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Pretreatment with atorvastatin (ATV) reduces infarct size (IS) and increases myocardial expression of phosphorylated endothelial nitric oxide synthase (p-eNOS), inducible NOS (iNOS), and cyclooxygenase-2 (COX2) in the rat. Inhibiting COX2 abolished the ATV-induced IS limitation without affecting p-eNOS and iNOS expression. We investigated 1) whether 3-day ATV pretreatment limits IS in [eNOS.sup.-/-] and [iNOS.sup.-/-] mice and 2) whether COX2 expression and/or activation by ATV is eNOS, iNOS, and/or NF-[kappa]B dependent. Male C57BL/6 wild-type (WT), University of North Carolina [eNOS.sup.-/-] and [iNOS.sup.-/-] mice received ATV (10 mg*[kg.sup.-1]*[day.sup.-1]; [ATV.sup.+]) or water alone ([ATV.sup.-]) for 3 days. Mice underwent 30 min of coronary artery occlusion and 4 h of reperfusion, or hearts were harvested and subjected to ELISA, immunoblotting, biotin switch, and electrophoretic mobility shift assay. As a result, ATV reduced IS only in the WT mice. ATV increased eNOS, p-eNOS, iNOS, and COX2 levels and activated NF-[kappa]B in WT mice. It also increased myocardial COX2 activity. In [eNOS.sup.-/-] mice, ATV increased COX2 expression but not COX2 activity or iNOS expression. NF-[kappa]B was not activated by ATV in the [eNOS.sup.-/-] mice. In the [iNOS.sup.-/-] mice, eNOS and p-eNOS levels were increased but not iNOS and COX2 levels; however, NF-[kappa]B was activated. In conclusion, both eNOS and iNOS are essential for the IS-limiting effect of ATV. The expression of COX2 by ATV is iNOS, but not eNOS or NF-[kappa]B, dependent. Activation of COX2 is dependent on iNOS. endothelial nitric oxide synthase; inducible nitric oxide synthase; nuclear factor-[kappa]B

We assessed whether aspirin (acetylsalicylic acid, ASA), administered before reperfusion, abrogates the infarct size (IS)-limiting effect of atorvastatin (ATV). Statins reduce IS. This dose-dependent effect is mediated by upregulation of cycloxygenase-2 (COX2) and PG[I.sub.2] production. Administration of selective COX2-inhibitors either with ATV for 3 days or immediately before coronary occlusion blocks the IS-limiting effect of ATV. Sprague-Dawley rats received 3-day ATV (10 mg x [kg.sup.-1] x [day.sup.-1]) or water alone. Rats underwent 30 min coronary artery occlusion and 4 h reperfusion (IS protocol, n = 8 in each group), or rats underwent 30 min coronary artery occlusion and 10 min reperfusion (enzyme expression and activity protocol, n = 4 in each group). Immediately before reperfusion rats received intravenous ASA (5, 10, or 20 mg/kg) or saline. Area-at-risk (AR) was assessed by blue dye and IS by triphenyltetrazolium chloride. ATV reduced IS (10.1 [+ or -] 1.4% of the AR) compared with controls (31.0 [+ or -] 2.2%). Intravenous ASA alone did not affect IS (29.0 [+ or -] 2.6%); however, ASA dose dependently (5, 10, and 20 mg/kg) attenuated the protective effect of ATV on IS (15.8 [+ or -] 0.9%, 22.0 [+ or -] 1.6%, and 23.7 [+ or -] 3.8%, respectively). ASA dose dependently blocked the upregulation of COX2 by ATV. COX2 activity was as follows: control, 8.93 [+ or -] 0.90 pg/mg; ATV, 75.85 [+ or -] 1.08 pg/mg; ATV + ASA5, 34.39 [+ or -] 1.48 pg/mg; ATV + ASA10, 19.87 [+ or -] 1.10 pg/mg; and ATV + ASA20, 9.36 [+ or -] 0.94 pg/mg. ASA, administered before reperfusion in doses comparable to those used in the clinical setting, abrogates the IS-limiting effect of ATV in a model with mechanical occlusion of the coronary artery. This potential adverse interaction should be further investigated in the clinical setting of acute coronary syndromes. acetylsalicylic acid; cyclooxygenase-2 doi:10.1152/ajpheart.01269.2006

The growth and evolutionary expansion of the cerebral cortex are defined by the spatial-temporal production of neurons, which itself depends on the decision of radial glial cells (RGCs) to self-amplify or to switch to neurogenic divisions. The mechanisms regulating these RGC fate decisions are still incompletely understood. Here, we describe a novel and evolutionarily conserved role of the canonical BMP transcription factors SMAD1/5 in controlling neurogenesis and growth during corticogenesis. Reducing the expression of both SMAD1 and SMAD5 in neural progenitors at early mouse cortical development caused microcephaly and an increased production of early-born cortical neurons at the expense of late-born ones, which correlated with the premature differentiation and depletion of the pool of cortical progenitors. Gain- and loss-of-function experiments performed during early cortical neurogenesis in the chick revealed that SMAD1/5 activity supports self-amplifying RGC divisions and restrains the neurogenic ones. Furthermore, we demonstrate that SMAD1/5 stimulate RGC self-amplification through the positive posttranscriptional regulation of the Hippo signalling effector YAP. We anticipate this SMAD1/5-YAP signalling module to be fundamental in controlling growth and evolution of the amniote cerebral cortex. [ABSTRACT FROM AUTHOR]

Pretreatment with atorvastatin (ATV) reduces infarct size (IS) and increases myocardial expression of phosphorylated endothelial nitric oxide synthase (p-eNOS), inducible NOS (iNOS), and cyclooxygenase-2 (COX2) in the rat. Inhibiting COX2 abolished the ATV-induced IS limitation without affecting p-eNOS and iNOS expression. We investigated 1) whether 3-day ATV pretreatment limits IS in eNOS-/- and iNOS-/- mice and 2) whether COX2 expression and/or activation by ATV is eNOS, iNOS, and/or NF-κB dependent. Male C57BL/6 wild-type (WT), University of North Carolina eNOS-/- and iNOS-/- mice received ATV (10 mg·kg-1·day-1; ATV+) or water alone (ATV-) for 3 days. Mice underwent 30 mm of coronary artery occlusion and 4 h of reperfusion, or hearts were harvested and subjected to ELISA, immunoblotting, biotin switch, and electrophoretic mobility shift assay. As a result, ATV reduced IS only in the WT mice. ATV increased eNOS, p-eNOS, iNOS, and COX2 levels and activated NF-κB in WT mice. It also increased myocardial COX2 activity. In eNOS-/- mice, ATV increased COX2 expression but not COX2 activity or iNOS expression. NF-κB was not activated by ATV in the eNOS-/- mice. In the iNOS-/- mice, eNOS and p-eNOS levels were increased but not iNOS and COX2 levels; however, NP-κB was activated. In conclusion, both eNOS and iNOS are essential for the IS-limiting effect of ATV. The expression of COX2 by ATV is iNOS, but not eNOS or NF-κB, dependent. Activation of COX2 is dependent on iNOS. [ABSTRACT FROM AUTHOR]

Objectives: To determine the time to maximal coronary dilation following intracoronary (IC) nitroglycerin (NTG) and whether the decrease in aortic pressure (AoP) is a surrogate marker for coronary vasodilatation., Background: Intravascular ultrasound (IVUS) facilitates assessment of coronary plaque severity and morphology and aids in stent sizing. NTG is often administered prior to IVUS to prevent catheter-induced spasm and to facilitate standardized and accurate vessel size measurements. The impact of dose, timing, and route of delivering NTG on vessel size remains undefined., Methods: Twelve patients undergoing IVUS-guided stent placement were studied. An IVUS catheter was positioned proximal to the target lesion and the following measurements made at baseline and 30 second (sec) intervals for 180 sec following 200 mcg IC NTG: AoP, IVUS-derived lumen diameter (Ld), lumen cross-sectional area (La), external elastic membrane diameter (EEMd) and EEM area (EEMa). Lumen and EEM measurements were compared at different time intervals and the relationship between time to max Ld and nadir AoP was analyzed., Results: All patients had a vasodilatory response to IC NTG. Increase from baseline to max Ld following IC NTG was statistically significant (mean change 0.31 ± 0.18 mm, P=.0001). Mean time to max Ld following IC NTG was 117 sec (range, 60-180 sec). No correlation between time to max Ld and AoP nadir was observed (r = 0.19)., Conclusions: Our study suggests that administration of 200 mcg IC NTG results in a significant change in lumen diameter and area with maximal vasodilation occurring on average approximately 2 minutes following IC NTG administration. There was no significant correlation between AoP change and maximal NTG-induced coronary vasodilation.

Elevated cardiac biomarkers in conjunction with electrocardiographic (ECG) changes are valuable in diagnosing acute coronary syndrome (ACS). Elevated troponin I (TnI), while commonly seen in ACS, can also occur in entities such as sepsis and pulmonary thromboembolic disease. Raised TnI levels in patients with sepsis result from various mechanisms, including hypoperfusion or direct extension of infection to cardiac tissue, and can also serve as an important prognostic indicator. Electrocardiographic changes in sepsis are not as well described. Some of the ECG findings associated with septic shock include loss of QRS amplitude, increase in QTc interval, bundle branch blocks, and development of narrowed QRS intervals with deformed, positively deflected J waves (commonly known as Osborn waves). ST-segment elevations in sepsis are rare and have only previously been noted in a handful of case reports involving patients with septic shock. We present a case of a 59-year-old woman with ST-segment elevations and increased levels of cardiac troponin from Escherichia coli septic shock in the setting of normal coronary angiography.

Background: Both statins and thiazolidinediones have antiinflammatory properties. However, the exact mechanisms underlying these effects are unknown. We investigated whether atorvastatin (ATV) and pioglitazone (PIO) increase the myocardial content of lipoxin-A4 and 15(R)-epi-lipoxin-A4 (15-epi-LXA4), both arachidonic acid products with strong antiinflammatory properties., Methods and Results: In experiment 1, rats received 3-day pretreatment with water; PIO 2, 5, or 10 mg x kg(-1) x d(-1); ATV 2, 5, or 10 mg x kg(-1) x d(-1); or PIO 10 mg x kg(-1) x d(-1)+ATV 10 mg x kg(-1) x d(-1). In experiment 2, rats received water; PIO 10 mg x kg(-1) x d(-1)+ATV 10 mg x kg(-1) x d(-1); PIO+ATV and valdecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor; PIO+ATV and zileuton, a selective 5-lipoxygenase inhibitor; or zileuton alone. There were 4 rats in each group. Hearts were harvested and analyzed for myocardial lipoxin-A4 and 15-epi-LXA4 levels and for COX-2 and 5-lipoxygenase protein expression. ATV and PIO at 5 and 10 mg x kg(-1) . d(-1) significantly increased myocardial 15-epi-LXA4 levels compared with the sham-treated group (0.51 +/- 0.02 ng/mg). Myocardial 15-epi-LXA4 were significantly higher in the PIO+ATV group (1.29 +/- 0.02 ng/mg; P < 0.001 versus each other group). Both valdecoxib and zileuton abrogated the PIO+ATV increase in 15-epi-LXA4, whereas zileuton alone had no effect. PIO, ATV, and their combination resulted in a small increase in myocardial lipoxin-A4 levels, which was not statistically significant. ATV alone or in combination with PIO markedly augmented COX-2 expression. PIO had a much smaller effect on COX-2 expression. Myocardial expression of 5-lipoxygenase was not altered by PIO, ATV, or their combination., Conclusions: Both PIO and ATV increase myocardial levels of 15-epi-LXA4, a mediator with antiinflammatory properties. This finding may explain the antiinflammatory properties of both PIO and ATV.