ABSTRACT
Adequate oxygen delivery to the heart during stress is essential for sustaining cardiac function. Acute increases in myocardial oxygen demand evoke coronary vasodilation and enhance perfusion via functional upregulation of smooth muscle voltage-gated K+ (Kv) channels. Because this response is controlled by Kv1 accessory subunits (i.e., Kvß), which are NAD(P)(H)-dependent aldo-keto reductases, we tested the hypothesis that oxygen demand modifies arterial [NAD(H)]i, and that resultant cytosolic pyridine nucleotide redox state influences Kv1 activity. High-resolution imaging mass spectrometry and live-cell imaging reveal cardiac workload-dependent increases in NADH:NAD+ in intramyocardial arterial myocytes. Intracellular NAD(P)(H) redox ratios reflecting elevated oxygen demand potentiate native coronary Kv1 activity in a Kvß2-dependent manner. Ablation of Kvß2 catalysis suppresses redox-dependent increases in Kv1 activity, vasodilation, and the relationship between cardiac workload and myocardial blood flow. Collectively, this work suggests that the pyridine nucleotide sensitivity and enzymatic activity of Kvß2 controls coronary vasoreactivity and myocardial blood flow during metabolic stress.
Subject(s)
NAD , Potassium Channels, Voltage-Gated , Muscle, Smooth , Nucleotides , Oxidation-Reduction , Oxygen , Potassium Channels, Voltage-Gated/physiology , PyridinesABSTRACT
[Figure: see text].
Subject(s)
Coronary Circulation , Kv1.3 Potassium Channel/metabolism , Muscle, Smooth, Vascular/metabolism , Oxygen/metabolism , Shaker Superfamily of Potassium Channels/metabolism , Action Potentials , Animals , Cells, Cultured , Kv1.3 Potassium Channel/genetics , Lactic Acid , Mice , Mice, Inbred C57BL , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/physiology , Myocardial Contraction , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/physiology , Myocytes, Smooth Muscle/metabolism , Shaker Superfamily of Potassium Channels/genetics , Vasoconstriction , VasodilationABSTRACT
CONTEXT: It is increasingly important to identify and use low-cost effective dressings for treating diabetic foot ulcers as medical costs and rates of diabetes continue to rise. Honey is an inexpensive moist dressing with antibacterial and tissue-healing properties that has shown promise in the medical literature. Many clinicians are unfamiliar with its use, but patients with diabetic foot ulcers may wish to try honey therapy or discuss it with their physicians. The purpose of this review is to familiarize physicians with practical aspects of using honey to treat diabetic foot ulcers. EVIDENCE ACQUISITION: The authors have experience using topical honey and are currently conducting a randomized controlled trial of its effectiveness in treating diabetic foot ulcers. In this review, the authors summarize evidence of honey's effectiveness, its hypothesized mechanism of action, potential risks and benefits, the types of honey available, and the nature of its application. Critical aspects of ulcer care are also reviewed. CONCLUSION: Honey is a low-cost topical therapy with important potential for healing. Its use may be considered in diabetic foot ulcers after a discussion of risks and benefits and in conjunction with standard wound care principles.
Subject(s)
Diabetic Foot/therapy , Honey , Administration, Topical , Humans , Wound HealingABSTRACT
We consider dark matter annihilation into standard model particles and show that the least detectable final states, namely, neutrinos, define an upper bound on the total cross section. Calculating the cosmic diffuse neutrino signal, and comparing it to the measured terrestrial atmospheric neutrino background, we derive a strong and general bound. This can be evaded if the annihilation products are dominantly new and truly invisible particles. Our bound is much stronger than the unitarity bound at the most interesting masses, shows that dark matter halos cannot be significantly modified by annihilations, and can be improved by a factor of 10-100 with existing neutrino experiments.
