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Negative inotropic and hypotensive effects of the superoxide dismutase mimetic tempol in pigs.
- Source :
-
European journal of pharmacology [Eur J Pharmacol] 2014 May 15; Vol. 731, pp. 20-30. Date of Electronic Publication: 2014 Mar 13. - Publication Year :
- 2014
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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.<br /> (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Enzyme Inhibitors pharmacology
Female
Heart drug effects
Heart physiology
Hemodynamics drug effects
In Vitro Techniques
Mesenteric Arteries drug effects
Mesenteric Arteries physiology
NG-Nitroarginine Methyl Ester pharmacology
Nitric Oxide Synthase antagonists & inhibitors
Spin Labels
Swine
Tetraethylammonium pharmacology
Biomimetic Materials pharmacology
Blood Pressure drug effects
Cyclic N-Oxides pharmacology
Muscle Contraction drug effects
Superoxide Dismutase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0712
- Volume :
- 731
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 24632458
- Full Text :
- https://doi.org/10.1016/j.ejphar.2014.02.036