Statins can act as preconditioning agents against ischemia reperfusion (IR)-injury through a mechanism involving cyclooxygenase (COX)-2 and the upregulation of prostaglandin synthesis. The following study investigated the effect of selective and non-selective COX inhibition on rosuvastatin-mediated protection against IR-induced endothelial dysfunction in the human forearm vasculature. Healthy volunteers were randomized to drugs with different COX-inhibiting properties: 81mg aspirin (OD), 325mg aspirin (OD), 400mg ibuprofen (QID), 200mg celecoxib (BID) or placebo. A single dose of 40mg rosuvastatin was also administered 24-hours prior to IR. Endothelial function before and after IR was assessed by measuring flow-mediated dilation of the radial artery. Our results show that 81mg and 325mg aspirin (more COX-1 selective), 400mg ibuprofen (similar selectivity for COX-1/2) and 200mg celecoxib (COX-2 selective) all effectively abolished statin-mediated protection against IR-induced endothelial dysfunction in the forearm (2-way ANOVA, p<0.05). These findings indicate that even partial COX-2 inhibition is sufficient to attenuate statin-induced preconditioning.

Statins can act as preconditioning agents against ischemia reperfusion (IR)-injury through a mechanism involving cyclooxygenase (COX)-2 and the upregulation of prostaglandin synthesis. The following study investigated the effect of selective and non-selective COX inhibition on rosuvastatin-mediated protection against IR-induced endothelial dysfunction in the human forearm vasculature. Healthy volunteers were randomized to drugs with different COX-inhibiting properties: 81mg aspirin (OD), 325mg aspirin (OD), 400mg ibuprofen (QID), 200mg celecoxib (BID) or placebo. A single dose of 40mg rosuvastatin was also administered 24-hours prior to IR. Endothelial function before and after IR was assessed by measuring flow-mediated dilation of the radial artery. Our results show that 81mg and 325mg aspirin (more COX-1 selective), 400mg ibuprofen (similar selectivity for COX-1/2) and 200mg celecoxib (COX-2 selective) all effectively abolished statin-mediated protection against IR-induced endothelial dysfunction in the forearm (2-way ANOVA, p<0.05). These findings indicate that even partial COX-2 inhibition is sufficient to attenuate statin-induced preconditioning.

Thesis (M. Phil.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 79-99).

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / toc / Pharmacology / Doctoral / Doctor of Philosophy

Contraction of cardiac muscle is a highly regulated event that relies on a delicate balance of ions entering and leaving the cell through ion channels. In particular, voltage gated sodium channels are responsible for the rapid depolarization that leads to a contraction. During an oxidative challenge, sodium channels rapidly activate, but do not fully turn off. This alters the rate of cardiac repolarization and can induce cardiac arrhythmias. It is currently unknown whether the most common sodium channel isoform found in the heart, NaV1.5, generates this oxidant-induced persistent current or if other isoforms are responsible. Therefore, I sought to further explore the biophysical properties NaV1.5, and determine if it can enter this persistent mode. I tested the biophysical properties of native INa in cardiac myocytes and in NaV1.5 transfected HEK293 cells under macro cell-attached voltage-clamp. I used a sodium channel enhancer (Anemonia sulcata toxin II; 10 nM), a sodium channel blocker (tetrodotoxin; 10 nM) and a model of oxidative stress (H2O2; 100 µM, 200 µM, 1000 µM) to compare and contrast the cellular responses between both cell types. I observed that transfected HEK293 cells and cardiac myocytes were unaffected by H2O2 at various concentrations. Given the lack of other isoforms in transfected HEK293 cells, and the low abundance (<5%) of other isoforms in cardiac myocytes, I propose that NaV1.5 function is unaffected by H2O2. Furthermore, ATX II prolonged the inactivation process in both HEK293 cells and cardiac myocytes in a voltage-dependent manner, indicating that NaV1.5 can give rise to persistent sodium current. Finally, by comparing both cell types under control settings, I found that transfected HEK293 cells inactivated at a much slower rate and at more negative potentials compared to the current in cardiac myocytes. My results suggest that NaV1.5 does not underlie oxidant-induced persistent current and that β subunits likely play a significant role in the inactivation process. / Thesis (Master, Physiology) -- Queen's University, 2011-08-19 14:46:42.665

No description available.

The Slit family of secreted proteins act as axonal repellents during embryogenesis. Slit2 via its receptor, Roundabout-1, also inhibits chemotaxis of multiple leukocyte subsets. Using static and microfluidic shear assays, we found that Slit2 inhibited multiple steps required to recruit circulating neutrophils. Slit2 blocked capture and firm adhesion of human neutrophils to and transmigration across inflamed primary vascular endothelial cells. To determine the response of Slit2 in renal ischemia reperfsuion injury, Slit2 was administered prior to bilateral renal pedicle clamping in mice. This led to significant decreases in both renal tubular necrosis score and neutrophil infiltration. Administration of Slit2 also prevented elevation of plasma creatinine following injury in a dose-dependent manner. Furthermore, administration of Slit2 did not increase hepatic bacterial load in mice infected with L.monocytogenes infection. Collectively, these data demonstrate Slit2 as an exciting therapeutic molecule to combat renal ischemia reperfusion injury without compromising protective host innate immune functions.

The Slit family of secreted proteins act as axonal repellents during embryogenesis. Slit2 via its receptor, Roundabout-1, also inhibits chemotaxis of multiple leukocyte subsets. Using static and microfluidic shear assays, we found that Slit2 inhibited multiple steps required to recruit circulating neutrophils. Slit2 blocked capture and firm adhesion of human neutrophils to and transmigration across inflamed primary vascular endothelial cells. To determine the response of Slit2 in renal ischemia reperfsuion injury, Slit2 was administered prior to bilateral renal pedicle clamping in mice. This led to significant decreases in both renal tubular necrosis score and neutrophil infiltration. Administration of Slit2 also prevented elevation of plasma creatinine following injury in a dose-dependent manner. Furthermore, administration of Slit2 did not increase hepatic bacterial load in mice infected with L.monocytogenes infection. Collectively, these data demonstrate Slit2 as an exciting therapeutic molecule to combat renal ischemia reperfusion injury without compromising protective host innate immune functions.

Thesis (Ph. D.)--University of Texas at Austin, 2007. / Vita. Includes bibliographical references.