Optimal Teaching of Cardiopulmonary Resuscitation in Schools: Better Education, More Lives Saved.

Teaching cardiopulmonary resuscitation in Romanian schools is a joint initiative of the Acute Cardiac Care Working Group of the Romanian Society of Cardiology, the Romanian National Resuscitation Council and the Romanian Society of Emergency Medicine and Disaster. Teaching young generations to save people in cardiac arrest requires a structural approach, whose starting point is the launching of a large-scale campaign in favor of introducing the basics of cardiopulmonary resuscitation (CPR) in the school curriculum. The training stages can be set according to the principle of repetition (i.e. every two years). Teachers seem to be the best candidates for the instructor position, taking into account the knowledge and skills they acquired throughout the teacher training programs, as well as, their continuous contact with the students; consequently, training teachers to become CPR instructors represents a long term investment. All acquired knowledge will implicitly spread to a secondary level (trainee's parents, relatives, etc.) and the number of individuals gaining access to CPR specific information will rise as a consequence. Entering the CPR training program should be promoted as a criterion for the accreditation and/or evaluation of primary schools, middle schools, and high schools. To begin with, this program must be implemented in Romania at first as part of the non-formal context of the special education week called "Scoala altfel" ("School otherwise").

Electrocardiographic changes in the most frequent endocrine disorders associated with cardiovascular diseases. Review of the literature.

Car- diovascular abnormalities associated with endocrine diseases are often frequent and due to complex relationships between endocrine glands (with internal secretion) and cardiovascular system (heart and vessels). Certain hormones secreted by the endocrine glands (particularly the thyroid and pituitary gland) excesses or deficiencies, are involved in morphogenesis, growth processes and activity regulation of cardiovascular system, most often in connection with the autonomic nervous system. There are also a lot of electrocardiographic changes caused by hormonal disorders that requires differential diagnosis and represents the source of erroneous diagnosis. Endocrine pathology occurred later than a heart disease, may worse heart function. Ignoring the cardiovascular events that may occur in the evolution of endo- crine diseases, may induce increased mortality due to cardiovascular complications.

Lasing in DNA-CTMA doped with Rhodamine 610 in butanol.

The light emission properties of the complex formed from deoxyribonucleic acid (DNA)-cetyltrimethylammonium chloride (CTMA) surfactant doped with different concentrations of Rhodamine 610 (Rh610) dye and dissolved in butanol are investigated and discussed. The results are compared to those obtained when only the Rh610 dye is dissolved in butanol, at the same concentrations. The light emission is excited in the investigated samples by the nanosecond pulses of a frequency-doubled Nd:YAG laser, at a wavelength of 532 nm. We have demonstrated the lasing effect in the investigated complex and we have studied its efficiency and coherence properties. The lasing properties of the Rh610 dye are favourably influenced by the presence of the DNA-CTMA complex in the investigated compound. It leads to an increase in the lasing efficiency and in the slope efficiency. Also the temporal coherence of the emitted light is larger and the emission can be tuned to shorter wavelengths.

Ischemic mitral regurgitation in patients with acute myocardial infarction.

AIM OF THE STUDY: Echocardiographic evaluation of mitral regurgitation (MR) during the evolution of patients with acute myocardial infarction (MI). MATERIAL AND METHODS: The study included 104 patients (73 males and 31 females), aged between 38-85, diagnosed with acute myocardial infarction (based on clinical, ECG and enzymatic evidences), in order to assess the MR (clinically--a new systolic murmur, and by echocardiography--the severity of MR). Echocardiography was performed upon admission and at 10-30 and 180 days after the onset of acute MI. The evaluation of MR was based on the following parameters: jet area, jet area indexed to left atrium, regurgitated volume, left atrial and left ventricular size, the evaluation of mitral valve apparatus in order to eliminate other possible causes of MR. RESULTS AND DISCUSSION: MR was found in 35 patients from 104 diagnosed with acute MI, as follows: severe in 20 patients (jet area > 8 square cm, jet area indexed to left atrium > 40%, regurgitated volume > 30 mL) and mild in 15 patients (jet area < 4 square cm, jet area indexed to left atrium < 20%, regurgitant volume < 30 mL). In 30 patients MR was produced by the dilatation of mitral annulus (because of the evolution to ischemic dilatative cardiomyopathy), 5 patients developed left ventricular aneurysm; in 3 patients, MR was produced by chordae rupture and in 2 patients we diagnosed an ischemic prolapse of posterior mitral leaflet. In evolution all the patients developed symptoms and signs of heart failure, and 2 patients were referred to surgery. CONCLUSIONS: The appearance of MR in the evolution of MI is an important sign of bad prognosis by its contribution to the appearance and/or to the worsening course of heart failure. Mechanisms of this MR are very complex based on the alteration of left ventricular geometry. Echocardiography plays an essential role in the early diagnosis of MR, estimating its severity, the mechanisms and also the prognosis.

Barriers of antiaggregant treatment.

UNLABELLED: In the present study we aimed to evaluate side effects of antiplatelet therapy in order to establish correlations with medication type, doses and association with other therapies. MATERIAL AND METHODS: In the study we prospectively evaluated a cohort of patients who received antiplatelet therapy for different pathologies. We included patients with acute coronary syndromes, valvular disease complicated with supraventricular arrhythmias (especially atrial fibrillation), carotidal critical stenosis, neurologic disease (ischemic or thrombotic), and peripheral artery disease. RESULTS AND DISCUSSIONS: The study included 125 patients (85 males and 40 females), aged between 45 and 85, and admitted in the 1st Cardiology Department, St Spiridon Hospital, between January 2012 and December 2013, who received antiplatelet therapy for different pathologies. All the patients included in the study received platelet antiaggregant therapy with Clopidogrel in association or not with Aspirin or low weight molecular heparin. Side effects reported (possibly correlated with antiplatelet therapy) were: macroscopic hematuria (7 cases), cutaneous ecchymosis (7 cases), purpuric lesions (9 cases), gingival bleeding (12 cases), upper gastrointestinal bleeding (6 cases), and hemoptysis (2 cases). CONCLUSIONS: Hemorrhagic events under the treatment with antiplatelet agents are rare in comparison with the large number of patients treated. Clinical manifestations are very different depending on the drug and also on the drug-associations used. Hemorrhagic accidents may sometimes be very serious, determining the specific therapeutic measures.

Cardiac tumors.

Cardiac tumors are a group of rare disorders with a frequency that varies in population studies between 0.0017% and 0.33%. There are primary cardiac tumors with an incidence of 5% of all cardiac tumors and secondary tumors (metastases of the heart) in 95% of cases. Symptoms are nonspecific and can mimic many other heart diseases. This fact makes the diagnosis of cardiac tumors very difficult. Approximately 75% of the primary cardiac tumors are benign; the most frequent histological type encountered is myxoma in 50% of cases, followed by cardiac fibromas, lipomas, rhabdomyomas, hemangiomas, teratomas, papillary fibroelastomas, pericardial cysts or cystic tumor of the atrioventricular node region. Secondary cardiac tumors (metastases) are 20 times more common than primary cardiac tumors. Paraclinical methods (especially imaging evaluation) are always necessary for the complete diagnosis: transthoracic and transesophageal echocardiograms are the gold standard investigations in the diagnosis of the cardiac tumors; CT scans together with MRIs are complementary diagnostic methods that are useful when the diagnosis is uncertain. In the majority of cases surgical treatment is recommended.

Hyponatremia--risk factor in patients with chronic heart failure--clinical, evolutive and therapeutic implications.

UNLABELLED: Patients with heart failure are, by definition, hemodynamically unstable. This condition may be accentuated by medication (digitalis, diuretics, antiarrhythmics), so that they become more sensitive to electrolyte disturbances. Hyponatremia is the most common electrolyte disorder, particularly common in the intensive care unit. AIM: The evaluation of the incidence of hyponatremia in patients diagnosed with chronic heart failure in order to establish a correlation with the evolution, prognosis and therapeutic implications. MATERIAL AND METHODS: We analyzed retrospectively 120 patients diagnosed with chronic heart failure NYHA II-IV classes, admitted in the Cardiology Clinic between 2009 and 2013. We analyzed electrolytic disturbances which occurred during different strategies of therapy. RESULTS: 120 patients with heart failure were admitted in the Cardiology Clinic between 2009 and 2013, 92 males and 28 females. Diagnosis was established by classical criteria. Evaluation was very complex and included: complete clinical examination, electrocardiogram, echocardiography, chest ray examination and biochemical analyses especially hepatic, renal function and electrolyte status. CONCLUSIONS: The data obtained showed that electrolyte disturbances are frequent in patients with chronic heart failure, irrespective of NYHA class. Hyponatremia is usually associated with diuretic therapy and may play a very important role in the subsequent development of life-threatening complications. Patients with heart failure who develop hyponatremia during their evolution had a worse prognosis.

Amiodarone-induced thyroid dysfunction--clinical picture. Study on 215 cases.

AIM: The purpose of this study was to investigate the prevalence and the clinical-evolutionary implications of thyroid damage in patients treated with amiodarone in the Cardiology Clinic of the "Sf. Spiridon" University Hospital of Iasi. MATERIAL AND METHODS: The study included a group of 215 patients, 90 men and 125 women with ages between 35 and 87, hospitalized in the Cardiology Clinic between 2004 and 2014, who received amiodarone treatment, in most cases for the prophylaxis of various arrhythmias, both supra-ventricular and ventricular. RESULTS: In 27.80% of the patients, the assessment of the thyroid function was imposed by the appearance of the clinical picture characteristic for hypo- and hyperthyroidism, and for 72.19% it was carried out as a routine examination. Amiodarone-induced hypothyroidism was clinically diagnosed in 20.85% of the patients. Hyperthyroidism occurring during treatment with Cordarone was found in 6.95% of the patients. The confirmation of the diagnosis of amiodarone-induced thyroid dysfunction was based on hormonal dosages (TSH, FT4 and even FT3 in some cases), on the endocrinological clinical consultation and on the imaging study--i.e. thyroid echography. CONCLUSIONS: Amiodarone-induced thyroid dysfunction is relatively rare compared to the number of patients treated with this anti-arrhythmic drug (27.8%) from the group under study. Thyroid dysfunction, regardless of the type (with hypo or hyper-function), represents a negative element in the evolution of patients with pre-existing heart diseases, not only by aggravating the clinical picture of the basic illness, but also by the necessity of permanently reviewing the therapeutic scheme imposed also by the association of thyroid dysfunction medication, according to case.

Associated factors of ejection fraction in insulin-treated patients with type 2 diabetes.

AIM OF THE STUDY: to evaluate the relation between ejection fraction (EF), diabetes characteristics and cardiovascular risk factors. MATERIAL AND METHODS: We carried out a cross-sectional study in 171 patients with insulin-treated type 2 diabetes hospitalized at the Sf. Spiridon Emergency Clinical Hospital, Iasi. All patients were evaluated for asymptomatic organ damage and cardiovascular risk factors of hypertension and diabetes metabolic control. Global ejection fraction (EF) was evaluated through 2-D echocardiography. RESULTS AND DISCUSSION: In the studied group the ejection fraction had significant negative correlations with the duration of the disease (p=0.007) and the presence of microalbuminuria (p=0.001). There were some differences between the categories realized by grouping the patients according to the presence of hypertension and/or previous myocardial infarction. In patients without personal history of cardiovascular disease EF was correlated only with LDLc levels. In the hypertensive patients without myocardial infarction it was correlated with diabetes duration, Hb A1e and LDLc, In those patients with both conditions, EF had significant correlations with Hb A1e and microalbuminuria. CONCLUSIONS: These results emphasized that the determinants associated with heart failure in patients with type 2, insulin-treated diabetes, differ according to the presence of high blood pressure and myocardial infarction.

[Uric acid, cardiovascular events and renal dysfunction: a circumstantial connection?]. / Acidul uric, evenimentele cardiovasculare si disfunctia renala--o legatura conjuncturala?

AIM: The relationship between asymptomatic hyperuricemia, cardiovascular events and renal dysfunction was studied (affirmed or challenged) long time ago. To investigate this relationship we conducted this study. MATERIAL AND METHODS: We analyzed 163 patients consecutively admitted in the Intensive Cardiac Care Unit of the 1st Cardiology Clinic, County Hospital "St. Spiridon" Iasi. The cut-off value of serum uric acid was defined as 7 mg%. There were recorded anthropometric, anamnesis, clinical and paraclinical data. RESULTS: We compared the normal uricemia group (108 patients) with the hyperuricemia group (55 patients). The serum uric acid value was 5.22 +/- 1.16 mg% in the normouricemia group and 8.58 +/- 1.86 mg% in the hyperuricemia group. The statistically significant differences between the two groups relate to sex, smoking as cardiovascular risk factor, diastolic blood pressure and ejection fraction (lower in the hyperuricemia group were the dilated cardiomyopathy prevail). If the patients are grouped according to creatinine clearance less than or greater than 60 ml/min we found statistically significant differences between the two groups in terms of serum uric acid value (p < 0.001), age (p < 0.001), renal dysfunction and dyslipidaemia (p 0.001). CONCLUSIONS: The analysis performed doesn't demonstrate the role of uric acid as independent risk factor in a group that includes patients with different heart diseases (dilated cardiomyopathy, ischemic heart disease or hypertension).

[Clopidogrel resistance--risk factor in patients with acute coronary syndromes]. / Rezistenta la clopidogrel--factor de risc pentru pacientii cu sindroame coronariene acute.

Clopidogrel is an ADP receptor antagonist, an inhibitor of platelet activation and aggregation. The effect is due to its selective and irreversible blockade of the P2Y12 receptor. The concept of clopidogrel resistance emerged since several years ago. This biological finding has a very important impact especially in patients with acute coronary syndromes, explaining by this their worse evolution. Mechanisms of this resistance are very complex including: differences in intestinal absorption, hepatic conversion to the active metabolite through cytochrome 3A4 (CYP3A4) activity, drug interactions, individual variations in the activity of hepatic cytochrome P450 izoenzymes, platelet receptor polymorphisms and also clinical factors. According to this resistance patients are divided in two groups : "low or non-responders" (with a high risk of thrombosis) and "high--responders" (with a high risk of bleeding). Carriers of CYP2C19*2 or *3 alleles have been shown to respond poorly to standard doses of clopidogrel due to reduced metabolic activation of the drug. So, they are likely to develop subsequent thrombotic events. Starting from these, a lot of studies have been performed in order to elucidate the mechanisms of this resistance offering new perspectives regarding a proper administration of antiplatelet therapy in patients with acute coronary syndromes.

Electrolyte disturbances in patients with chronic heart failure--clinical, evolutive and therapeutic implications.

UNLABELLED: Patients with heart failure are, by definition, hemodynamic unstable. Often, this condition may be accentuated by medication (digitalis, diuretics, antiarrhythmics), so that they become more sensitive to electrolyte disturbances, reacting sometimes violently with severe and life threatening rhythm troubles. AIM: the evaluation of the incidence of electrolyte disturbances in patients diagnosed with chronic heart failure in order to establish a correlation with the evolution, prognosis and therapeutic implications. MATERIAL AND METHODS: We analyzed retrospectively 100 patients diagnosed with chronic heart failure NYHA II-IV classes, admitted in Cardiology Clinic during 2009-2011. We analyzed electrolytic disturbances occurred during different strategies of therapy. RESULTS: 100 patients with heart failure were admitted in Cardiology Clinic during 2009-2011, 75 males and 25 females. Diagnosis was established by classical criteria. Evaluation was very complex and included: complete clinical examination, electrocardiogram, echocardiography, chest ray examination and biochemical analyses especially hepatic, renal function and electrolyte status. CONCLUSIONS: The obtained data showed that electrolyte disturbances are frequent in patients with chronic heart failure, irrespectively of NYHA class. Hyperkalaemia, hypokalaemia and hyponatraemia are associated with diuretic therapy and may play a very important role in subsequent development of life-threatening arrhythmias.

Impact of clopidogrel response on the clinical evolution in patients with acute coronary syndromes.

AIM: the purpose of the present study was to determine the relationship between the Clopidogrel genetic response (based on laboratory specific tests) and the worse evolution of the patients with acute coronary syndromes. MATERIAL AND METHODS: The study included 80 patients (11 females and 69 males), aged between 45 - 85 years, admitted in the 1st Department of Cardiology, between January June 2012, diagnosed with acute coronary syndromes (especially unstable angina). All the patients received Clopidogrel as antiplatelet agent, in some cases associated with aspirin. The diagnosis of acute coronary syndrome was based on clinical, ECG, echocardiographic and enzymatic signs. All the patients accepted to be included in the present study and signed a consent formulary. The Clopidogrel resistance was determined by specific genetic laboratory tests. RESULTS AND DISCUSSION: Of 80 cases, 4 patients were identified as normal responders (5%), 3 patients were low responders (3.75%), 58 patients were high responders (72.5%) and 15 patients were unpredictable (18.75%). In the high responders' group a lot of hemorrhagic disorders in different territories were identified. Normal responders had a good evolution. In patients with low response and unpredictable status the recurrence of angina and left ventricular failure as complications were frequent. CONCLUSIONS: The present study allowed a positive correlation between the haemorrhagic events and the high responder status to Clopidogrel. Low responder patients or those with an unpredictable phenotype had a worse evolution caused by the recurrence of angina or left ventricular failure.

[Cardiotoxicity of anthracyclines]. / Cardiotoxicitatea la antracicline. Mecanisme, metode de depistare precoce, posibilitati de influentare terapeutica.

It is a well known fact that the antitumor agents like the anthracyclines induces a dose-related cardiotoxicity and more to add, the new agents used in the treatement of breast cancer may stimulate these cardiotoxic effects, causing in the end an increased morbidity and mortality rate by cardiovascular diseases. Cardiotoxicity caused by anthracyclines can be divided into 3 types: acute (during administration), early (several days to month following administration) and late (years to decades following exposure to anthracyclines). Mechanisms of this cardiotoxicity are very complex: myocyte damage has been attributed to the production of toxic oxygen free radicals, which cause lipid peroxidation of membranes leading to vacuolation, irreversible damage and myocyte replacement by fibrous tissue. Clinical manifestations of anthracycline cardiotoxicity are variable, depending in part upon the time course of appearence (acute, early or late). A number of risk factors for the development of anthracyclines cardiotoxicity have been identified. The strongest predictor is cumulative dose, age, concomitant administration of other chemotherapeutic agents and underlying heart disease. Approaches to reducing anthracyclines cardiotoxicity involved the use of novel infusion protocols, the development of new anthracycline compounds, the use of adjunctive agents, endomyocardial biopsy and noninvasive monitoring of cardiac function.

Saturated near-resonant refractive optical nonlinearity in CdTe quantum dots.

In this work, we report on an experimental investigation of the nonlinear optical properties near the first electronic resonance of thiol-capped CdTe quantum dots (QDs) being in the strong confinement regime. Using a cw laser excitation in a Z-scan experimental setup, we show the presence of saturated Kerr-type nonlinear optical properties of the QDs, at low intensity levels. The large optical nonlinearity and the control of the linear and nonlinear optical properties by the size of the QDs are of special interest for applications in integrated nanophotonic devices.

[Correlation between plasma level of endothelin-1 and heart remodeling in dilated cardiomyopathy]. / Interrelatii intre nivelele plasmaticeale endotelinei-1 si remodelarea cardiaca in cardiomiopatia dilatativa.

UNLABELLED: The link between plasma level of endothelin-1 (ET-1) and heart failure has been established. This study demonstrate the role of endothelin-1 in progression of morphological and haemodynamic alteration of heart in patients with dilatative cardiomyopathy. MATERIALS AND METHODS: We included 71 patients with dilatative cardiomyopathy (ischemic and/or alcoholic)--36 men (50.7%) and 35 women (49.3%). We excluded patients who suffered from chronic renal failure, malignancies, systemic autoimmune disorders, liver cirrhosis. The echocardiography evaluated the chambers dimensions, valvular regurgitations, ejection and shortening fraction, systolic pulmonary artery pressure, cardiac output. All patients were assessed with endothelin-1 and usual hematological and biochemical tests, chest X-ray and electrocardiogram. RESULTS: The plasma level of endothelin-1 was increased of all patients (5.2775 +/- 2.65 fmol/ml). The value of ET-1 was associated with NYHA class of congestive heart failure (p < 0.000002). All patients were ejection fraction low (< 40%) and it was strongly associated with high level of plasma ET-1 (p < 0.001). The shortening fraction was very low at 87.32% of patients (value was between 5% and 15%) and the relation with ET-1 was significantly (r = - 0.3911, p = 0.001). The same relation was between ET-1 and tele-diastolic and telesystolic left ventricular volume (p = 0.026, respectively, p = 0.001), regional kinetics alteration (p = 0.023), systolic pulmonary arterial pressure (p = 0.0001, r = 0.71) and cardiac output (p = 0.0234). CONCLUSIONS: The plasma level of endothelin-1 is high at all patients with dilatative cardiomyopathy. Functional and morphological heart alterations are tightly connected to the changes of the endothelin system.

[Endothelial dysfunction assessment using vascular ultrasound in heart failure patients]. / Evaluarea disfunctiei endoteliale prin ecografie vasculara la pacientii cu insuficienta cardiaca cronica.

Endothelial dysfunction is an important factor leading to atherosclerosis, hypertension and heart failure. Flow mediated dilatation (endothelium dependent function) can be evaluated by vascular ultrasound. We investigated 71 heart failure patients (36 men-50.7%, 35 women-49.3%). The evaluation methods were: electrocardiogram, vascular ultrasound, echocardiography, chest X ray, hematological and biochemical tests. The statistical correlations were performed between clinical data, morphologic and hemodynamic parameters. Our results showed that endothelial dysfunction was present in all heart failure patients but it did not correlate with hemodynamic parameters. Elastic arterial parameters variation correlated with heart failure severity and flow mediated vasodilation.

(2+1)-dimensional soliton formation in photorefractive Bi12SiO20 crystals.

(2+1)-dimensional spatial solitons in Bi12SiO20 (BSO) photorefractive crystals with large optical activity are experimentally demonstrated. The soliton formation when a Gaussian beam is injected at the input has been previously analyzed numerically and then experimentally investigated. We demonstrate analytically, numerically, and experimentally that by applying static electric biases of high values, the polarization rotation accelerates: this acceleration prevents the beam from broadening if the polarization rotation period becomes shorter than the diffraction length. Contemporary to this nonlinear optical activity, an induced birefringence affects the beam polarization state. Analysis of the polarization dynamics shows that the polarization changes nonuniformly across the beam (with a field dependent speed) until about 30-35 kV/cm; above this limit, the whole beam has just one polarization state. Representation on the Poincaré sphere of the polarization dynamics reveals the existence of a stable polarization trajectory closed around a polarization attractor that depends on the linear optical activity and on the photorefractive nonlinearity. The experimental soliton is well described by the analytical solutions already obtained [Fazio et al., Phys. Rev. E 66, 016605 (2002)].

Large-conductance calcium-activated potassium channels in neonatal rat intracardiac ganglion neurons.

The properties of single Ca2+-activated K+ (BK) channels in neonatal rat intracardiac neurons were investigated using the patch-clamp recording technique. In symmetrical 140 mM K+, the single-channel slope conductance was linear in the voltage range -60/+60 mV, and was 207+/-19 pS. Na+ ions were not measurably permeant through the open channel. Channel activity increased with the cytoplasmic free Ca2+ concentration ([Ca2+]i) with a Hill plot giving a half-saturating [Ca2+] (K0.5) of 1.35 microM and slope of approximately equals 3. The BK channel was inhibited reversibly by external tetraethylammonium (TEA) ions, charybdotoxin, and quinine and was resistant to block by 4-aminopyridine and apamin. Ionomycin (1-10 microM) increased BK channel activity in the cell-attached recording configuration. The resting activity was consistent with a [Ca2+]i <100 nM and the increased channel activity evoked by ionomycin was consistent with a rise in [Ca2+]i to > or =0.3 microM. TEA (0.2-1 mM) increased the action potential duration approximately equals 1.5-fold and reduced the amplitude and duration of the afterhyperpolarization (AHP) by 26%. Charybdotoxin (100 nM) did not significantly alter the action potential duration or AHP amplitude but reduced the AHP duration by approximately equals 40%. Taken together, these data indicate that BK channel activation contributes to the action potential and AHP duration in rat intracardiac neurons.

Verapamil block of large-conductance Ca-activated K channels in rat aortic myocytes.

The effects of verapamil on the large conductance Ca-activated K (BK) channel from rat aortic smooth muscle cells were examined at the single channel level. Micromolar concentrations of verapamil produced a reversible flickering block of the BK channel activity. Kinetic analysis showed that verapamil decreased markedly the time constants of the open states, without any significant change in the time constants of the closed states. The appearance of an additional closed state-specifically, a nonconducting, open-blocked state--was also observed, whose time constant would reflect the mean residence time of verapamil on the channel. These observations are indicative of a state-dependent, open-channel block mechanism. Dedicated kinetic (group) analysis confirmed the state-dependent block exerted by verapamil. D600 (gallopamil), the methoxy derivative of verapamil, was also tested and found to exert a similar type of block, but with a higher affinity than verapamil. The permanently charged and membrane impermeant verapamil analogue D890 was used to address other important features of verapamil block, such as the sidedness of action and the location of the binding site on the channel protein. D890 induced a flickering block of BK channels similar to that observed with verapamil only when applied to the internal side of the membrane, indicating that D890 binds to a site accessible from the cytoplasmic side. Finally, the voltage dependence of D890 block was assessed. The experimental data fitted with a Langmuir equation incorporating the Woodhull model for charged blockers confirms that the D890-binding site is accessed from the internal mouth of the BK channel, and locates it approximately 40% of the membrane voltage drop along the permeation pathway.