In the present study, we have investigated whether changes in vascular reactivity in congestive heart failure (CHF) patients can be detected in the cutaneous microvessels and whether these changes are due to endothelial dysfunction, are affected by increasing age and related to an ongoing inflammation. The responses to local warming and iontophoretically administered endothelium-dependent and -independent vasodilators were investigated in healthy young adults, healthy elderly adults and elderly adults with CHF. The results were correlated with plasma concentrations of vascular risk factors and markers for endothelial dysfunction and inflammation. The vasorelaxant responses were reduced in the elderly groups and were attenuated further in the CHF group. This group also had increases in levels of several markers associated with inflammation, higher blood glucose and homocysteine levels, a lower low-density lipoprotein-cholesterol and a rise in the concentration of von Willebrand factor, indicating a prothrombotic endothelial function. The severity of the heart failure, measured as the plasma level of brain natriuretic peptide, correlated with the intensity of inflammation and to the changes in vascular risk factors and endothelial function. It is concluded that the reactivity of the cutaneous microvessels is reduced with age, and the presence of CHF causes a further impairment. There is endothelial dysfunction in CHF, but it is uncertain to what extent this contributes to the reduced vasodilatory capacity. The inflammatory response appears central for many of the manifestations of the CHF syndrome.

No abstract

No abstract

No abstract

The relative binding affinities to human dihydrofolate reductase of four new potential antifolates, containing ester linkages between the two aromatic systems, were estimated by free energy perturbation simulations. The ester analogue, predicted to exhibit the highest binding affinity to human dihydrofolate reductase, and a reference ester (more structurally related to methotrexate) were synthesized. As deduced from the measured IC(50) values, the calculated ranking of the ligands was correct although a greater difference in affinity was indicated by the experimental measurements. Among the new antifolates the most potent inhibitor exhibited a similar pharmacokinetic profile to methotrexate but lacked activity in a complex antiarthritic model in rat in vivo.

No abstract

No abstract

The action of (Gln4)-neurotensin was studied on the spontaneous motor activity in isolated canine fundic, antral and intestinal pouches. All pouches had been prepared more than 6 months prior to the experiments. Spontaneous motor activity was recorded for at least 1 h before the Gln4)-neurotensin was infused i.v. for 30 min in doses ranging between 6.3 and 100 ng X kg-1 X min-1. In the vagally denervated fundic pouches (Gln4)-neurotensin inhibted motor activity in doses above 25 ng X kg-1 X min-1. The vagally innervated antral pouches were more sentitive than the vagally denervated fundic pouches to the action of (Gln4)-neurotensin. Thus motor inhibition was induced by doses as low as 6.3 ng X kg-1 X min-1. The effect of (Gln4)-neurotensin on motor activity in intestinal pouches was inconsistent. Inhibition was seen in 1 out of 7 expts. The present results show that the gastric motor activity is the most sensitive function to (Gln4)-neurotensin so far studied.