Dexmedetomidine is α2-adrenergic agent and commonly used in the intensive care setting. It is used primarily to sedate critically ill patients in various surgical, endoscopic and radiologic procedures. This medication gained superiority with other sedatives with a distinct advantage of less depression of the respiratory system. Although dexmedetomidine is often administered to septic patients, the vascular effect has not been fully studied in this clinical setting. In this thesis, rats were administered saline or bacterial lipopolysaccharide (LPS) 1, 10 and 20 mg/kg. Aortic rings were obtained after two, 24 and 72 hours exposure and dexmedetomidine-induced contractions were investigated. Rats could not tolerate prolonged exposure to 20 mg/kg LPS and died during the process. Systolic, diastolic and mean arterial pressures were reduced after LPS exposure while heart rates were elevated. Body temperatures were elevated after LPS administration (all doses and time), except a reduction at two hours with 1 mg/kg LPS. LPS increased the plasma levels of tissue necrosis factor-α and interleukin-6 after two hours LPS administration but not at 24 and 72 hours. In aortic rings with functional endothelium from rats with or without LPS exposure, dexmedetomidine had no effect on resting tension. Dexmedetomidine produced concentration-dependent contractions (10 nM to 10 μμM) after incubation with endothelial nitric oxide synthase (NOS) inhibitor L-NAME or removal of endothelium in rings without and with exposure to LPS for two, 24, 72 hours. LPS administration dose-dependently attenuated dexmedetomidine-induced contractions. In the presence of 1400W (inducible NOS inhibitor) the contractile response to dexmedetomidine was potentiated suggesting a role of NO produced by iNOS. Treatment with MnTMPyP attenuated dexmedetomidine-induced contractions indicating that the superoxide dismutase mimetic might increase NO availability by reducing superoxide. A significant role of iNOS was further supported by the detection of iNOS expression in aortic rings after LPS exposure at two, 24, and 72 hours when compared to non-LPS exposed group. Use of selective α2A and α2B receptor antagonists (BRL44408 and ARC239 respectively) showed that dexmedetomidine-induced contractions were mediated mostly via α2A receptor subtype as the former but not the latter agent significantly reduced contractions. Serotonin (5-HT, 10 nM to 100 μμM) and phenylephrine (1 nM to 100 μμM) produced concentration-dependent contractions in aortic rings with and without LPS exposure. The maximal responses to 5-HT and phenylephrine were increased at 10 mg/kg LPS as compared to a reduction in contractions by dexmedetomidine with LPS exposure at 1 and 10 mg/kg supporting alterations in α2 receptors occurred after LPS administration. In conclusion, the present study demonstrated that the vascular contractile responses of dexmedetomidine in the absence of endothelium or in the presence of eNOS inhibition were reduced in the presence of LPS at different time points and at different doses in aortic rings while two other receptor mediated vasoconstrictors, 5-HT and phenylephrine were affected. Our findings suggest that LPS may preferentially reduce the vascular contractile responses of dexmedetomidine and it is essential to exercise caution when the drug is administered to critically ill patients or with endothelial dysfunction. / published_or_final_version / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy

Thesis (M. Phil.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 107-121) Also available in print.

published_or_final_version / Anaesthesiology / Master / Master of Philosophy

Th ocular bilateral hypotensive effect after unilateral topical administration of medetomidine and 4 analogs was demonstrated in a dose-response study (0.5%-2%) in NZW rabbits (bilateral IOP-lowering efficacy: medetomidine>detomidine and MPV-1440>MPV-1441 and MPV-305BIII).

published_or_final_version / Anaesthesiology / Master / Doctor of Medicine

published_or_final_version / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy

A selective a2-adrenergic agonist, lofexidine, significantly reduced intraocular pressure (lOP) in intact ocular normotensive NZW rabbits, producing a differential dose-dependent decrease in IOP in'the ipsilateral and contralateral eye. Contralateral IOP reduction was most observable at low doses. Unilateral superior cervical ganglionectomy and extraocular muscle excision studies were undertaken to elucidate the factors influencing differential IOP reduction by lofexidine. Similar significant contralateral decreases in IOP were noted when the agent was applied to either the intact or operated eye. Biochemical studies demonstrated that lofexidine inhibited isoproterenol-stimulated adenylcyclase in isolated iris-ciliary body preparations. Yohimbine, an α2-adrenergic antagonist, blocked this inhibitory response. Hence, these observations suggested that lofexidine's site of IOP reduction was probably at the cellular level.