title: Effects of hypochlorite and hydrogen peroxide on cardiac autonomic receptors and vascular endothelial function.
abstract: 1. Reactive oxygen species (ROS) are known to be involved in the progression of various cardiovascular diseases. One source of ROS is activated neutrophils, which can release superoxide anion radicals and hydrogen peroxide by membrane-bound NAD(P)H oxidases. These ROS not only destroy bacteria, but may also affect mammalian tissue. In addition, hydrogen peroxide serves as a substrate for myeloperoxidase, an enzyme that is released by activated neutrophils during inflammatory processes, as seen, for instance, in reperfusion injury and atherosclerosis. Myeloperoxidase catalyses the oxidation of chloride by hydrogen peroxide, yielding hypochlorite, an extremely potent oxidant. 2. The purpose of the present study was to evaluate the effects of hypochlorite on a variety of receptor-dependent processes in rat isolated left atria and rat thoracic aorta and to compare these results with the phenomena observed after incubation with hydrogen peroxide. 3. In the presence of hypochlorite (300 micro mol/L), the positive inotropic response of alpha1-adrenoceptor stimulation by methoxamine (300 micro mol/L) was converted into a negative inotropic response. In contrast, the positive inotropic effects of the beta1/beta2-adrenoceptor agonist isoprenaline (3 micro mol/L) and endothelin (ET)-1 (100 nmol/L) remained largely unaffected. 4. The inversion of alpha1-adrenoceptor-mediated inotropy was not obtained in the presence of hydrogen peroxide (500 micro mol/L). Hydrogen peroxide did not affect the positive inotropic response of isoprenaline, but it completely abolished the inotropic effect of ET-1. 5. The effect of cardiac M2-receptor stimulation was studied in the presence of hypochlorite and hydrogen peroxide. The negative inotropic response to acetylcholine (ACh) was significantly enhanced after hypochlorite incubation compared with control. 6. In the rat thoracic aorta, endothelial function, evaluated by means of ACh-induced vasodilation, was completely abolished in the presence of hypochlorite (100 micro mol/L), but remained unaffected by treatment with the same concentration of hydrogen peroxide. 7. From these data, we conclude that hypochlorite exerts more toxic properties than its precursor hydrogen peroxide, leading to substantial physiological alterations in cardiac and vascular tissue.
authors.affiliation: Department of Pharmacotherapy, Academic Medical Center, University of Amsterdam, The Netherlands. csand_amc@yahoo.com
authors.forename: Carsten
authors.initials: C
authors.lastname: Sand
authors.forename: Stephan L M
authors.initials: SL
authors.lastname: Peters
authors.forename: Martin
authors.initials: M
authors.lastname: Pfaffendorf
authors.forename: Pieter A
authors.initials: PA
authors.lastname: van Zwieten
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D018679:Cholinergic Agonists / Q000494:pharmacology; D003864:Depression, Chemical; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D006325:Heart Atria / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology*; D006997:Hypochlorous Acid / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D016877:Oxidants / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043585:Receptor, Muscarinic M2 / Q000187:drug effects* / Q000502:physiology; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000502:physiology
chemical_list: D000316:Adrenergic alpha-Agonists; D018679:Cholinergic Agonists; D016877:Oxidants; D043585:Receptor, Muscarinic M2; D018340:Receptors, Adrenergic, alpha-1; D006997:Hypochlorous Acid; D006861:Hydrogen Peroxide; D008729:Methoxamine; D000109:Acetylcholine