title: Negative inotropic and hypotensive effects of the superoxide dismutase mimetic tempol in pigs.
abstract: Through interference with free radicals, the nitroxide tempol potentially increases bioavailability of nitric oxide (NO) and along with modulation of potassium channels reduces blood pressure (BP). We studied whether tempol in pigs lowers BP by mechanisms sensitive to inhibition of NO synthase or large conductance calcium-activated potassium channels (BKCa). The cardiovascular effects of intravenous tempol (25-50mg/kg) were examined in anesthetized pigs with myocardial function being evaluated by echocardiography. While saline-treated animals remained hemodynamically stable, tempol induced fast, dose-dependent and transient reductions in BP lasting 5-10 min with a simultaneous impairment of left ventricular contraction. Pretreatment with the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME, 4 mg/kg) or a blocker of BKCa (tetraethylammonium (TEA), 100mg/h) increased baseline BP but also enhanced BP reductions to tempol. Isolated myocardial trabeculae subjected to an identical protocol also demonstrated dose-related reductions in contractility to tempol. This effect was not affected by l-NAME, but attenuated by TEA. In isolated mesenteric resistance arteries contracted with noradrenaline, tempol caused small postjunctional l-NAME sensitive relaxations, while neurogenic contractions were inhibited by tempol by TEA-sensitive mechanisms and mechanisms insensitive to TEA and l-NAME. In conclusion intravenous tempol induces fast transient reductions in BP associated with simultaneous reductions in myocardial contraction. Tempol exerts direct negative inotropic effects which are partly sensitive to BKCa-blockade but independent of NOS inhibition. In addition tempol has direct vasodilatory effects despite NOS and potassium channel blockade. The negative inotropic and hypotensive effects raise concerns using tempol, or structurally similar drugs, for intravenous use.
authors.affiliation: Institute of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Denmark.
authors.forename: Mads Nyboe
authors.initials: MN
authors.lastname: Kristensen
authors.affiliation: Department of Anesthesiology & Intensive Care, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Christian Alcaraz
authors.initials: CA
authors.lastname: Frederiksen
authors.affiliation: Institute of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Denmark; Department of Anesthesiology & Intensive Care, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Sivén
authors.affiliation: Department of Anesthesiology & Intensive Care, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Janus Adler
authors.initials: JA
authors.lastname: Hyldebrandt
authors.affiliation: Department of Anesthesiology & Intensive Care, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Juhl-Olsen
authors.affiliation: Department of Anesthesiology & Intensive Care, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Erik
authors.initials: E
authors.lastname: Sloth
authors.affiliation: Institute of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Denmark.
authors.forename: Ulf
authors.initials: U
authors.lastname: Simonsen
authors.affiliation: Institute of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Denmark. Electronic address: nhbuus@dadlnet.dk.
authors.forename: Niels Henrik
authors.initials: NH
authors.lastname: Buus
mesh_terms: D000818:Animals; D040761:Biomimetic Materials / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000378:metabolism*; D013552:Swine; D019789:Tetraethylammonium / Q000494:pharmacology
chemical_list: D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D013113:Spin Labels; D019789:Tetraethylammonium; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; C001803:tempol; D019331:NG-Nitroarginine Methyl Ester
keywords: Blood pressure; Myocardial function; Pig; Resistance artery; Tempol