U74389F, a 21-aminosteroid antioxidant, improves neoendothelial morphology, but not neointimal thickening after balloon catheter injury.

U74389F is a compound in a family of 21-aminosteroids devoid of classical glucocorticoid action that inhibit lipid peroxidation. These compounds improve neurologic function and tissue survival after head or spinal cord injury. Dexamethasone inhibits development of intimal hyperplasia (IH) and improves attenuated nitric oxide (NO) production of the rabbit aorta subsequent to balloon catheter injury. We tested the hypothesis that U74389F is protective in a catheter-induced endothelial-denuded and arterial injury model. A 4-Fr Fogarty balloon (BALL) embolectomy catheter was passed through the thoracic aorta of New Zealand White rabbits treated with 15 mg/kg U74389F (LAZ) 2 days before and 1 week after injury. Animals were killed at 4 weeks after surgical intervention, and formation of IH was determined by calculating the intimal/medial ratio (I/M). The treatment groups of animals were injured untreated (BALL), injured treated (BALL/LAZ), uninjured treated (CONTROL/LAZ), and sham-operated treated (SHAM/LAZ). Scanning electron microscopy revealed that after injury lazaroid treatment produced an improvement of the neoendothelium (alignment in the direction of blood and fewer intercellular gaps) as compared with injured but untreated aortas. Relaxation to acetylcholine (NO formation) was impaired in aortic rings from catheterized animals; lazaroid treatment improved the relaxation to 10-6 mol/L acetylcholine but not to lower concentrations. I/M for SHAM/LAZ, BALL, and BALL/LAZ was 0.02 +/- 0.02, 21.6 +/- 1.6, and 17.2 +/- 2.5, respectively; BALL vs. BALL/LAZ, p < 0.06. An increased contractile response to 120 mmol/L KCl was observed after lazaroid treatment. This is the first report of lazaroid-mediated improvement in the neoendothelial morphology, improved neoendothelial NO generation, and augmented hypopolarizing contractile response, but no attenuation in the development of IH.

Acute and prolonged effects of sildenafil on brachial artery flow-mediated dilatation in type 2 diabetes.

OBJECTIVE: Flow-mediated dilatation (FMD), induced by occlusion of the brachial artery, is an index of nitric oxide-dependent endothelial function that is impaired in patients with type 2 diabetes. Sildenafil (Viagra) is an inhibitor of phosphodiesterase 5 (PDE-5), which is used for management of erectile dysfunction in a broad range of patients, including those with type 2 diabetes. Its effects on endothelial function in these patients have not been previously assessed. RESEARCH DESIGN AND METHODS: We assessed the acute and prolonged effects of a low dose of sildenafil (25 mg) on FMD in patients with type 2 diabetes. We performed a double-blind, placebo-controlled cross-over trial in 16 patients (14 of whom completed the study) with type 2 diabetes who had erectile dysfunction without overt clinical heart disease. RESULTS: In these patients, the mean +/- SD brachial artery diameter (BAD) measured by ultrasound was 4.33 +/- 0.6 mm. After inducing FMD, the BAD increased 8% to 4.66 +/- 0.6 mm (P = 0.2). One hour after oral administration of sildenafil 25 mg, FMD increased the BAD significantly by 15% to 4.99 +/- 0.5 mm (P < or = 0.01), whereas it did not change with placebo (4.6 +/- 0.6 mm, P = 0.1). After treatment with sildenafil 25 mg daily for 2 weeks and testing 24 h after the last dose, the mean FMD was 14% (P = 0.01). In contrast, the mean FMD with placebo was 9% (P = 0.45). CONCLUSIONS: We conclude that acute and prolonged sildenafil treatment has a favorable effect on brachial artery flow-mediated dilatation that persists for at least 24 h after the last dose. Further investigation is needed to determine whether this prolonged effect has clinical implications in patients with type 2 diabetes.

Pioglitazone restores endothelial function in patients with type 2 diabetes treated with insulin.

The primary aim of this study was to evaluate the effect of pioglitazone on endothelial function, as assessed by flow-mediated dilatation (FMD) nitroglycerine-induced dilatation (NID) in patients with type 2 diabetes mellitus treated with insulin. A randomized double-blind placebo-controlled trial involved 20 patients with insulin-treated type 2 diabetes. Patients received either pioglitazone 30 mg or placebo for 4 months. FMD, NID, and HbA1c were measured before and after 4 months of treatment. HbA1c decreased from 10.0 (+/- 2.3) to 8.4 (+/- 2.0) in the pioglitazone group, a statistically significant improvement in glycemic control (p = 0.018). HbA1c was unchanged in the placebo group (p = 0.477). Endothelial function as assessed by FMD significantly improved from 10.1 (+/- 4.0)% to 14.6 (+/- 6.2)% in the pioglitazone group (p = 0.036) as compared to the placebo group (p = 0.705). There was a trend towards improvement in the NID in the pioglitazone group (from 13.3 +/- 8.0% to 18.9 +/- 5.4%; p = 0.056). In insulin-treated patients with type 2 diabetes, the addition of pioglitazone improves endothelial function, as measured by FMD. Addition of pioglitazone to insulin in type 2 diabetes patients may favorably impact vascular function in diabetes, even after many years of insulin resistance and hyperglycemia.

A phase I trial of alfimeprase for peripheral arterial thrombolysis.

PURPOSE: To evaluate the safety profile, pharmacokinetics, and thrombolytic activity of alfimeprase, a novel direct-acting thrombolytic agent, in patients with chronic peripheral arterial occlusion (PAO). MATERIALS AND METHODS: In this multicenter, open-label, single-dose, dose-escalation study, 20 patients with worsening symptoms of lower extremity ischemia within 6 months of enrollment were treated with alfimeprase in five escalating dose cohorts (0.025 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.3 mg/kg, and 0.5 mg/kg) by means of intraarterial and sometimes intrathrombic pulsed infusion. The primary endpoint was safety assessed by adverse event rates. Additional safety assessments included vital sign monitoring, serum chemistry testing, hematologic testing, and coagulation testing for 28 days after the procedure, as well as alpha2-macroglobulin and antialfimeprase antibody testing for as long as 3 months after treatment. Pharmacokinetic parameters were evaluated with use of an assay that measures free and alpha2-macroglobulin-bound (ie, total) alfimeprase. RESULTS: No patient experienced a hemorrhagic adverse event. Mean plasminogen and fibrinogen concentrations were not substantially altered by treatment. Three transient treatment-related adverse events were reported in the same patient: one incidence each of increased blood fibrinogen level, skin rash, and headache. All three adverse events were graded as mild. The pharmacokinetic profile of alfimeprase suggested that the half-life for total alfimeprase ranges from 11 to 54 minutes (median, 25 min) in patients with PAO. The serum alpha2-macroglobulin concentrations decreased transiently in a dose response-like manner between 12 and 24 hours and returned to within normal limits approximately 14 days after alfimeprase exposure. CONCLUSIONS: Alfimeprase in doses as high as 0.5 mg/kg was generally well-tolerated in patients with chronic PAO. No bleeding complications were noted. The stable fibrinogen concentrations suggest that the activity of alfimeprase may be limited to the target thrombus. Alfimeprase holds the potential to achieve dissolution of thrombus with a diminished risk of hemorrhage.

A selective somatostatin type-2 receptor agonist inhibits neointimal thickening and enhances endothelial cell growth and morphology following aortic balloon injury in the rabbit.

Somatostatin analogs have been shown to inhibit vascular smooth muscle cell (VSMC) proliferation and attenuate neointimal thickening following experimental balloon catheter injury. In this study, the effects of a selective agonist for the somatostatin receptor subtype 2, PRL-2486, on neointimal thickening and endothelial cell regrowth 2 weeks following balloon catheterization of male New Zealand White rabbits were determined. Rabbits treated 2 days prior to and 2 weeks after catheter injury with 10 microg/kg/day PRL-2486 (PRL-tx) had decreased I/M ratios (intimal area/medial area x 100; p < 0.05) but had no effect at lower (5 microg/kg/day) or higher (20 microg/kg/day) doses. PRL-tx had significantly decreased VSMC proliferation compared to untreated animals. PRL-tx increased endothelial regrowth by over 2-fold (p < 0.002) and improved endothelial cell morphology. Endothelial-dependent relaxation responses to acetylcholine were attenuated by catheter injury, and were not improved with PRL-tx. These data suggest that the PRL-2486-mediated inhibition of neointimal thickening exhibits a bell-shaped dose-response curve. This inhibition may be due in part to decreased VSMC proliferation, which may be a function of enhanced endothelial regrowth, but not the return of endothelium-dependent vascular function.