion of endothelin-1 prior to ischaemia did not modify the incidence or severity of arrhythmias at any of the concentrations used. Bolus administration of endothelin-1 (10 pmol) in hearts perfused with Kreb's Henseleit solution containing normal K+ (4.4 mM) was found to cause a small rise in coronary perfusion pressure, with no preceding depressor response. Under these conditions, endothelin-1 exerted only a very moderate reduction in arrhythmias, by reducing the arrhythmia count in the 21-30-min post-occlusion period. Furthermore, in hearts perfused with low K+ solution, bolus injection of endothelin-1, in a dose that either had no effect on coronary perfusion pressure (0.1 pmol) or produced a significant vasodilator effect with no significant pressor effect (2 pmol), had no effect on ventricular fibrillation. Thus, in concentrations that are sufficient to exert effects on the coronary vasculature, endothelin-1 fails to modify arrhythmias in an isolated heart preparation. These results suggest that the antiarrhythmic effects of endothelin-1 previously observed in vivo are not due to a direct effect on either the myocardium or the coronary blood vessels.

The aim of this study was to investigate whether the endothelin-B- (ETB) receptor agonist sarafotoxin 6c (S6c) can protect against ischaemia-induced cardiac arrhythmias. Arrhythmias were induced by a 30 min period of coronary artery occlusion in pentobarbitone-anaesthetized male rats, or in Langendorff-perfused rat hearts. Rats or rat hearts were administered a bolus dose of vehicle or S6c (0.8 nmol/kg i.v. or 10(-8) M into the coronary circulation, respectively) 5 min before the onset of ischaemia. In vivo administration of S6c significantly reduced the incidence of ventricular fibrillation (VF) from 59% to 13% and the number of premature ventricular beats. This effect was associated with a transient fall in mean arterial blood pressure. In isolated hearts, S6c reduced significantly both the incidences of ventricular tachycardia (VT) and VF while having no statistically significant effect on coronary perfusion pressure. This is the first report to show that stimulation of ETB-receptors, with a bolus dose of S6c, has an antiarrhythmic effect on rat hearts both in vivo and in vitro, suggestive of a direct effect on the myocardium.

Objectives: Left ventricular hypertrophy (LVH) has been reported to produce differential electrophysiological effects in isolated epicardial and endocardial cells. This study aimed to examine regional electrophysiological effects of LVH in normal and ischaemic conditions in the whole heart., Methods: LVH was secondary to perinephritis-induced hypertension. Monophasic action potential duration (MAPD(90)), effective refractory period (ERP) and conduction delay were measured in paced, isolated working rabbit hearts either at one right ventricular and two left ventricular sites (apical and basal epicardium) or at three left ventricular sites (apical and basal epicardium, apical endocardium). The hearts were subjected to 30 min of regional ischaemia and 15 min of reperfusion., Results: In non-ischaemic conditions, LVH produced uniform prolongation of MAPD(90) and ERP in the left ventricular epicardium, but not in the endocardium. After coronary artery occlusion, LVH significantly increased ischaemia-induced transepicardial dispersion of repolarisation, but not refractoriness. LVH did not affect arrhythmogenesis in either non-ischaemic or ischaemic conditions., Conclusions: Differential effects of LVH on epicardial and endocardial electrophysiological parameters are also observed in the whole heart. In addition, the sensitivity of hypertrophied myocardium to ischaemia is increased and leads to an increase in ischaemia-induced dispersion of repolarisation. However, neither dispersion of refractoriness nor arrhythmogenesis are affected by LVH in non-ischaemic or ischaemic conditions in this experimental model.

The effects of study-test lags of between 0 and 32 items on conscious (C) and automatic (A) memory processes in a running word-completion task were investigated with event-related potentials (ERPs). The process dissociation procedure (PDP) can distinguish between C and A contributions to memory by comparing performance when subjects respond with either an old item (inclusion) or a new item (exclusion). C can be estimated by subtracting the probability of an intrusion of an old item during the exclusion task (due to A without C) from the probability of correctly producing an old item during the inclusion task (due to C and/or A). The behavioral results showed that C was stronger when the test item followed the studied word in the next trial or after a lag of one stimulus. The strength of A did not vary with lag. The ERP waveforms contained a broad parietal positive wave between 300 and 800 ms. This parietal wave distinguished between correctly recalled old and new words. The early portion of this old-new effect was significantly affected by lag. Subtracting waveforms to obtain a measure of C revealed an effect in the later portion of this wave, lateralized over the left hemisphere. A sustained frontal negativity occurred during all recordings and was larger during conscious retrieval. There was no consistent ERP effect related to automatic memory retrieval.