Abstract-Heart failure remains a leading cause of morbidity and mortality worldwide. Although depressed pump function is common, development of effective therapies to stimulate contraction has proven difficult. This is thought to be attributable to their frequent reliance on cAMP stimulation to increase activator Ca 2ϩ . A potential alternative is nitroxyl (HNO), the 1-electron reduction product of nitric oxide (NO) that improves contraction and relaxation in normal and failing hearts in vivo. The mechanism for myocyte effects remains unknown. Here, we show that this activity results from a direct interaction of HNO with the sarcoplasmic reticulum Ca 2ϩ pump and the ryanodine receptor 2, leading to increased Ca 2ϩ uptake and release from the sarcoplasmic reticulum. HNO increases the open probability of isolated ryanodine-sensitive Ca 2ϩ -release channels and accelerates Ca 2ϩ reuptake into isolated sarcoplasmic reticulum by stimulating ATP-dependent Ca 2ϩ transport. Contraction improves with no net rise in diastolic calcium. These changes are not induced by NO, are fully reversible by addition of reducing agents (redox sensitive), and independent of both cAMP/protein kinase A and cGMP/protein kinase G signaling. Rather, the data support HNO/thiolate interactions that enhance the activity of intracellular Ca 2ϩ cycling proteins. These findings suggest HNO donors are attractive candidates for the pharmacological treatment of heart failure. (Circ Res. 2007;100:96-104.) Key Words: nitroxyl Ⅲ contractility Ⅲ ryanodine receptor Ⅲ sarcoplasmic reticulum Ca 2ϩ -ATPase Ⅲ excitation/contraction coupling C ongestive heart failure affects an estimated 5 million people in the United States and has an annual mortality rate approaching 20%. More than half of the patients have depressed cardiac function, and, although improvement in function is clearly beneficial, as revealed by heart transplantation, development of effective pharmacological therapy to safely stimulate contraction has proven problematic. 1 Most such agents rely on enhancing cAMP and protein kinase A (PKA) to stimulate activator Ca 2ϩ and increase contractility. However, this approach is less effective in failing hearts, because of downregulation of the signaling, 2 and is chronically linked to toxicity and increased mortality.We recently reported that donors of nitroxyl (HNO), the 1-electron reduction product of nitric oxide (NO), 3 have novel cardiovascular effects quite different from NO. In intact in vivo hearts, the HNO donor Angeli's salt (AS) enhances function independent of ␤-adrenergic blockade or stimulation and unaccompanied by changes in cGMP. 4,5 Unlike most prior positive inotropes, HNO donors are similarly effective in normal and failing hearts. 5 Their combined ability to enhance heart function, while reducing venous pressures, has suggested potential utility as a heart failure treatment.The mechanisms underlying cardiac action of HNO remain unknown. HNO can stimulate ion channels such as the N-methyl-D-aspartate receptor. 6,7 Recent data suggest...

It is currently not known whether caffeine has an enhancing effect on long-term memory in humans. We used post-study caffeine administration to test its effect on memory consolidation using a behavioral discrimination task. Caffeine enhanced performance 24 h after administration according to an inverted U-shaped dose-response curve; this effect was specific to consolidation and not retrieval. We conclude that caffeine enhanced consolidation of long-term memories in humans.

A series of para-substituted N-methyl-N-phenylnitrenium ions (N-(4-biphenylyl)-N-methylnitrenium ion, N-(4-chlorophenyl)-N-methylnitrenium ion, N-(4-methoxyphenyl)-N-methylnitrenium ion, and N-(4-methylphenyl)-N-methylnitrenium ion) were generated through photolysis of the appropriately substituted 1-aminopyridinium salt. Laser flash photolysis using UV−vis detection as well as photoproduct analysis verified that the expected nitrenium ions were formed cleanly and rapidly following photolysis. Laser flash photolysis with time-resolved infrared detection allowed for structural characterization of the nitrenium ions through observation of a symmetrical aromatic CC stretch in the region 1580−1628 cm-1. The specific frequencies reflect the degree of quinoidal character present in each phenylnitrenium ion (i.e., the degree to which the nitrenium ion resembles a 4-iminocyclohexa-2,5-dienyl cation). The 4-methoxy derivative shows the highest frequency CC stretch, indicating that this strongly π-electron-donating substituent imparts more quinoidal character, and the 4-chloro derivative shows the lowest frequency CC stretch, suggesting that it possesses the least quinoidal character. Quantum calculations using density functional theory (BPW91/cc-pVDZ) were carried out on the same nitrenium ions. The theoretically derived IR frequencies showed excellent quantitative agreement with the experiment. The computed structures show significant bond length alternation in the phenyl rings, shortened C−N bond lengths, and substantial positive charge delocalization into the phenyl rings. All of these effects are more pronounced with increasing π-donating character of the ring substituent. Arylnitrenium ions are well described as 4-iminocyclohexa-2,5-dienyl cations.