Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation.

Atrial fibrillation (AF), the most common chronic arrhythmia, increases the risk of stroke and is an independent predictor of mortality. Available pharmacological treatments have limited efficacy. Once initiated, AF tends to self-perpetuate, owing in part to electrophysiological remodeling in the atria; however, the fundamental mechanisms underlying this process are still unclear. We have recently demonstrated that chronic human AF is associated with increased atrial oxidative stress and peroxynitrite formation; we have now tested the hypothesis that these events participate in both pacing-induced atrial electrophysiological remodeling and in the occurrence of AF following cardiac surgery. In chronically instrumented dogs, we found that rapid (400 min(-1)) atrial pacing was associated with attenuation of the atrial effective refractory period (ERP). Treatment with ascorbate, an antioxidant and peroxynitrite decomposition catalyst, did not directly modify the ERP, but attenuated the pacing-induced atrial ERP shortening following 24 to 48 hours of pacing. Biochemical studies revealed that pacing was associated with decreased tissue ascorbate levels and increased protein nitration (a biomarker of peroxynitrite formation). Oral ascorbate supplementation attenuated both of these changes. To evaluate the clinical significance of these observations, supplemental ascorbate was given to 43 patients before, and for 5 days following, cardiac bypass graft surgery. Patients receiving ascorbate had a 16.3% incidence of postoperative AF, compared with 34.9% in control subjects. In combination, these studies suggest that oxidative stress underlies early atrial electrophysiological remodeling and offer novel insight into the etiology and potential treatment of an enigmatic and difficult to control arrhythmia. The full text of this article is available at http://www.circresaha.org.

Oxidative pathways in cardiovascular disease: roles, mechanisms, and therapeutic implications.

Despite some recent declines, cardiovascular disease (CVD) remains the major cause of death in the United States and worldwide. Most recent advances in the treatment of CVD states have been produced by inhibition of mechanisms involved in disease progress. Many studies conducted in the last decade have illustrated increased biological oxidative pathways during CVD in animals and humans. Thus, increased production of reactive oxygen species may be a unifying mechanism in CVD progression, and antioxidants may have therapeutic value in this setting. In this review we address the following questions: Do oxidative mechanisms play a role in CVD? Where do the oxidants come from? What are the relevant oxidative events? What are the therapeutic implications?

Analysis of isobutyl nitrite inhalant in rat and human blood: application for pharmacokinetic investigations.

Organic nitrites have been used therapeutically for the treatment of angina pectoris and as diagnostic agents for the evaluation of cardiac heart murmurs. In addition, these highly volatile vasodilators are being used as inhalant drugs of abuse. We developed a gas chromatographic assay using electron capture detection for the analysis of a representative nitrite inhalant, isobutyl nitrite (ISBN), in rat and human whole blood. Unconventional sampling and processing techniques were required because of the high volatility and chemical instability of nitrites in biological fluids. Our method produced a mean recovery of ISBN from rat blood of about 86% over a concentration range of 1.0 to 400 ng/ml. The inter-day coefficient of variation was below 15% at the lowest quantifiable concentration of 1 ng/ml ISBN in rat blood. In this report, we applied the analytical method to obtain new pharmacokinetic information about ISBN. Results show that rats inhaling 900 ppm ISBN for 45 min produced steady-state blood concentrations of about 290 ng/ml, and a rapid elimination half-life of 1.4 min.

Evaluation of linear polyethyleneimine/nitric oxide adduct on wound repair: therapy versus toxicity.

A full-thickness wound model was used to evaluate the effects of a topically applied polyethyleneimine-based nitric oxide donor on wound repair in aged rats. Polymer applications were applied over a 10-day period on days 0, 2, 4, 6, and 8 comparing treatment (linear polyethyleneimine-nitric oxide) and control groups (linear polyethyleneimine). Urinary nitrate excretion was quantified as a measure of nitric oxide released. The nitric oxide released from the linear polyethyleneimine-nitric oxide group was significant compared with controls (p

Effects of morphine withdrawal syndrome on endo-oligopeptidase (EC 3.4.22.19) activity.

Endo-oligopeptidase (EC 3.4.22.19), an enzyme capable of generating enkephalin by single cleavage from enkephalin-containing peptides, was examined in several areas of the central nervous system (CNS) as well as in the immune and endocrine tissues of rats chronically treated with morphine and submitted to naloxone-induced withdrawal. A specific fluorogenic substrate was used to determine the endopeptidase 22.19 activity. A non-uniform increase in endopeptidase 22.19 activity was detected in the CNS. The highest increase in endopeptidase 22.19 specific activity was found in the dorsal hippocampus (about 3.5-fold higher than control), followed by occipital and frontal cortex, substantia nigra, thalamus and hypothalamus. In peripheral tissues, a significant decrease of endopeptidase 22.19 was observed in the pineal gland, whereas the morphine withdrawal syndrome caused a slight but significant increase in lymphoid tissues such as lymph nodes and thymus. These findings are indicative of a possible participation of endopeptidase 22.19 in naloxone-induced withdrawal.

Caring as the central focus in nursing curriculum development.

Nursing literature and conferences are advocating a return to the humanistic values and caring approach to people that has been a hallmark of nursing. A theory base for caring in nursing is emerging. Over the past 10 years several research studies in nursing have focused on the concept of caring. Most studies have dealt with defining and understanding the concept of caring and identifying attributes of caring from the perspective of the patient/client and from that of the nurse. New work on caring is looking at teaching of the concept in schools of nursing (Bauer, 1988), the economics of caring (Buerhaus, 1986), the relationship between caring and nurse burnout (Gustafson, 1984), issues of ethics and caring (Fry, 1988 & 1989), to name just a few. The concept of caring is being legitimized as an area appropriate for nurses to study. As nursing educators know, building a program on a strong philosophical base with faculty committed to implementation of the program philosophy is crucial for success of program outcome. Using a caring framework for teaching nursing exposes nursing students to more than an empirical basis for practice. An holistic approach to really understanding people as human beings of value, worth, and having needs becomes the focus of content. To effectively teach caring, faculty must role model the attributes of caring to nursing students. This involves accepting and treating students as having value, worth, and the potential for growth. Faculty must also feel good about themselves and their abilities as teachers. Faculty need to feel confident and comfortable in their role as educators, master their subject matter, and be willing to get involved with students. Faculty development programs, recruitment of faculty espousing a caring philosophy, and mentoring new faculty into their modeling role are important considerations for the effective teaching of caring. Promoting a caring framework for nursing and faculty modeling of caring behaviors and attitudes could affect student recruitment. In our highly technologic society, great emphasis is being placed on person-to-person relationships. Reaffirming the caring nature of nursing to the public and actively promoting these behaviors may make the nursing profession a more attractive and appealing career choice.

Modulation of resynthesis of 1-alkyl-2-arachidonyl-glycero-3-phosphocholine and phosphatidylinositols for interception in vivo of free arachidonic acid, lyso-PAF, diacyl-glycerols, and phosphoinositides.

Thermal injury causes directly a liberation of inositolphosphates, diacylglycerols, free arachidonic acid, and lyso PAF from eukaryotic cells. From lyso PAF derivates PAF, from free arachidonic acid are derivating PG, LT, and TX. These "soluble mediators" are stimulating inflammatory cell populations in a feedback mechanism: the stimulus activates the inflammatory cells to produce the same soluble mediators (Fig.1). The arising soluble mediators are the take off for the inflammation cascade causing as later step the activation of kinin, clotting, and complement systems. The pure biochemical lesions at the onset results in the clinical manifestation of oedema, increased dermal temperature, and pains. The possibilities for prevention and allevation of early pain, due to the acute burn, lie in the inhibition of the spreading out of inflammatory mediators (Bauer 1987a) (Fig.2).