On the mechanism underlying the action of D-600 on slow inward current and tension in mammalian myocardium

D-600 the methoxy derivative of verapamil, is said to affect the force of cardiac contraction and the slow inward current (LSi) specifically by reducing the membrane conductance for Ca2+ (gsi). However, it is apparent that many effects of D-600 cannot be adequately explained solely by an effect on gsi. We studied the effects of D-600 on membrane current and tension of cat papillary muscle, using a conventional single sucrose gap voltage clamp technique. The results indicate that D-600 not only reduces the maximal Ca conductance but also, depending on concentration and duration of exposure, alters both the kinetics of the Ca-carrying system and the amplitude of the steady state outward current. No changes in the steady state activation and inactivation variables or in the rate of Isi inactivation were found. However, a substantial increase in the time to peak Lsi, as much as 7 times normal, was observed after exposure to D-600 (0.5 X 10(-6) to 2.0 X 10(-6) M) for at least 20 minutes. Because approximately only 75% of the reduction in Lsi induced by D-600 could be attributed to change in the maximum value of gsi (gsi), we conclude that the change in time to peak and about 25% of the reduction in Isi must be due to a change in the activation kinetics of the Ca-carrying system, Calculations suggest that the time to 70% activation of gsi can be prolonged to as much as 10 times normal by prolonged exposure to negatively inotropic concentrations of D-600.     

Changing threshold for cataract surgery in Denmark between 1980 and 1992. Results from the Danish Cataract Surgery Outcomes Study. II

In Denmark the number of cataract extractions has increased 350% from 1980 to 1991. During the same period the elderly population at risk has only increased 17%, and thus cannot account for the large increase in the number of extractions. In order to investigate whether more comprehensive clinical indications could be a possible explanation, we compared pre-operative visual acuity and visual impairment in two consecutive samples of Danish cataract surgery patients obtained in 1980 (n = 73) and in 1992 (n = 290). Criteria for inclusion were similar and both samples were representative for the whole country. During the period mean pre-operative visual acuity increased from 0.04 to 0.16 in the eye enlisted for surgery (p < 0.00001). Visual functional impairment could be compared by using the same questionnaire for patient interview in 1992 as was used in 1980. In 1992 the degree of impairment was significantly less for reading, outdoor orientation and self care activities. A change in surgical threshold or clinical indications for surgery appears to be a major contributing factor to the large increase in surgical rates, even though a trend to perform second eye cataract surgery more often might also be of some importance.     

Cicaprost and the type IV phosphodiesterase inhibitor, rolipram, synergize in suppression of tumor necrosis factor-alpha synthesis

Suppression of tumor necrosis factor-alpha (TNF) synthesis is one major target in pharmacological immunomodulation. We now showed the synergistic suppressive effect of the specific type IV phosphodiesterase inhibitor, rolipram, and of the stable prostacyclin analogue, cicaprost, on TNF synthesis. This effect was seen with lipopolysaccharide and Staphylococcus epidermidis as stimuli in human peripheral blood mononuclear cells and in whole blood. Lipopolysaccharide-induced TNF synthesis by mononuclear cells decreased from 3.4 ng/ml to 1.5 ng/ml in the presence of 100 nM rolipram and to 0.7 ng/ml in the presence of 10 nM cicaprost. The combination of both agents suppressed TNF synthesis more than 10-fold, to 0.3 ng/ml. Synergistic suppression was also demonstrated for TNF mRNA.