Sarcolemmal K(ATP) channels: what do we really know?

K(ATP) channels are present at an extremely high density in the heart, and we know from in vitro studies that channel activation causes dramatic action potential shortening and contractile failure. But, if and when this happens in vivo is still a matter of debate. Twenty one years of intense study have led to a well-developed understanding of the molecular basis of K(ATP) channel activity. Structure-function studies, together with cellular experiments probing regulatory molecules have told us much about the way the K(ATP) channel can activate, and gene-targeting and proteomic tools have further elucidated determinants of in vivo function. However, the true physiological determinants of sarcolemmal K(ATP) activity remain elusive, we still await full illumination of the role of the channel in the intact heart.     

Kir6.2-deficient mice are susceptible to stimulated ANP secretion: K(ATP) channel acts as a negative feedback mechanism?

OBJECTIVE: While atrial natriuretic peptide (ANP) has been shown to be released mainly from cardiac muscle cells in response to atrial distension, the regulatory mechanisms of ANP secretion are still not fully understood. We sought to determine whether the ATP-sensitive K+ (K(ATP)) channel modulates the secretion of ANP, using mice with homozygous knockout of the Kir6.2 (a pore-forming subunit of cardiac K(ATP) channel) gene. METHODS: K(ATP) channel currents were recorded from isolated mouse atrial cells with patch-clamp techniques. Plasma ANP concentrations in anesthetized mice and ANP content and secretion in isolated atrial preparations were determined by radioimmunoassay. Action potentials were recorded from the isolated atria. RESULTS: Exposure to 2,4-dinitrophenol (100 microM) evoked a glibenclamide-sensitive K(ATP) channel current in atrial cells from wild-type (WT) but not Kir6.2 knockout (Kir6.2 KO) mice. Although there were no significant differences in the basal plasma ANP levels between WT and Kir6.2 KO mice, volume expansion caused a significant elevation of plasma ANP concentration in Kir6.2 KO but not WT mice with accompanying hypotension. When isolated left atria were stretched, ANP secreted into the bath from Kir6.2 KO atria was significantly higher than that from WT atria. Furthermore, stretching the atria from WT but not Kir6.2 KO mice significantly shortened the action potential duration. A hypotonic stretch of the membrane induced the glibenclamide-sensitive K(ATP) channel current in atrial cells from WT but not Kir6.2 KO mice. CONCLUSIONS: Kir6.2 is essential for the function of K(ATP) channel in mouse atrial cells. Given that Kir6.2 KO mice are susceptible to stretch-induced secretion of ANP, our results suggest that K(ATP) channels may act as a negative feedback mechanism for the control of ANP secretion.     

Percutaneous coronary intervention versus fibrinolytic therapy in acute myocardial infarction: is timing (almost) everything?

The mortality benefit associated with primary percutaneous coronary intervention in ST-segment elevation myocardial infarction may be lost if door-to-balloon time is delayed by >1 hour as compared with fibrinolytic therapy door-to-needle time. Interventional cardiology laboratories endeavoring to achieve the benefits of primary percutaneous coronary intervention seen in randomized clinical trials should aim to match their short door-to-balloon times.     

Cardioprotection by opening of the K(ATP) channel in unstable angina. Is this a clinical manifestation of myocardial preconditioning? Results of a randomized study with nicorandil. CESAR 2 investigation. Clinical European studies in angina and revascularization.

AIMS: To assess the anti-ischaemic and anti-arrhythmic effects and overall safety of nicorandil, an ATP sensitive potassium (K+) channel opener, with 'cardioprotective' effects, in patients with unstable angina. METHODS: In a multicentre, randomized, double-blind, parallel-group, placebo-controlled study, oral nicorandil 20 mg twice daily or a matching placebo was administered for a minimum of 48 h to patients admitted with unstable angina. Treatment was standardized to include, where tolerated, oral aspirin, a beta-blocker and diltiazem. Continuous Holter ECG monitoring was performed for 48 h to assess the frequency and duration of transient myocardial ischaemia and any tachyarrhythmia, as the predefined end-points of the study. A pain chart recorded the incidence and severity of chest pain throughout the study period. Patients with myocardial infarction identified retrospectively from troponin-T analysis were excluded. RESULTS: Two hundred and forty-five patients were recruited into the study. Forty-three patients were excluded with an index diagnosis of myocardial infarction, two were not randomized and 12 had unsatisfactory tape data. In the remaining 188 patients, six out of 89 patients (6.7%) on nicorandil experienced an arrhythmia, compared with 17 out of 99 patients (17.2%) on placebo (P=0.04). Three nicorandil patients experienced three runs of non-sustained ventricular tachycardia compared to 31 runs in 10 patients on placebo (P=0.087 patients; P<0.0001 runs). Three nicorandil patients had four runs of supraventricular tachycardia, compared to 15 runs in nine patients on placebo (P=0.14 patients; P=0.017 runs). Eleven (12.4%) patients on nicorandil had 37 episodes of transient myocardial ischaemia (mostly silent) compared with 74 episodes in 21 (21.2%) patients on placebo (P=0.12 patients; P=0.0028 episodes). In the overall safety analysis, which included all patients who received at least one dose of study medication, there were no significant differences in the rates of myocardial infarction or death between the nicorandil or placebo-treated groups. CONCLUSIONS: Nicorandil, added to aggressive anti-anginal treatment for unstable angina, reduces transient myocardial ischaemia, non-sustained ventricular, and supraventricular arrhythmia compared to placebo. The anti-arrhythmic activity with nicorandil is probably a secondary effect resulting from its anti-ischaemic action and we suggest that this may be related to its effect on the ATP sensitive potassium channel causing pharmacological preconditioning.     

Defining disease activity in ankylosing spondylitis: is a combination of variables (Bath Ankylosing Spondylitis Disease Activity Index) an appropriate instrument?

OBJECTIVE: Disease activity has been defined using a self-administered instrument, focusing on fatigue, axial pain, peripheral pain, enthesopathy and morning stiffness [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)]. This validated instrument is simple and takes 40 s to complete, but whether the index is an accurate expression of the component parts, or whether additional weighting would enhance its efficacy, is unclear. METHODS: Four hundred and seventy-three patients with ankylosing spondylitis received placebo or active non-steroidal anti-inflammatory drug (NSAID) for 6 weeks, and changes between entry and completion were captured by BASDAI and the individual components. Principle component analysis (PCA) was used to explore the best combinations of variables in decreasing order of explained total dispersion and to assess whether a single sum (or algebraic expression) best defined disease activity status. RESULTS: At entry, the correlation between BASDAI and the first axis was 0.99, 0.11 with the second, and zero thereafter. Data at study end and relating to change revealed a 100% correlation (R = 1) between the first axis and the sum, with zero for the remainder. CONCLUSIONS: The data support BASDAI as being a valid and appropriate composite to define disease activity in ankylosing spondylitis. Developed as a simple sum of its components, BASDAI has excellent content validity.     

Verified bites by yellow sac spiders (genus Cheiracanthium) in the United States and Australia: where is the necrosis?

Spiders of the genus Cheiracanthium are frequently reported in review articles and medical references to be a definitive cause of dermonecrosis or necrotic arachnidism in humans. We provide 20 cases of verified bites by Cheiracanthium spiders from the United States and Australia, none with necrosis. A review of the international literature on 39 verified Cheiracanthium bites found only one case of mild necrosis in the European species C. punctorium. The basis for the suggestion that this spider genus causes dermonecrosis seems to be mostly inference from venom experiments in rabbits and guinea pigs, circumstantial spider involvement in human skin lesions, and repetitive citation of non-definitive reports in the medical literature. We discuss factors that lead to the erroneous elevation of virtually innocuous spiders to that of significant medical concern, which is a recurring problem in the medical community.