Genitourinary symptoms and sexual function in women with primary ovarian insufficiency.

OBJECTIVE: There are limited studies on urogenital symptoms in women who experience menopause before the age of 40 years due to primary ovarian insufficiency (POI) or bilateral oophorectomy (surgical POI). This study aimed to compare the urogenital symptoms, including sexuality, of women with POI to those without the condition. METHODS: This cross-sectional study conducted was in seven Latin American countries, in which postmenopausal women (with POI and non-POI) were surveyed with a general questionnaire, the Menopause Rating Scale (MRS) and the six-item Female Sexual Function Index (FSFI-6). The association of premature menopause with more urogenital symptoms and lower sexual function was evaluated with logistic regression analysis. RESULTS: Women with POI experience more urogenital symptoms (MRS urogenital score: 3.54 ± 3.16 vs. 3.15 ± 2.89, p < 0.05) and have lower sexual function (total FSFI-6 score: 13.71 ± 7.55 vs. 14.77 ± 7.57 p < 0.05) than women who experience menopause at a normal age range. There were no significant differences in symptoms when comparing women based on the type of POI (idiopathic or surgical). After adjusting for covariates, our logistic regression model determined that POI is associated with more urogenital symptoms (odds ratio [OR]: 1.38, 95% confidence interval [CI] 1.06-1.80) and lower sexual function (OR: 1.67, 95% CI 1.25-2.25). CONCLUSION: POI, whether idiopathic or secondary to bilateral oophorectomy, is associated with symptoms that affect vaginal and sexual health.

miRNAs: una nueva mirada de la enfermedad de Vogt-Koyanagi-Harada / miRNAs: a new look at Vogt-Koyanagi-Harada disease

Vogt-Koyanagi-Harada disease (VKH) is an autoimmune multisystemic syndrome that includes bilateral intraocular inflammation, associated with exudative retinal detachments, and systemic manifestations in the auditory, integumentary, and central nervous systems. The frequency of VKH disease in the world is variable, but in Santiago, Chile, it causes approximately 17% of non-infectious uveitis, an incidence 2 to 3-fold greater than in the USA or European countries. The evidence shows that the pathogenesis of VKH would be caused by cell-mediated autoimmunity directed against melanocytes present in the uveal tissue. CD4+ T lymphocytes (especially hyperactivity of Th17 and Th1 cells), B lymphocytes, cytokines (e.g., TGF-ß, IL-2, IL-6, IL-23 and INF-γ) and chemokines appear to play an important role in the development of VKH. Several lines of evidence support that the pathogenesis of uveitis observed in VKH involves an altered pattern of micro-ribonucleic acids (miRNA) expression, driving the loss of immunological tolerance. In this review, we discuss the evidence related to regulation and altered expression of miRNA associated with Vogt-Koyanagi-Harada and other autoimmune diseases. (AU)

Immunogenicity of sequential 13-valent conjugated and 23-valent unconjugated pneumococcal vaccines in a population of children with lupus.

Pneumococcal vaccination is recommended as a quality indicator for management of children with systemic lupus erythematosus. Literature on the immunogenicity of pneumococcal vaccines (PCVs) in children is scant. We sought to prospectively evaluate via an observational study, the immunogenicity to sequential children with lupus. Out of a cohort of 26 patients, approximately 65% achieved > 70% vaccinated serotype antibody levels of > 1.3 mcg/dL following PCV13, and of 22 patients followed through PPSV23 vaccination, 59% achieved the same. Patients with rituximab exposure in the 6 months prior to a vaccination were more likely to not achieve protective serotype levels ( p < 0.01 for PCV13, trend p = 0.07 for PPSV23). Three of 22 patients with no apparent risk factors did not achieve protective serotype levels. Non-responders to PCV13 generally did not respond to PPSV23. Retrospective healthy controls achieved 100% protective levels in response to PPSV23 vaccination, with 95% of serotypes being > 1.3 mcg/dL. Thus, sequential 13- and 23-valent pneumococcal vaccines achieve protective status for approximately two thirds of pediatric lupus patients in our population. Lack of response to vaccine may be secondary to induced or inherent functional impairments in the patient.

Evaluación de la reproducibilidad de un protocolo de resonancia magnética dinámica para el estudio farmacocinético de los tumores de mama / Evaluation of the reproducibility of a protocol for the pharmacokinetic study of breast tumors by dynamic magnetic resonance imaging

Objetivo. Evaluar la reproducibilidad de un protocolo de resonancia magnética dinámica (RM-DC) con contraste para el estudio farmacocinético de los tumores de mama. Material y métodos. Estudio prospectivo realizado entre octubre y diciembre de 2009, que incluyó 12 pacientes con cáncer de mama infiltrante en estadios ii-iii sin tratamiento previo. Este trabajo fue aprobado por el Comité de Ética de Investigación de nuestro centro. A las 12 pacientes se les realizó 2 RM-DC en 2 días consecutivos con un protocolo de alta resolución temporal (21 adquisiciones/minuto). Se analizaron por separado los datos obtenidos en un ROI trazado alrededor del diámetro tumoral mayor (ROI 1) y otro que abarcaba la zona de mayor intensidad de Ktrans de la lesión (ROI 2). Se emplearon pruebas estadísticas paramétricas y no paramétricas para estudiar la reproducibilidad y concordancia de las principales variables farmacocinéticas (Ktrans, Kep, Ve y AUC90). Resultados. Las correlaciones fueron muy altas (r > 0,80; p < 0,01) en todas las variables del ROI 1, y altas (r = 0,70-0,80; p < 0,01) en todas las del ROI 2, excepto en Ve tanto en el ROI 1 (r = 0,44; p = 0,07) como en el ROI 2 (r = 0,13; p = 0,235). No hubo diferencias estadísticamente significativas entre los 2 estudios para los valores obtenidos de Ktrans, Kep y AUC90 (p > 0,05 para todas ellas), pero sí que las hubo para Ve en el ROI 2 (p = 0,008). Conclusión. El protocolo de alta resolución temporal de RM-DC de nuestro centro es muy reproducible para las principales constantes farmacocinéticas de los tumores de mama (AU)

Objective. To evaluate the reproducibility of a protocol for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for the pharmacokinetic study of breast tumors. Material and methods. We carried out this prospective study from October 2009 through December 2009. We studied 12 patients with stage ii-iii invasive breast cancer without prior treatment. Our center's research ethics committee approved the study. The 12 patients underwent on two consecutive days DCE-MRI with a high temporal resolution protocol (21 acquisitions/minute). The data obtained in an ROI traced around the largest diameter of the tumor (ROI 1) and in another ROI traced around the area of the lesion's highest Ktrans intensity (ROI 2) were analyzed separately. We used parametric and nonparametric statistical tests to study the reproducibility and concordance of the principal pharmacokinetic variables (Ktrans, Kep, Ve and AUC90). Results. The correlations were very high (r>.80; P<.01) for all the variables for ROI 1 and high (r=.70-.80; P<.01) for all the variables for ROI 2, with the exception of Ve both in ROI 1 (r=.44; P=.07) and in ROI 2 (r=.13; P=.235). There were no statistically significant differences between the two studies in the values obtained for Ktrans, Kep and AUC90 (P>.05 for each), but there was a statistically significant difference between the two studies in the values obtained for Ve in ROI 2 (P=.008). Conclusions. The high temporal resolution protocol for DCE-MRI used at out center is very reproducible for the principal pharmacokinetic constants of breast (AU)

Evaluation of the reproducibility of a protocol for the pharmacokinetic study of breast tumors by dynamic magnetic resonance imaging.

OBJECTIVE: To evaluate the reproducibility of a protocol for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for the pharmacokinetic study of breast tumors. MATERIAL AND METHODS: We carried out this prospective study from October 2009 through December 2009. We studied 12 patients with stage ii-iii invasive breast cancer without prior treatment. Our center's research ethics committee approved the study. The 12 patients underwent on two consecutive days DCE-MRI with a high temporal resolution protocol (21 acquisitions/minute). The data obtained in an ROI traced around the largest diameter of the tumor (ROI 1) and in another ROI traced around the area of the lesion's highest K(trans) intensity (ROI 2) were analyzed separately. We used parametric and nonparametric statistical tests to study the reproducibility and concordance of the principal pharmacokinetic variables (K(trans), Kep, Ve and AUC90). RESULTS: The correlations were very high (r>.80; P<.01) for all the variables for ROI 1 and high (r=.70-.80; P<.01) for all the variables for ROI 2, with the exception of Ve both in ROI 1 (r=.44; P=.07) and in ROI 2 (r=.13; P=.235). There were no statistically significant differences between the two studies in the values obtained for K(trans), Kep and AUC90 (P>.05 for each), but there was a statistically significant difference between the two studies in the values obtained for Ve in ROI 2 (P=.008). CONCLUSIONS: The high temporal resolution protocol for DCE-MRI used at out center is very reproducible for the principal pharmacokinetic constants of breast.

Cannabinoid receptor type 1 activation by arachidonylcyclopropylamide in rat aortic rings causes vasorelaxation involving calcium-activated potassium channel subunit alpha-1 and calcium channel, voltage-dependent, L type, alpha 1C subunit.

Cannabinoids are key regulators of vascular tone, some of the mechanisms involved include the activation of cannabinoid receptor types 1 and 2 (CB); the transient receptor potential cation channel, subfamily V, member 1 (TRPV1); and non-(CB(1))/non-CB2 receptors. Here, we used the potent, selective CB(1) agonist arachidonylcyclopropylamide (ACPA) to elucidate the mechanism underlying vascular tone regulation. Immunohistochemistry and confocal microscopy revealed that CB(1) was expressed in smooth muscle and endothelial cells in rat aorta. We performed isometric tension recordings in aortic rings that had been pre-contracted with phenylephrine. In these conditions, ACPA caused vasorelaxation in an endothelium-independent manner. To confirm that the effect of ACPA was mediated by CB(1) receptor, we repeated the experiment after blocking these receptors with a selective antagonist, AM281. In these conditions, ACPA did not cause vasorelaxation. We explored the role of K(+) channels in the effect of ACPA by applying high-K(+) solution to induce contraction in aortic rings. In these conditions, the ACPA-induced vasorelaxation was about half that observed with phenylephrine-induced contraction. Thus, K(+) channels were involved in the ACPA effect. Furthermore, the vasorelaxation effect was similarly reduced when we specifically blocked calcium-activated potassium channel subunit alpha-1 (KCa1.1) (MaxiK; BKCa) prior to adding ACPA. Finally, ACPA-induced vasorelaxation was also diminished when we specifically blocked the calcium channel, voltage-dependent, L type, alpha 1C subunit (Ca(v)1.2). These results showed that ACPA activation of CB(1) in smooth muscle caused vasorelaxation of aortic rings through a mechanism involving the activation of K(Ca)1.1 and the inhibition of Ca(v)1.2.

Tratamiento del cáncer de próstata y cáncer renal con fármacos orales (abiraterona y antiangiogénicos): posicionamiento de la Asociación Española de Urología / Treatment of prostate and renal cancer with oral drugs (abiratarone and antiangiogenic agents): Positioning statement from the Spanish Association of Urology

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La estadificación con resonancia magnética puede cambiar el manejo terapéutico en el cáncer de mama / Using magnetic resonance imaging for staging can change the therapeutic management in patients with breast cancer

Objetivo. Comparar 2 series de pacientes con cáncer de mama, una estadificadas mediante resonancia magnética (RM) preoperatoria y la otra con técnicas convencionales, y estudiar los cambios de tratamiento y el número de mastectomías y de reintervenciones por afectación de los bordes. Material y métodos. Se revisaron 600 pacientes divididas en 300 con RM preoperatoria (serie 1) y 300 sin RM (serie 2). Se valoraron: la edad, el estado menopáusico, el tamaño tumoral anatomopatológico, la multiplicidad y bilateralidad, el tratamiento quirúrgico y tipo de tratamiento, la administración de quimioterapia neoadyuvante y las reintervenciones por márgenes afectos. Las variables fueron comparadas con las pruebas t de Student y la Chi-cuadrado. Resultados. La edad media fue similar (51,5 y 51,8 años, p=0,71). El tamaño tumoral medio fue menor (p<0,001) en la serie 1 (16,9 vs 22,3mm). Se detectaron más tumores múltiples (p<0,001) en la serie 1 (28,7 vs 15,7%). La tasa de mastectomías en la serie 1 (25%) fue menor (p<0,001) que en la 2 (48%). Las técnicas de cirugía oncoplástica y bilaterales solo fueron realizadas en la serie 1. La quimioterapia neoadyuvante fue administrada más frecuentemente (p<0,001) en la serie 1 (30,7 vs 9,3%). La diferencia no fue significativa (p=0,095) en el número de reintervenciones por márgenes afectos (7,2% serie 1; 3,2% serie 2). Conclusión. Las mastectomías disminuyen al emplear la RM, con disponibilidad de técnicas de cirugía oncoplástica y quimioterapia neoadyuvante. Pese al aumento de cirugías conservadoras en la serie con RM, no observamos un aumento significativo del número de reintervenciones por márgenes afectos, aunque existe una tendencia (AU)

Objective. To compare two series of patients with breast cancer, one staged using preoperative MRI and the other staged using conventional techniques, analyzing the changes to treatment, the number of mastectomies, and the number of reinterventions due to involvement of the margins. Material and methods. We reviewed 600 patients divided into 300 patients with preoperative MRI (series 1) and 300 without preoperative MRI (series 2). We recorded the following variables: age, menopausal status, tumor size on pathological examination, multiplicity and bilaterality, surgical treatment and type of treatment, the administration of neoadjuvant chemotherapy, and reintervention for involved margins. We used Student's t-test and the chi-square test to compare the variables between the two series. Results. The mean age of patients in the two series was similar (51.5 and 51.8 years, P=0.71). The mean size of the tumor was smaller in series 1 (16.9mm vs 22.3mm) (P<.001). More multiple tumors were detected in series 1 (28.7 vs 15.7%) (P<.001). The rate of mastectomies was lower in series 1 (25 vs 48%) (P<.001). Oncoplastic and bilateral surgeries were performed only in series 1. Neoadjuvant chemotherapy was administered more often in series 1 (30.7 vs 9.3%) (P<.001). The difference in the number of reinterventions for involved margins did not reach significance (7.2% in series 1 vs 3.2% in series 2) (P=.095). Conclusion. When MRI was used for staging, neoadjuvant chemotherapy and oncoplastic surgery were used more often and the mastectomy rate decreased. Despite the increase in conservative surgery in patients staged with MRI, the number of reinterventions for involved margins did not increase, although there was a trend towards significance (AU)

Intensive educational course in allergy and immunology.

A one-day intensive educational course on allergy and immunology theory and diagnostic procedure significantly increased the competency of allergy and immunology fellows-in-training.

[Using magnetic resonance imaging for staging can change the therapeutic management in patients with breast cancer]. / La estadificación con resonancia magnética puede cambiar el manejo terapéutico en el cáncer de mama.

OBJECTIVE: To compare two series of patients with breast cancer, one staged using preoperative MRI and the other staged using conventional techniques, analyzing the changes to treatment, the number of mastectomies, and the number of reinterventions due to involvement of the margins. MATERIAL AND METHODS: We reviewed 600 patients divided into 300 patients with preoperative MRI (series 1) and 300 without preoperative MRI (series 2). We recorded the following variables: age, menopausal status, tumor size on pathological examination, multiplicity and bilaterality, surgical treatment and type of treatment, the administration of neoadjuvant chemotherapy, and reintervention for involved margins. We used Student's t-test and the chi-square test to compare the variables between the two series. RESULTS: The mean age of patients in the two series was similar (51.5 and 51.8 years, P=0.71). The mean size of the tumor was smaller in series 1 (16.9 mm vs 22.3 mm) (P<.001). More multiple tumors were detected in series 1 (28.7 vs 15.7%) (P<.001). The rate of mastectomies was lower in series 1 (25 vs 48%) (P<.001). Oncoplastic and bilateral surgeries were performed only in series 1. Neoadjuvant chemotherapy was administered more often in series 1 (30.7 vs 9.3%) (P<.001). The difference in the number of reinterventions for involved margins did not reach significance (7.2% in series 1 vs 3.2% in series 2) (P=.095). CONCLUSION: When MRI was used for staging, neoadjuvant chemotherapy and oncoplastic surgery were used more often and the mastectomy rate decreased. Despite the increase in conservative surgery in patients staged with MRI, the number of reinterventions for involved margins did not increase, although there was a trend towards significance.

Passive mechanical properties of cardiac tissues in heart hypertrophy during pregnancy.

We evaluated changes in passive mechanical properties in cardiac tissues during rat pregnancy. Left and right ventricular free walls were dissected from hearts of nonpregnant, late-pregnant, and postpartum rats. Mechanical experiments in ventricular strips were done by stretch-release cycles using a step motor. The results show that during pregnancy, there is cardiac hypertrophy associated with (1) an increase in myocyte size, particularly of augmented myocyte length, (2) a decrease in passive tension developed by the myocardial walls, and (3) a decrease in both elastic modulus and hysteresis. All changes observed during rat pregnancy were reversed during postpartum. In conclusion, a heart with less ventricular rigidity could contribute to facilitating the ventricular filling in conditions of a greater circulating volume characteristic of pregnancy.

Forskolin versus sodium cromoglycate for prevention of asthma attacks: a single-blinded clinical trial.

To determine the efficacy of forskolin in preventing asthma attacks, we performed a single-blinded clinical study in children and adult out-patients at a public hospital in Mexico. Forty patients of either sex with mild persistent or moderate persistent asthma were assigned randomly to 6 months of treatment with forskolin at 10 mg/day orally (capsules) or with two inhalations of sodium cromoglycate every 8 h, i.e. three times a day. The number of patients who had asthma attacks during the treatment period was significantly lower among those receiving forskolin (8/20, 40%) than among those receiving sodium cromoglycate (17/20, 85%). Values of forced expiratory volume in 1 s and forced expiratory flow, mid-phase, A similar in the two groups during the treatment period. We conclude that forskolin is more effective than sod cromoglycate in preventing asthma attacks in patients with mild persistent or moderate persistent asthma.

[Colorectal cancer: 74 patients treated by laparoscopic resection with a mean follow-up of 5 years]. / Cancer colorectal: 74 patients traités par laparoscopie avec un recul moyen de 5 ans.

OBJECTIVE: The aims of this study were to analyse the results and long term outcome in a prospective non randomised trial of 74 patients treated by laparoscopic colo-rectal resection for cancer, and to determine wether survival and recurrence are or are not compromised by an initial laparoscopic approach. PATIENTS AND METHODS: Seventy-four patients with colo-rectal carcinoma were included in a prospective trial and treated by laparoscopic resection. All patients were reviewed at 1, 3, and 6 months interval. A median of 5 years follow up was available. Forty-eight patients (65%) had more than 3 years of follow up. RESULTS: Six conversions (8.1%) were necessary: 2 for tumor invasion of adjacent organs, 2 for limited margin resection in lower rectal tumors, 1 for small bowel injury and 1 for obesity. After surgery, passing flatus occurred at 34.3 +/- 16.7 h and oral intake could be reinstaured at 42.6 +/- 22 h. Mean postoperative stay was 8.2 +/- 3.4 days. No death occurred. The overall morbidity was about 13.5%. The rate of late complications was 5.4%. Two port site metastasis (2.6%) were seen in locally advanced carcinoma. Recurrence rate at 5 years was 0% for Dukes A, 20% for Dukes B, 39.2% for Dukes C. Survival rate at 5 years was 100% for Dukes A, 80% for Dukes B, and 60.7% for Dukes C. These results are similar to those of conventional open surgery. CONCLUSION: Laparoscopic colorectal resection for cancer can be performed safely, with a low morbidity and rare late complications. Long term follow up (5 years) assessment shows similar outcome compared with conventional surgery.

Developmental differences in delayed rectifying outward current in feline ventricular myocytes.

In the present work, we found that the delayed rectifying outward potassium current (I(K)) in adult and neonatal cat ventricular myocytes consists of both rapid and slow components, I(Kr) and I(Ks), respectively, which can be isolated pharmacologically. Thus after complete blockade of I(Kr) with dofetilide, the remaining I(Ks) current is homogeneous, as shown by an envelope of tails test. I(Kr) maximum tail current density, measured at -40 mV, was similar in adult and neonatal myocytes. I(Ks) maximum tail current density in neonatal myocytes, measured at -40 mV, was significantly smaller than in adult myocytes. Activation kinetics of I(Kr) and I(Ks) was similar in both age groups. However, the I(Kr) deactivation time course was significantly faster in neonatal than in adult myocytes. Developmental differences in the subunit composition of I(Kr) that display distinctly different deactivation kinetics are suggested.

Frequency-dependent effects of 4-aminopyridine and almokalant on action-potential duration of adult and neonatal rabbit ventricular muscle.

The effects of 4-aminopyridine (1 mM) and almokalant (1 microM) on action-potential duration of neonatal and adult rabbit ventricular multicellular preparations and plateau membrane currents of single ventricular myocytes were studied. In adult ventricular preparations, 4-aminopyridine increased action-potential duration in a frequency-dependent manner, with a greater effect at low stimulation frequencies ("reverse" use dependence). In neonatal preparations, the increase in action-potential duration by 4-aminopyridine was significantly smaller than in adults, and the effect was frequency independent. Almokalant increased the action-potential duration more in neonatal than in adult myocytes. The effect of almokalant was frequency independent between 0.5 and 2 Hz. The block of transient outward current and delayed rectifier current in single myocytes was quantitatively similar. We propose that differences in the kinetic behavior of the transient outward current between adult and neonatal ventricular preparations, slower inactivation, and recovery from inactivation in adults determine differences in the frequency-dependent changes induced by 4-aminopyridine and almokalant on action-potential duration.

Embolization of nonvariceal portosystemic collaterals in transjugular intrahepatic portosystemic shunts.

Percutaneous embolization of large portosystemic collaterals was performed in three patients following placement of a transjugular intrahepatic portosystemic shunt in order to improve hepatopetal portal flow. Improved hepatic portal perfusion was achieved in these cases, thereby theoretically reducing the risk of chronic hepatic encephalopathy.

Characterization of a complex translocation [t(4;9;22)(p16;q34;q11)] in chronic myelogenous leukemia by fluorescence in situ hybridization technique.

A patient was referred with a high leukocyte count and diagnosed with chronic myelogenous leukemia (CML). Although practically asymptomatic since the time of diagnosis, he had a variable and inconsistent response to treatment. All of his bone marrow cells had a complex, three-way translocation, involving chromosomes 4, 9 and 22. Translocation of chromosome 4 to chromosome 9 was undetectable by routine cytogenetic techniques; however, by the fluorescence in situ hybridization technique, a three-way translocation was identified, 46,XY,t(4;9;22)(p16;q34;q11). Although, other chromosomes are frequently involved in complex or variant translocations with chromosome 9 and 22, participation of chromosome 4 is a very rare event. So far, two previous cases have been described in the literature with translocations involving chromosome 4p16. We present a third case of CML having similar break points whose clinical presentation is unusual.

Imipramine blocks rapidly activating and delays slowly activating K+ current activation in guinea pig ventricular myocytes.

Imipramine is a tricyclic antidepressant drug that also exhibits antiarrhythmic effects and whose clinical spectrum of activity is similar to that of quinidine. It has been previously demonstrated that imipramine inhibits the aggregate time-dependent outward K+ current (IK). IK is composed of at least two components: a slowly activating La(3+)-resistant delayed rectifying current (IK,s) and a rapidly activating La(3+)-sensitive current (IK,r). To assess the effects of imipramine on IK,r and IK,s, single guinea pig ventricular myocytes were studied using the nystatin-perforated patch-clamp technique in the absence and in the presence of La3+. Imipramine inhibited IK,r and IK,s in a concentration-dependent manner. The effects of imipramine on the aggregate time-dependent outward current were more marked than those on IK,s alone. Thus, 1 mumol/L imipramine decreased the tail currents elicited on return to -30 mV after long depolarizing pulses (5 seconds, from -40 to +50 mV) in the absence and in the presence of La3+ by 27 +/- 4% and 15 +/- 3% (n = 6), respectively. Moreover, the inhibition induced by imipramine was greater after short (0.5-second) pulses than after 5-second depolarizing pulses, both in the absence and in the presence of La3+ (53 +/- 3% and 30 +/- 5%, respectively; n = 6; P < .05). Imipramine did not significantly modify either the activation midpoint or the slope factor of the aggregate IK and IK,s activation curves. The reduction of IK,s by imipramine was voltage dependent and was more marked at negative membrane potentials. In the presence of 1 mumol/L imipramine, the ratio of tail current to time-dependent current remained constant at 0.37 +/- 0.03, regardless of the test pulse duration at +50 mV. Thus, the envelope-of-tails test was satisfied in the presence of 1 mumol/L imipramine, which indicates that imipramine, at this concentration, blocks IK,r. Imipramine (1, 5, and 10 mumol/L) had no effect on the kinetics of the later phase of IK activation but delayed the beginning of the activation of IK,s by 62 +/- 22, 74 +/- 23, and 155 +/- 53 milliseconds in the presence of 1, 5, and 10 mumol/L imipramine, respectively. These results suggest that imipramine preferentially blocks rapidly activating K+ channels. In addition, experiments performed in the presence of 30 mumol/L La3+ suggest that the drug preferentially binds, but maybe not exclusively, to a closed state of the slowly activating K+ channel.