iloprost and Insulin-Resistance

Central obesity shows impaired platelet responses to the antiaggregating effects of nitric oxide (NO), prostacyclin, and their effectors--guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP). The influence of weight loss on these alterations is not known. To evaluate whether a diet-induced body-weight reduction restores platelet sensitivity to the physiological antiaggregating agents and reduces platelet activation in subjects affected by central obesity, we studied 20 centrally obese subjects before and after a 6-month diet intervention aiming at reducing body weight by 10%, by measuring (i) insulin sensitivity (homeostasis model assessment of insulin resistance (HOMA(IR))); (ii) plasma lipids; (iii) circulating markers of inflammation of adipose tissue and endothelial dysfunction, and of platelet activation (i.e., soluble CD-40 ligand (sCD-40L) and soluble P-selectin (sP-selectin)); (iv) ability of the NO donor sodium nitroprusside (SNP), the prostacyclin analog Iloprost and the cyclic nucleotide analogs 8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP) and 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) to reduce platelet aggregation in response to adenosine-5-diphosphate (ADP); and (v) ability of SNP and Iloprost to increase cGMP and cAMP. The 10 subjects who reached the body-weight target showed significant reductions of insulin resistance, adipose tissue, endothelial dysfunction, and platelet activation, and a significant increase of the ability of SNP, Iloprost, 8-Br-cGMP, and 8-Br-cAMP to reduce ADP-induced platelet aggregation and of the ability of SNP and Iloprost to increase cyclic nucleotide concentrations. No change was observed in the 10 subjects who did not reach the body-weight target. Changes of platelet function correlated with changes of HOMA(IR). Thus, in central obesity, diet-induced weight loss reduces platelet activation and restores the sensitivity to the physiological antiaggregating agents, with a correlation with improvements in insulin sensitivity.

Topics: Adenosine Diphosphate; Adipose Tissue; Adult; Blood Platelets; Cyclic AMP; Cyclic GMP; Diet, Reducing; Endothelium, Vascular; Epoprostenol; Female; Humans; Iloprost; Insulin Resistance; Male; Nitric Oxide; Nitroprusside; Obesity, Abdominal; Platelet Activation; Platelet Aggregation Inhibitors; Weight Loss

Fourteen hypertensive (174.3/98.3 mmHg) non-diabetic patients were given a euglyceamic glucose clamp along with infusion of 0.9% NaCl and the prostacyclin (PGI2) analogue Iloprost (0.7 ng x kg x min(-1)). Substrate oxidation was also determined by indirect calorimetry. Over the last 60 min of the clamp, Iloprost vs saline improved whole body glucose disposal (WBGD) (35 vs 28.3 micromol x kg(-1) LBM) and non-oxidative glucose metabolism (24.7 vs 18.1 micromol x kg(-1) LBM x min(-1). Iloprost delivery was associated with a significant decrease in membrane microviscosity (0.253 vs 0.205), but did not affect arterial blood pressure and heart rate. In nine patients, skeletal muscle blood flow (SMBF) and insulin-stimulated glucose uptake (GU) were also studied. At the end of the study, despite a similar SMBF (37 vs 38 ml x min(-1) x kg(-1)), GU (0.55 vs 0.46 mmol x l(-1)) was significantly increased by Iloprost infusion. Percentage decrease in membrane microviscosity was correlated with percentage increase in WBGD (r = 0.65) and non-oxidative glucose metabolism (r = 0.68). In conclusion, low-dose Iloprost infusion improves insulin action and non-oxidative glucose metabolism in hypertensive patients.

Topics: Blood Glucose; Blood Pressure; Cell Membrane; Dose-Response Relationship, Drug; Drug Synergism; Epoprostenol; Female; Glucose; Heart Rate; Humans; Hypertension; Iloprost; Infusions, Intravenous; Insulin; Insulin Resistance; Male; Middle Aged; Muscle, Skeletal; Oxidation-Reduction; Vasodilator Agents; Viscosity

Insulin resistance (IR) increases the risk of stroke in humans. One possible underlying factor is cerebrovascular dysfunction resulting from altered K(+) channel function. Thus, the goal of this study was to examine K+ channel-mediated relaxation in IR cerebral arteries.. Experiments were performed on pressurized isolated middle cerebral arteries (MCAs) from fructose-fed IR and control rats.. Dilator responses to iloprost, which are BK(Ca) channel mediated, were reduced in the IR compared with control arteries (19+/-2% versus 33+/-2% at 10(-6) mol/L). Similarly, relaxation to the K(ATP) opener pinacidil was diminished in the IR MCAs (17+/-2%) compared with controls (38+/-2% at 10(-5) mol/L). IR also reduced the K(ATP) channel-dependent component in calcitonin gene-related peptide-induced dilation; however, the magnitude of the relaxation remained unchanged in IR because of a nonspecified K+ channel-mediated compensatory mechanism. In contrast, K(ir) channel-mediated relaxation elicited by increases in extracellular [K+] (4 to 12 mmol/L) was similar in the control and IR arteries. Blockade of the K(ir) and K(v) channels with Ba2+ and 4-aminopyridine, respectively, constricted the MCAs in both experimental groups with no significant difference. Pretreatment of arteries with superoxide dismutase (200 U/mL) plus catalase (150 U/mL) restored the dilatory responses to iloprost and pinacidil in the IR arteries. Immunoblots showed that the expressions of the pore-forming subunits of the examined K+ channels are not altered by IR.. IR induces a type-specific K+ channel dysfunction mediated by reactive oxygen species. The alteration of K(ATP) and BK(Ca) channel-dependent vascular responses may be responsible for the increased risk of cerebrovascular events in IR.

Topics: Animals; Culture Techniques; Iloprost; Insulin Resistance; Male; Middle Cerebral Artery; Pinacidil; Potassium Channel Blockers; Potassium Channels; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Vasodilation; Vasodilator Agents