The sGC stimulator riociguat inhibits platelet function in washed platelets but not in whole blood.

BACKGROUND AND PURPOSE: Stimulation of soluble guanylyl cyclase (sGC) is a valuable therapeutic strategy for the treatment of several cardiovascular diseases. The sGC stimulator riociguat has been approved for the treatment of two forms of pulmonary hypertension. Platelets contain large amounts of sGC and play a key role in the regulation of haemostasis. Therefore, we investigated the effects of riociguat on platelet function. EXPERIMENTAL APPROACH: The effect of riociguat treatment on human platelet activation and aggregation was investigated. The sGC-specific effects of riociguat were determined by comparing wild-type and platelet-specific sGC-knockout mice. KEY RESULTS: Riociguat induced cGMP synthesis and subsequent PKG activation in human platelets, suggesting that the inhibitory effects are mediated by cGMP signalling. This finding was confirmed when sGC-knockout platelets were not inhibited by riociguat. In washed human platelets, 100 nM riociguat reduced ADP-induced GPIIb/IIIa activation, while a 10-fold higher concentration was required to reduce convulxin-stimulated GPIIb/IIIa activation. Riociguat inhibited ADP-induced platelet shape change and aggregation, while ATP-induced shape change remained unaffected. However, in PRP and whole blood, 50-100 µM riociguat was required to inhibit platelet activation and aggregation. Riociguat in combination with iloprost significantly inhibited platelet aggregation, even in whole blood. CONCLUSIONS AND IMPLICATIONS: Riociguat inhibits platelet activation in whole blood only at concentrations above 50 µM, while the plasma concentrations in riociguat-treated patients are 150 to 500 nM. This finding indicates that riociguat treatment does not affect platelet function in patients. Nevertheless, the possibility that riociguat acts synergistically with iloprost to inhibit platelet activation should be considered.

A space-variant filter model of texture segregation: parameter adjustment guided by psychophysical data.

This article presents a space-variant version of a standard spatial filter model of texture segregation of the "back-pocket" type (i.e., two filter layers with an intermediate pointwise nonlinearity). The model was tested with psychophysical data from experiments with line textures in which target lines differed in orientation from background lines. The textures were presented briefly and then masked. Segregation performance was evaluated along the horizontal meridian up to retinal eccentricities of about 10 deg. Data are reported from two experiments with different line densities (Kehrer 1989) and two experiments with different orientation contrasts between target lines and background lines (Kehrer 1990). Segregation performance proved to depend strongly on these texture variations, and it peaked several degrees from fixation in all cases. The filter model provided satisfactory predictions of experimental data when model parameters were adjusted appropriately. It is concluded (1) that filter models defined in strictly spatial terms (i.e., without temporal properties) offer a sufficient framework to account for the psychophysical data and (2) that the particular course of the performance curve (i.e., the performance peak outside the central region) must be attributed to the characteristics of second-layer filters.

Peripheral and foveal segmentation of angle textures.

Studies of the effects of retinal eccentricity on the visual segmentation of textures are presented. The textures used in these studies were composed of angle elements. These were presented tachistoscopically to college students in three different experiments. Results showed that there were different relationships between segmentation performance and eccentricity, depending on the width of the angles used in the background and target texture. One major difference was that peak performance was found in the fovea in some conditions, and in peripheral areas in other conditions. Performance in the fovea and the periphery seemed to be determined by qualitatively different features. It was assumed that an appropriate explanation is that the system-internal representation of a specific stimulus within the early visual system differs as a function of the retinal location at which it is projected. Thus, the critical features discriminating between target and background texture have to be sought in the system-internal representation of the stimulus instead of in the stimulus itself. The data show that a relatively exact system-internal representation of the stimulus is present in the fovea, where performance is determined by angle width. In the periphery, in contrast, angles seem to be represented as "blobs," and performance is determined by the orientation of the blobs' main axes.

Central performance drop on perceptual segregation tasks.

The main concern of this study is the range of the central (foveal) performance drop in perceptual segregation tasks reported by Kehrer (Spatial Vision 2, 247-261, 1987). This effect suggests that parafoveal areas of the retina make a significant contribution to the perceptual segregation of textures. Results showed that: (1) the central performance drop was not due to retinal criterion shifts in the sense of signal detection theory; (2) the central performance drop was not restricted to very short presentation times but could also be observed in 80- or 120-ms presentation times; (3) the retinal area in which maximal segmentation performance was found could be shifted by manipulating the spacing between the elements of the stimulus. This finding suggests that each different area of the retina is linked to the processing of a specific, limited area of the spatial frequency band.

Perceptual segregation and retinal position.

This study is concerned with the dependence of perceptual segregation performance on the retinal position at which the performance is evaluated. Segregation performance consisted in detecting a target texture composed of line elements of constant length and orientation embedded in a background texture. The background texture was made up of the same line elements as the target texture but the background line elements were set at 90 deg to the target elements. Results showed that, at least for 40- and 50-ms presentation times, this task could be much more effectively completed outside the fovea centralis than within this area. These findings indicate that extrafoveal areas of the retina may make a significant and previously underestimated contribution to perceptual segregation.