A. Rigoni

Elevated levels of soluble E-selectin in patients with IDDM and NIDDM: relation to metabolic control

SummaryThe adhesion of leucocytes to the endothelium, an early step in atherogenesis, is mediated by cell adhesion molecules. In this study we evaluated the concentration of soluble adhesion molecules in patients with insulin-dependent (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) and studied its relation to glycaemic control. Soluble adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) were measured in 31 diabetic patients (18 with IDDM and 13 with NIDDM), 20 hyperlipoproteinaemic patients (10 with type IIa and 10 with type IIb) and 20 healthy subjects. Increased E-selectin concentrations were found in the patients with IDDM and NIDDM and in the hyperlipoproteinaemic patients when compared to the control subjects (p<0.01 for all the groups). ICAM-1 was found to be elevated only in the patients with NIDDM (p<0.01). No significant differences in VCAM-1 concentration were found in the different groups of subjects. The concentration of plasma E-selectin was positively correlated with the glycated haemoglobin (r=0.54, p<0.01) in patients with IDDM and NIDDM. In the same patients E-selectin was not related to the concentrations of plasma lipids in spite of the fact that it was found to be elevated in hyperlipoproteinaemic subjects. The results though preliminary suggest that in diabetic patients the concentration of soluble adhesion molecules and especially of E-selectin may be related to metabolic control.

The expression of adhesion molecules on endothelial cells is inhibited by troglitazone through its antioxidant activity

The adhesion of monocytes to endothelium, an early event in atherosclerosis, is mediated by cell adhesion molecules. Signal-transduction pathways for these binding molecules include the translocation of the transcription factor NF-kappaB; moreover, intracellularly generated oxygen-derived free radicals (ODFR) play a major role in this process. This study evaluated the extent to which troglitazone, an oral antidiabetic agent with antioxidant properties, affects the expression of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin on human umbilical vein endothelial cells (HUVECs), induced by different prooxidant signals such as oxidized LDL and tumor necrosis factor-alpha (TNF-alpha). Furthermore we assessed whether the NF-kappaB activation is modulated by the antioxidative effect of troglitazone. Oxidized LDL not only caused a dose-dependent increase of ICAM-1, VCAM-1 and E-selectin (p<0.001), but also synergically increased their TNF-alpha-induced expression (p<0.001). Troglitazone reduced in a dose-dependent manner the expression of VCAM-1, ICAM-1 and E-selectin induced by different amounts of oxidized LDL (p<0.001). The addition of troglitazone to HUVECs significantly reduced the expression of ICAM-1, VCAM-1 and E-selectin induced by TNF-alpha alone or in combination with oxidized LDL (p<0.001); this reduction was paralleled by a significant fall in NF-kappaB translocation. The results suggest that troglitazone may have prevented NF-kappaB-mediated adhesion molecule expression by exerting its antioxidant effect on ODFR.

Effects of troglitazone on in vitro oxidation of LDL and HDL induced by copper ions and endothelial cells

Summary Troglitazone is a new oral antidiabetic agent able to reduce lipid peroxidation. In this study we evaluated its effect on the susceptibility of LDL and HDL to in vitro oxidation induced by copper ions and endothelial cells. In Cu ++ -induced LDL modification, different amounts of troglitazone were added to aliquots of the same pool of plasma with subsequent ultracentrifuge separation of LDL and HDL. Differences in LDL and HDL susceptibility to in vitro oxidation with Cu ++ were studied by measuring the changes in fluorescence intensity (expressed as lag phase). LDL derived from plasma incubated with different amounts of troglitazone were also incubated with umbilical vein endothelial cells (HUVEC), the modification being monitored by LDL relative electrophoretic mobility and fluorescence. During Cu ++ - and HUVEC-induced LDL oxidation, the decay rate of vitamin E, and the potency of troglitazone as a radical scavenger in comparison with vitamin E were also studied. Troglitazone determined a significant, dose-dependent decrease in Cu ++ -induced LDL and HDL oxidation. Incubation with HUVEC was also followed by a progressive, significant decrease of LDL relative electrophoretic mobility and fluorescence intensity. During Cu ++ - and HUVEC-induced-LDL modification, troglitazone significantly reduced the rate of vitamin E decay. In this study we also demonstrated that under the same oxidative stress, troglitazone was much more potent as a radical scavenger than vitamin E. In conclusion, the results demonstrate that troglitazone can reduce LDL and HDL in vitro oxidation and that, during this process, it can protect vitamin E. In addition to ensuring blood glucose control, the drug may therefore be useful in inhibiting lipoprotein peroxidation. [Diabetologia (1997) 40: 165–172]

Effects of smoking on cardiopulmonary baroreceptor activation and peripheral vascular resistance

Patients and Methods  We studied 16 healthy smokers and 16 nonsmokers acting as controls. We subjected smokers and nonsmokers to cardiopulmonary baroreceptor stimulation by studying forearm and common carotid haemodynamic and sympathovagal balance. Smokers repeated the tests after smoking one cigarette. Smokers and controls were subjected to passive elevation of the legs and the trunk in a horizontal position with pressure monitoring and measurement of the calibre and flow in the brachial and common carotid arteries using a colourDoppler ultrasound. We calculated forearm resistance and carotid wall tension. We also studied R‐R variability, calculating the ratio between low frequency (LF) and high frequency (HF) R‐R interval variability.

Haemodynamic effects of AT1 inhibition and Ca2+-channel blockade in hypertensive patients during isometric stress.

To assess the effects of valsartan and amlodipine on the haemodynamics of forearm circulation in hypertensive patients undergoing isometric stress. A total of 24 patients with essential hypertension were subjected to a double blind-cross-over study. The artery left arm flow (strain gauge plethysmography), distensibility of digital arteries (piezoelectric plethysmography) and blood pressure were measured. District resistance was calculated as the ratio between mean arterial pressure and blood flow. The tests were performed at basal conditions (T0) and after 8 days (T8) of therapy with valsartan (160 mg) or amlodipine (10 mg), at rest and during handgrip (HG); treatments were inverted after 15 days of washout. Valsartan and amlodipine reduced blood pressure after 8 days (P<0.05), handgrip increased systolic and diastolic values and heart rate at T0 and only a slight raising in diastolic values at T8. The recovery time of pressure values was longer in hypertensives treated with amlodipine (P<0.05). The forearm flow increased after HG (at T0 an T8) and increased even further after valsartan (P<0.005). Valsartan increased arteriolar distensibility, expressed by the ratio between time to peak and total time (PT/TT) calculated on the sphygmic wave. Amlodipine did not affect PT/TT ratio, whereas it reduced local resistance (T8 vs T0, P<0.05). The reduction effect of valsartan on resistance was detectable also during handgrip, on the contrary amlodipine did not control the increase. Inhibition of AT1 is able to reduce haemodynamic modifications elicited by isometric stress in hypertensive patients.