Coronary vasodilation is impaired in the postischemic heart with a loss of endothelial nitric oxide synthase (eNOS) activity, but the mechanisms underlying ischemia-induced eNOS dysfunction are not understood. For nitric oxide (NO) synthesis, eNOS requires the redox-sensitive cofactor tetrahydrobiopterin (BH 4); however, the role of BH 4 in ischemia-induced endothelial dysfunction remains unknown. Therefore, isolated rat hearts were subjected to varying durations of ischemia, and the alterations in NOS-dependent vasodilation were measured and correlated with assays of eNOS activity and cardiac BH 4 concentrations. Ischemia timedependently decreased cardiac BH 4 content with 85, 95, or 97% irreversible degradation after 30, 45, or 60 min of ischemia, respectively. Paralleling the decreases in BH 4, reductions of eNOS activity were seen of 58, 86, or 92%, and NOS-derived superoxide production was greatly increased. Addition of 10 M BH4 enhanced eNOS activity in nonischemic hearts and partially restored activity after ischemia. It also suppressed NOS-derived superoxide production. Impaired coronary flow during postischemic reperfusion was improved by BH 4 infusion. Thus, BH4 depletion contributes to postischemic eNOS dysfunction, and BH 4 treatment is effective in partial restoration of endothelium-dependent coronary flow. Supplementation of BH 4 may therefore be an important therapeutic approach to reverse endothelial dysfunction in postischemic tissues.ischemia reperfusion injury ͉ nitric oxide ͉ nitric oxide synthase uncoupling ͉ superoxide ͉ vascular function N itric oxide synthase (NOS) converts L-arginine and O 2 to nitric oxide (NO) and L-citrulline. This enzymatic process consumes NADPH and requires Ca 2ϩ /calmodulin, flavin adenine dinucleotide, flavin mononucleotide, and tetrahydrobiopterin (BH 4 ) as NOS cofactors. Endothelial NO synthase (eNOS) contributes to the regulation of vasomotor tone and blood pressure by producing NO that activates soluble guanylate cyclase in vascular smooth muscle, resulting in vasorelaxation (1-3).Endothelial dysfunction is a prognostic marker of cardiovascular disease (4). It has been suggested that limited availability of BH 4 contributes to eNOS dysfunction in hypercholesterolemia, diabetes, atherosclerosis, hypertension, and heart failure (5-9). It was also observed previously that eNOS function is impaired in ischemic hearts (10). In vivo coronary artery occlusion triggers endothelial dysfunction and decreased eNOSdependent vasoreactivity, although reactivity is preserved to exogenous NO (11,12). Endothelial-dependent coronary vasoreactivity is impaired in hearts subjected to periods of global ischemia and reperfusion (10). Endothelium-dependent vasodilators induce a relatively high increase in coronary flow in control hearts or in those made ischemic for short times, but longer periods of ischemia result in an abrupt decline in vasodilatory response.In addition to impairing eNOS-mediated NO formation, BH 4 depletion may have additional detrimental effects in postischem...

We examined mechanical alternans and electromechanical restitution in normal and failing rat hearts. Alternans occurred at 5 Hz in failing versus 9 Hz in control hearts and was reversed by 300 nM isoproterenol, 6 mM extracellular Ca2+, 300 nM −BAY K 8644, or 50 nM ryanodine. Restitution curves comprised phase I, which was completed before relaxation of the steady-state beat, and phase II, which occurred later. Phase I action potential area and developed pressure ratios were significantly reduced in the failing versus control hearts. Phase II was a monoexponential increase in relative developed pressure as the extrasystolic interval was increased. The plateau of phase II was significantly elevated in failing hearts. Thapsigargin (3 μM) plus ryanodine (200 nM) potentiated phase I to a significantly greater extent in control versus failing hearts and abolished phase II in both groups. The results suggest that both regulation of Ca2+ influx across the sarcolemma and Ca2+ release by the sarcoplasmic reticulum may contribute to altered excitation-contraction coupling in the failing spontaneously hypertensive heart failure prone rat heart.

Background: Chronic insomnia is characterized by disturbed sleep that occurs despite adequate opportunity and circumstances to sleep. Many patients with chronic insomnia have comorbid mental illnesses or medical illnesses that contribute and precipitate insomnia. Hallmark of chronic insomnia treatment includes non-pharmacological measures such as Cognitive Behavioral Therapy for Insomnia (CBT-I). Pharmacologic treatment (sedative or hypnotic agents) has been disappointing because of poor efficacy and numerous undesirable side effects. Other new therapies including meditation have been proven to be effective. Objective: This study investigates the effectiveness of Heartfulness meditation coupled with sleep hygiene to treat chronic insomnia. Methods: In this prospective pre-post design cohort study, 32 adult patients with chronic primary insomnia engaged in Heartfulness meditation along with appropriate sleep hygiene for eight weeks. Insomnia Severity Index (ISI) scores, usage of sedative or hypnotic agents were measured at baseline and at the end of the eight-week period. Results: There was a significant decrease in the mean ISI scores from 20.9 to 10.4 (p < 0.001) after eight weeks of Heartfulness meditation. Twenty four of 32 patients were initially on sedative or hypnotic medications. At week eight, 21 of 24 patients (87.5%) were off these medications or the dosage was reduced (p < 0.001). Conclusion: This study demonstrated statistical improvements in the measures of ISI in patients undergoing a Heartfulness meditation program. Heartfulness meditation may facilitate the taper and eventual cessation of sedative hypnotics in patients suffering from chronic insomnia.

Interleukin-1beta (IL-1beta) is a potent negative inotrope implicated in the functional abnormalities of heart failure. Because the adipokine, leptin, protects against some of the cardiovascular effects of endotoxin, we hypothesized that leptin may modulate the cardiosuppressive effects of IL-1beta in isolated cardiomyocytes. Ventricular cardiac myocytes isolated from adult male Sprague Dawley rats were analyzed simultaneously for electrically stimulated contractility and calcium transients following 30 min exposure to IL-1beta (10 ng/ml) with or without 60 min pretreatment with leptin (25 ng/ml). IL-1beta decreased cell shortening, depressed maximal velocities of shortening and relengthening, and prolonged the time to 90% relaxation. The change in fura2-AM fluorescence ratio amplitude (Delta[Ca(2+)]) was significantly depressed and the time to return to baseline [Ca(2+)] was prolonged. The negative inotropic effects of IL-1beta were blocked by the neutral sphingomyelinase inhibitor Manumycin A (5 microM) or the ceramidase inhibitor N-oleoyl ethanolamine (1 microM). Prior exposure of myocytes to leptin blocked IL-1beta-induced cardiosuppression in conjunction with a blunting of IL-1beta stimulated ceramide accumulation. These data suggest that leptin may modulate IL-1beta signaling through the sphingolipid signaling pathway in cardiomyocytes.