Pretreatment with paricalcitol attenuates inflammation in ischemia-reperfusion injury via the up-regulation of cyclooxygenase-2 and prostaglandin E2.

BACKGROUND: The effect of paricalcitol on renal ischemia-reperfusion injury (IRI) has not been investigated. We examined whether paricalcitol is effective in preventing inflammation in a mouse model of IRI, and evaluated the cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) pathways as a protective mechanism of paricalcitol. METHODS: Paricalcitol (0.3 µg/kg) was administered to male C57BL/6 mice 24 h before IRI. Bilateral kidneys were subjected to 23 min of ischemia, and mice were killed 72 h after IRI. The effects of paricalcitol on renal IRI were evaluated in terms of renal function, tubular necrosis, apoptotic cell death, inflammatory cell infiltration and inflammatory cytokines. The effects of paricalcitol on COX-2, PGE2 and its receptors were investigated. RESULTS: Paricalcitol pretreatment improved renal function (decreased blood urea nitrogen and serum creatinine levels), tubular necrosis and apoptotic cell death in IRI-mice kidneys. The infiltration of inflammatory cells (T cells and macrophages), and the production of proinflammatory cytokines (RANTES, tumor necrosis factor-α, interleukin-1ß and interferon-γ) were reduced in paricalcitol-treated mice with IRI. Paricalcitol up-regulated COX-2 expression, PGE2 synthesis and mRNA expression of receptor subtype EP4 in post-ischemic renal tissue. The cotreatment of a selective COX-2 inhibitor with paricalcitol restored functional injury and tubular necrosis in paricalcitol-treated mice with IRI. CONCLUSIONS: Our study demonstrates that paricalcitol pretreatment prevents renal IRI via the inhibition of renal inflammation, and the up-regulation of COX-2 and PGE2 is one of the protective mechanisms of paricalcitol in renal IRI.

Cardioprotective effect of glucose-insulin on acute propafenone toxicity in rat.

OBJECTIVE: We recently observed a case of propafenone self-poisoning in which the patient was initially unresponsive to conventional therapies such as sodium bicarbonate, dopamine, and norepinephrine but recovered with intravenous glucose-insulin infusion. We raised the hypothesis that insulin may have a cardioprotective effect in acute propafenone toxicity. METHODS: We evaluated the effect of glucose-insulin infusion on mortality and electrocardiographic abnormalities during acute propafenone toxicity in rats. After measurements of basal mean arterial pressure, heart rate, PR interval, and QRS duration, rats received intravenous propafenone (36 mg/kg per hour) for 12 minutes. Two minutes after the induction of toxicity, the rats (n=10 per group) received either normal saline solution (NSS) or insulin with glucose. Rats in the insulin-treated (Insulin group) and the NSS-treated (NSS group) groups received an intravenous infusion of 36 mg/kg per hour of propafenone until death occurred. Rats receiving only NSS intravenously without propafenone toxicity served as control (Control group, n=10). RESULTS: Insulin treatment improved survival and delayed the hemodynamic and electrocardiographic consequences of propafenone toxicity. Survival was significantly greater in the insulin group than that in the NSS group (P<.001). Insulin prevented the decline in mean arterial pressure and heart rate (P<.05). Insulin also prevented the increase of the PR interval and the QRS duration (P<.05). CONCLUSION: Glucose-insulin infusion delayed the abnormalities in cardiac conduction and improved rat survival after acute propafenone toxicity. These results suggest a cardioprotective effect of glucose-insulin in acute propafenone toxicity.