Competitive and cooperative effects of Bay K8644 on the L-type calcium channel current inhibition by calcium channel antagonists

Phenylalkylamines, benzothiazepines, and dihydropyridines bind noncompetitively to the L-type calcium channel. The molecular mechanisms of this interaction were investigated in enzymatically isolated rat ventricular myocytes using the whole-cell patch-clamp technique. When applied alone, felodipine, verapamil, and diltiazem inhibited the L-type calcium current with values of inhibitory constant (K(B)) of 11, 246, and 512 nM, respectively, whereas 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-[trifluoromethyl]phenyl)-3-pyridine carboxylic acid methyl ester (Bay K8644) activated I(Ca) with activation constant (K(A)) of 33 nM. Maximal activation of I(Ca) by 300 nM Bay K8644 strongly reduced the inhibitory potency of felodipine (apparent K(B) of 165 nM), significantly reduced the inhibitory potency of verapamil (apparent K(B) of 737 nM), but significantly increased the inhibitory potency of diltiazem (apparent K(B) of 310 nM). In terms of a new pseudoequilibrium two-drug binding model, the interaction between the dihydropyridine agonist Bay K8644 and the antagonist felodipine was found purely competitive. The interaction between Bay K8644 and verapamil or diltiazem was found noncompetitive, and it could be described only by inclusion of a negative interaction factor nu = -0.60 for verapamil and a positive interaction factor nu = +0.24 for diltiazem. These results suggest that at physiological membrane potentials, the L-type calcium channel cannot be simultaneously occupied by a dihydropyridine agonist and antagonist, whereas it can simultaneously bind a dihydropyridine agonist and a nondihydropyridine antagonist. Generally, the effects of the drugs on the L-type calcium channel support a concept of a channel domain responsible for binding of calcium channel antagonists and agonists changing dynamically with the membrane voltage and occupancy of individual binding sites.     

Hopelessness depression in depressed inpatients: Symptomatology,patient characteristics,and outcome

This exploratory study examined the association between level of hopelessness and specific depression symptomatology, patient characteristics, and treatment outcome. Results from 80 unipolar depressed inpatients suggested that high-hopelessness patients could be discriminated from low-hopelessness patients on hypothesized symptoms of depression, characterized by retarded initiation of voluntary responses (a motivational symptom) and sad affect (an emotional symptom). Moreover, high-hopelessness patients could be discriminated from patients low in hopelessness on the patient characteristics of greater suicidal ideation, social dysfunction, and cognitive dysfunction. Finally, compared to low-hopelessness patients, depressed inpatients high in hopelessness exhibited a poorer outcome to pharmacological and cognitive-behavioral treatment interventions.This research was supported by National Institute of Mental Health grants MH-35945 and MH 44778. Preparation of this article was supported by a grant from the National Alliance for Research on Schizophrenia and Depression. Portions of this article were presented at the 26th annual convention of the Association for Advancement of Behavior Therapy, Boston, November 1992.     

Comparison of image quality and patient discomfort in prostate MRI: pelvic phased array coil vs. endorectal coil

Purpose

To compare image quality (IQ) and patient discomfort during prostate MRI using a pelvic phased array (PPA) coil and an endorectal (ER) coil.

Materials and methods

Ninety-eight patients (median age, 65.7; range 42.1–78.1) underwent prostate MRI on a 3T scanner including T2w and DWI acquired with PPA and an ER coil within the same exam. Acquisition time was kept similar for both acquisitions. Two radiologists evaluated aspects of IQ on a 5-point Likert scale and classified image artifacts. All patients completed a questionnaire on discomfort/pain regarding the ER coil using a visual analogue scale from 1 to 10.

Results

There was no significant difference in overall IQ for T2w images for both readers (reader 1, 3.27 ± 0.91 and 3.07 ± 0.84, p = 0.057; reader 2, 3.70 ± 0.75 and 3.77 ± 0.81, p = 0.555) for PPA and ER coils, respectively. Overall IQ for DWI acquired with PPA and ER coils was rated similar by reader 1 (3.03 ± 1.10 and 3.08 ± 0.80, respectively, (p = 0.67)), while reader 2 preferred ER coil images (3.27 ± 0.81 and 3.66 ± 0.85 (p < 0.05)). Susceptibility artifacts were more frequent in ER than in PPA coil images (109 vs. 75). Discomfort and pain experienced during insertion of the ER coil was low altogether (VAS score, 3.5 ± 2.1 for “discomfort” and 2.4 ± 2.4 for “pain”).

Conclusion

T2-weighted images may be acquired with comparable IQ using a PPA coil as compared to an ER coil, while DWI images showed better IQ using the ER coil for one of two readers. The insertion of the ER coil caused low to moderate discomfort and pain in patients.

     

Predictors of bone fractures in a single-centre cohort of hemodialysis patients: a 2-year follow-up study

International Urology and Nephrology - Bone involvement represents one of the complications of end-stage chronic kidney disease, with fractures being its major risk. The aim of our study was to...