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The CXC chemokine IL-8, which promotes adhesion, activation, and transmigration of polymorphonuclear neutrophils (PMN), has been associated with production of tissue injury in reperfused myocardium. Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric peptide that is a key regulator of genes such as heine oxygenase (HO)-1 expressed under hypoxic conditions. We hypothesized that HO-1 plays an important role in regulating proinflammatory mediator production under conditions of ischemia-reperfusion. HIF-1 was activated in the human microvascular endothelial cell line (HMEC-1) with the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG). DMOG significantly attenuated cytokine-induced IL-8 promoter activity and protein secretion and cytokine-induced PMN migration across human microvascular endothelial cell line HMEC-1 monolayers. In vivo studies in a rabbit model of myocardial ischemia-reperfusion showed that rabbits pretreated with a 20 mg/kg DMOG infusion (n = 6) 24 h before study exhibited a 21.58 [+ or -] 1.76% infarct size compared with 35.25 [+ or -] 2.06% in saline-treated ischemia-reperfusion animals (n = 6, change in reduction = 39%; P < 0.001). In DMOG-pretreated (20 mg/kg) animals, plasma IL-8 levels at 3 h after onset of reperfusion were 405 [+ or -] 40 pg/ml vs. 790 [+ or -] 40 pg/ml in saline-treated ischemia-reperfusion animals (P < 0.001). DMOG pretreatment reduced myocardial myeloperoxidase activity, expressed as number of PMN per gram of myocardium, to 1.43 [+ or -] 0.59 vs. 4.86 [+ or -] 1.1 (P = 0.012) in saline-treated ischemia-reperfused hearts. Both in vitro and in vivo DMOG-attenuated IL-8 production was associated with robust HO-1 expression. Thus our data show that HIF-1 activation induces substantial HOd expression that is associated with attenuated proinflammatory chemokine production by microvascular endothelium in vitro and in vivo. hypoxia-inducible factor 1; cardiac ischemia-reperfusion; interleukin-8

Das, Anindita, Ramzi Ockaili, Fadi Salloum, and Rakesh C. Kukreja. Protein kinase C plays an essential role in sildenafil-induced cardioprotection in rabbits. Am J Physiol Heart Circ Physiol 286: H1455-H1460, 2004; 10.1152/ajpheart.01040.2003.--Sildenafil citrate (Viagra) is the most widely used pharmacological drug for treating erectile dysfunction in men. It has potent cardioprotective effects against ischemia-reperfusion injury via nitric oxide and opening of mitochondrial ATP-sensitive [K.sup.+] channels. We further investigated the role of protein kinase C (PKC)-dependent signaling pathway in sildenafil-induced cardioprotection. Rabbits were treated (orally) with sildenafil citrate (1.4 mg/kg) 30 min before index ischemia for 30 min and reperfusion for 3 h. The PKC inhibitor chelerythrine (5 mg/kg iv) was given 5 min before sildenafil. Infact size (% of risk area) reduced from 33.65 [+ or -] 2.17 in the vehicle (saline) group to 15.07 [+ or -] 0.63 in sildenafil-treated groups, a 45% reduction compared with vehicle (mean [+ or -] SE, P < 0.05). Chelerythrine abolished sildenafil-induced protection, as demonstrated by increase in infarct size to 31.14 [+ or -] 2.4 (P < 0.05). Chelerythrine alone had an infarct size of 33.5 [+ or -] 2.5, which was not significantly different compared with DMSO-treated group (36.8 [+ or -] 1.7, P > 0.05). Western blot analysis demonstrated translocation of PKC-[alpha] -[theta], and -[delta] isoforms from cytosol to membrane after treatment with sildenafil. However, no change in the PKC-[beta] and -[epsilon] isoforms was observed. These data provide direct evidence of an essential role of PKC, and potentially PKC-[alpha], -[theta], and -[delta], in sildenafil-induced cardioprotection in the rabbit heart. chelerythrine

Sildenafil citrate (Viagra) is the pharmacological agent used to treat erectile dysfunction in men. Because this drug has a vasodilatory effect, we hypothesized that such an action may induce a preconditioning-like cardioprotective effect via opening of mitochondrial ATP-sensitive K ([K.sub.ATP]) channels. Rabbits were treated with sildenafil citrate (0.7 mg/kg iv) either 30 min (acute phase) or 24 h (delayed phase) before 30 min of ischemia and 3 h of reperfusion. Mitochondrial [K.sub.ATP] channel blocker 5-hydroxydecanoate (5-HD, 5 mg/kg iv) was given 10 min before ischemia-reperfusion. Infarct size was measured by tetrazolium staining. Sildenafil caused reduction in arterial blood pressure within 2 min of treatment, which returned to nearly baseline levels 3 min later. The infarct size (% risk area, means [+ or -] SE) reduced from 33.8 [+ or -] 1.7 in control rabbits to 10.8 [+ or -] 0.9 during the acute phase (68% reduction, P < 0.05) and 19.9 [+ or -] 2.0 during the delayed phase (41% reduction, P < 0.05). 5-HD abolished protection with an increase in infarct size to 35.6 [+ o r -] 0.4% and 36.8 [+ or -] 1.6% during the acute and delayed phase, respectively (P < 0.05). Similar acute and delayed cardioprotective effects were observed when sildenafil was administered orally. Systemic hemodynamics also decreased after oral administration of the drug. However, these changes were mild and occurred slowly. For the first time, we demonstrate that sildenafil induces acute and delayed protective effects against ischemia-reperfusion injury, which are mediated by opening of mitochondrial [K.sub.ATP] channels. ATP-sensitive potassium channel; ischemia-reperfusion; phosphodiesterase-5

Chemical preconditioning with 3-nitropropionic acid in hearts: role of mitochondrial [K.sub.ATP] channel. Am J Physiol Heart Circ Physiol 280: H2406-H2411, 2001.--We investigated the cardioprotective effect of 3-nitropropionic acid (3-NPA), an inhibitior of mitochondrial succinate dehydrogenase, and we wanted to show whether this protection is mediated by of opening mitochondrial ATP-sensitive potassium ([K.sub.ATP]) channels. Adult rabbits were treated with either 3-NPA (3 mg/kg iv) or saline (n = 6 rabbits/group). After 30 min (for early phase) or 24 h (for late phase) of the treatment, the animals were subjected to 30 min of ischemia and 3 h of reperfusion (ischemia-reperfusion). 5-Hydroxydecanoate (5-HD, 5 mg/kg iv), the mitochondrial [K.sub.ATP] channel blocker, was administered 10 min before ischemia-reperfusion in the saline- and 3-NPA-treated rabbits. 3-NPA caused a decrease in the infarct size from 27.8 [+ or -] 4.2% in the saline group to 16.5 [+ or -] 1.0% in the 3-NPA-treated rabbits during early phase and from 30.4 [+ or -] 4.2% in the saline group to 17.6 [+ or -] 1.05 in the 3-NPA group during delayed phase (P [is less than] 0.05, % of risk area). The anti-infarct effect of 3-NPA was blocked by 5-HD as shown by an increase in infarct size to 33 [+ or -] 2.7% (early phase) and 31 [+ or -] 2.4% (delayed phase) (P [is less than] 0.05 vs. 3-NPA groups). 5-HD had no proischemic effect in control animals. Also, 3-NPA had no effect on systemic hemodynamics. We conclude that 3-NPA induces long-lasting anti-ischemic effects via opening of mitochondrial [K.sub.ATP] channels. ischemia; succinate dehydrogenase; oxidative phosphorylation

Ockaili, Ramzi, Venkata R. Emani, Shinji Okubo, Michael Brown, Kavitha Krottapalli, and Rakesh C. Kukreja. Opening of mitochondrial [K.sub.ATP] channel induces early and delayed cardioprotective effect: role of nitric oxide. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H2425-H2434, 1999.--Opening of mitochondrial ATP-sensitive (mito[K.sub.ATP]) channel with diazoxide induces an early phase (EP) of cardioprotection. It is unknown whether diazoxide also induces a delayed phase (DP) of cardioprotection. Because nitric oxide (NO) modulates ATP sensitivity of the [K.sub.ATP] channel, we hypothesized that NO may play a role in diazoxide-induced cardioprotection. Diazoxide (1 mg/kg) was administered either 30 min (for EP) or 24 h (DP) before 30 min of lethal ischemia. Blockers of mito[K.sub.ATP] channel [5-hydroxydecanoate (5-HD)] or NO synthase [[N.sup.G]-nitro-L-arginine methyl ester (L-NAME)] were given 10 min before ischemia-reperfusion performed by 30 min of left anterior descending coronary artery occlusion and 3 h of reperfusion. A risk area (RA) was demarcated by Evans blue dye, and infarct size (IS) was measured by tetrazolium staining. Diazoxide caused a decrease in IS (%RA) from 27.8 [+ or -] 4.2% in the vehicle group to 12.9 [+ or -] 1.2% during EP and from 30.4 [+ or -] 4.2% in vehicle-treated rabbits to 19.6 [+ or -] 2.4% during DP (P [is less than] 0.05). IS increased to 31.3 [+ or -] 1.1% and 27.9 [+ or -] 1.0% (EP) and 29.9 [+ or -] 2.3% and 35.1 [+ or -] 1.8% (DP) with 5-HD and L-NAME, respectively (P [is less than] 0.05). 5-HD and L-NAME caused no proischemic effect in controls. Diazoxide induced both early and delayed anti-ischemic effects via opening of mito[K.sub.ATP] channels, which was NO dependent. mitochondria; adenosine 5'-triphosphate-sensitive potassium channel; ischemia-reperfusion; infarction

Abstract: cGMP and opening of mitochondrial KATP channel play an important role in preconditioning of the heart following ischemia/reperfusion (I/R) injury. We investigated the cardioprotective effect of vardenafil (VAR) (Levitra™), a highly selective and biochemically potent inhibitor of phosphodiesterase-5 (PDE-5) that enhances erectile function in men through up-regulation of cGMP. Rabbits were treated with VAR (0.014 mg/kg, iv) or volume-matched saline, 30 min prior to 30 min of sustained regional ischemia followed by 3 h of reperfusion. 5-hydroxydecanoate (5-HD, 5 mg/kg, iv) or HMR 1098 (HMR, 3 mg/kg, iv), the respective blockers of mitochondrial or sarcolemmal KATP channels were administered 10 min before I/R. Infarct size was measured by computer morphometry of tetrazolium stained sections. Vardenafil treatment caused decrease in mean arterial blood pressure from 93.5±2.6 to 82.2±1.5 mmHg and increase in heart rate from baseline value of 151±20 to 196±4.6 bpm (mean±standard error of mean (S.E.M.), P <0.05) within 5 min. The infarct size (% of risk area) was reduced from 33.8±1.3 in control rabbits to 14.3±2.2 (58% reduction, P <0.05). 5-HD abolished VAR-induced protection as demonstrated by increase in infarct size to 34.5±2.3 (P <0.05, N =6 per group). In contrast, HMR failed to block the protective effect of VAR (infarct size, 14.3±2.2 versus 16.3±1.0 in VAR + HMR, P >0.05). Neither inhibitors of the KATP channel influenced the infarct size in the control rabbits, as shown by infarct size of 34.9±1.1 and 33.3±1.4 in animals treated with 5-HD and HMR, respectively. For the first time, we demonstrate that VAR induces protective effect against I/R injury via opening of mitochondrial KATP channel. These results further support our hypothesis that the novel class of PDE-5 inhibitors induce protective effect in the ischemic heart, in addition to their well known clinical effects in the treatment of erectile dysfunction in men. [Copyright &y& Elsevier]

Reports that the sildenafil citrate or Viagra induces powerful cardioprotective effect through opening of mitochondrial ATP-sensitive channels in rabbits. Hemodynamics; Infarction size; Effectiveness of Viagra for the treatment of erectile dysfunction in men.

Presents information on a study which investigated the role of mitochondrial adenosine triphosphate-sensitive potassium channels in the cardioprotective effect of 3-nitropropionic acid in the heart. Methodology; Results of the study; Discussion.