title: Rho-kinase inhibition improves vasodilator responsiveness during hyperinsulinemia in the metabolic syndrome.
abstract: In patients with the metabolic syndrome (MetS), the facilitatory effect of insulin on forearm vasodilator responsiveness to different stimuli is impaired. Whether the RhoA/Rho kinase (ROCK) pathway is involved in this abnormality is unknown. We tested the hypotheses that, in MetS patients, ROCK inhibition with fasudil restores insulin-stimulated vasodilator reactivity and that oxidative stress plays a role in this mechanism. Endothelium-dependent and -independent forearm blood flow responses to acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, were assessed in MetS patients (n = 8) and healthy controls (n = 5) before and after the addition of fasudil (200 μg/min) to an intra-arterial infusion of insulin (0.1 mU/kg/min). In MetS patients (n = 5), fasudil was also infused without hyperinsulinemia. The possible involvement of oxidative stress in the effect of fasudil during hyperinsulinemia was investigated in MetS patients (n = 5) by infusing vitamin C (25 mg/min). In MetS patients, compared with saline, fasudil enhanced endothelium-dependent and -independent vasodilator responses during insulin infusion (P < 0.001 and P = 0.008, respectively), but not in the absence of hyperinsulinemia (P = 0.25 and P = 0.13, respectively). By contrast, fasudil did not affect vasoreactivity to ACh and SNP during hyperinsulinemia in controls (P = 0.11 and P = 0.56, respectively). In MetS patients, fasudil added to insulin and vitamin C did not further enhance vasodilation to ACh and SNP (P = 0.15 and P = 0.43, respectively). In the forearm circulation of patients with the MetS, ROCK inhibition by fasudil improves endothelium-dependent and -independent vasodilator responsiveness during hyperinsulinemia; increased oxidative stress seems to be involved in the pathophysiology of this phenomenon.
authors: Department of Internal Medicine, Catholic University Medical School, Rome, Italy.
authors: Francesca
authors: F
authors: Schinzari
authors: Manfredi
authors: M
authors: Tesauro
authors: Valentina
authors: V
authors: Rovella
authors: Nicola
authors: N
authors: Di Daniele
authors: Paolo
authors: P
authors: Gentileschi
authors: Nadia
authors: N
authors: Mores
authors: Umberto
authors: U
authors: Campia
authors: Carmine
authors: C
authors: Cardillo
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D004351:Drug Resistance / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D005260:Female; D005542:Forearm; D006801:Humans; D006946:Hyperinsulinism / Q000209:etiology*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009765:Obesity / Q000209:etiology; D018384:Oxidative Stress / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000975:Antioxidants; D007004:Hypoglycemic Agents; D007328:Insulin; D047428:Protein Kinase Inhibitors; D014665:Vasodilator Agents; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil