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Aims/hypothesisRecent evidence suggests that reduced synthesis of nitric oxide in endothelial cells, i.e. endothelial dysfunction, contributes to the impaired action of insulin in the vasculature of patients with type 2 diabetes. We investigated whether selective inhibition of phosphodiesterase-5 by tadalafil has beneficial effects on peripheral microcirculation and glucose uptake in these patients.MethodsWe enrolled seven postmenopausal women with type 2 diabetes and ten age-matched healthy women as controls in a placebo-controlled study to evaluate the acute metabolic effects of tadalafil. We performed microdialysis and blood flow measurements in muscle, and sampled arterial and deep venous blood before and after a single dose of tadalafil 20 mg or placebo. Circulating glucose and insulin levels, muscle capillary recruitment as reflected by permeability surface area for glucose (PSglu) and forearm glucose uptake were measured.ResultsIn women with type 2 diabetes, but not in the control group, tadalafil induced increases in the incremental AUC for PSglu (tadalafil vs placebo 41 ± 11 vs 4 ± 2 ml [100 g]−1 min−1, p < 0.05) and forearm glucose uptake (46 ± 9 vs 8 ± 4 µmol [100 g]−1 min−1, p < 0.05). The variable that best predicted forearm glucose uptake was PSglu, which explained 70% of its variance. However, fasting glucose and insulin concentrations were similar following treatment with placebo or tadalafil in the two groups.Conclusions/interpretationThis study suggests that tadalafil evokes positive metabolic effects in insulin-resistant women with type 2 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-010-1819-4) contains supplementary material, which is available to authorised users.

We have developed a new computerized biomechanical ex vivo perfusion system for intact conduit vessels in which a wide range of combinations of intraluminal pressure, fluid flow and shear stress could be set and maintained at target levels in mammalian conduit vessels under controlled metabolic conditions. Mean wall shear stress is calculated using the formula:τ = 1/2 * (ΔP/L)^3/4 * (8ηQ/Π)^1/4.Accuracy of the wall shear stress calculation was validated by ultrasonographic imaging of the vessel radius. In a series of simulation experiments, the hemodynamic homeostasis functions of the system were challenged by generating a wide range of vascular resistance in artificial vessels and by pharmacologically induced changes in vascular tone in intact human vessels. Despite rapid changes in vessel resistance, shear stress and pressure, or flow and pressure were maintained well at target levels. Shear- and pressure-stimulated production of the vasodilator prostaglandin E₂ (PGE₂) was used to validate the biological relevance of the model. PGE₂ release was significantly more stimulated by high (25 dyn/cm²) compared to low (<4 dyn/cm²) shear (ANOVA, p = 0.012). High compared to low intraluminal pressure depressed the production of PGE₂ (ANOVA, p = 0.019). In summary, the computerized perfusion model appears to offer new possibilities of investigating the complex interplay between fluid mechanics and the vascular wall.

Abstract-We recently discovered that patients with essential hypertension have a markedly impaired capacity for stimulated release of tissue plasminogen activator (tPA) from vascular endothelium. This defect may reduce the chance of timely spontaneous thrombolysis in case of an atherothrombotic event. We now investigated whether increased intraluminal pressure as such may depress vascular tPA release or downregulate its gene expression. Segments of human umbilical veins were studied in a new computerized vascular perfusion model under steady laminar flow conditions for 3 or 6 hours. Paired segments were perfused at high or physiological intraluminal pressure (40 versus 20 mm Hg) under identical shear stress (10 dyne/cm 2 ). Quantitative immunohistochemical evaluation of cellular tPA immunoreactivity was performed on paraffin-embedded 5-m vascular sections. tPA mRNA in endothelial cells was quantified with reverse transcription real-time TaqMan polymerase chain reaction with GAPDH as endogenous control. Secretion of tPA into perfusion medium was evaluated with SDS-PAGE and Western blotting, followed by densitometric quantification. High-pressure perfusion downregulated tPA gene expression with a 38% decrease in tPA mRNA levels (Pϭ0.01) compared with vessels perfused under normal intraluminal pressure. tPA release into the perfusion medium was markedly suppressed by high pressure (PϽ0.01 ANOVA). The intracellular storage pool of tPA was reduced after 6 but not 3 hours. Thus, elevated intraluminal pressure downregulates tPA gene and protein expression and inhibits its release from the endothelium independently of shear stress. The defective capacity for stimulated tPA release that we demonstrated in patients with essential hypertension might thus be an effect of the elevated intraluminal pressure per se.