Lasse Enkebølle Rasmussen

Prostaglandin E2 Induces Vascular Relaxation by E-Prostanoid 4 Receptor-Mediated Activation of Endothelial Nitric Oxide Synthase

The present experiments were designed to test the hypothesis that prostaglandin (PG) E2 causes vasodilatation through activation of endothelial NO synthase (eNOS). Aortic rings from mice with targeted deletion of eNOS and E-prostanoid (EP) receptors were used for contraction studies. Blood pressure changes in response to PGE2 were measured in conscious mice. Single doses of PGE2 caused concentration-dependent relaxations during contractions to phenylephrine (EC50=5*10−8 mol/L). Relaxation after PGE2 was absent in rings without endothelium and in rings from eNOS−/− mice and was abolished by NG-nitro-l-arginine methyl ester and the soluble guanylate cyclase inhibitor 1H1,2,4-oxadiazolo-[4,3-a]quinoxalin-1-one. In PGE2-relaxed aortic rings, the cGMP content increased significantly. PGE2-induced relaxations were abolished by the EP4 receptor antagonist AE3–208 (10−8 mol/L) and mimicked by an EP4 agonist (AE1–329, 10−7 mol/L) in the presence of endothelium and eNOS only. Relaxations were attenuated significantly in rings from EP4−/− mice but normal in EP2−/−. Inhibitors of the cAMP-protein kinase A pathway attenuated, whereas the inhibitor of protein phosphatase 1C, calyculin (10−8 mol/L), abolished the PGE2-mediated relaxation. In aortic rings, PGE2 dephosphorylated eNOS at Thr495. Chronically catheterized eNOS−/− mice were hypertensive (137±3.6 mm Hg, n=13, versus 101±3.9 mm Hg, n=9) and exhibited a lower sensitivity of blood pressure reduction in response to PGE2 compared with wild-type mice. There was no difference in the blood pressure response to nifedipine. These findings show that PGE2 elicits EP4 receptor-mediated, endothelium-dependent stimulation of eNOS activity by dephosphorylation at Thr495 resulting in guanylyl cyclase–dependent vasorelaxation and accumulation of cGMP in aortic rings.

Microdialysis as a tool to determine the local tissue concentration of dicloxacillin in man

The most common pathogen to cause postoperative infections in Denmark is Staphylococcus aureus. Despite using prophylactic antibiotics, infections are still seen. Whether the tissue concentration is above the minimal inhibitory concentration (MIC) for the pathogen is unknown. Thus, the concentration of dicloxacillin in muscle and adipose tissue was measured after intravenous administration, in healthy men.