Analysis of vasodilator responses to peroxynitrite in the hindlimb vascular bed of the cat

Bobby D. Nossaman, Trinity Bivalacqua, Hunter C. Champion, Syed R. Baber, Philip J. Kadowitz

Research output: Contribution to journalArticle

Abstract

The free radical peroxynitrite (ONOO) is formed in biological systems from the reaction of nitric oxide (NO) with superoxide (O2) and can react with protein and nonprotein thiol groups to produce tissue injury. However, these pathologic actions of ONOO may have been overemphasized, in that ONOO has vasorelaxant properties through activation of soluble guanylate cyclase; inhibits leukocyte-endothelial cell interactions; and reduces ischemia-reperfusion injury in the heart, lung, and liver. It has been reported that tolerance develops to the vasodilator actions of ONOO and that ONOO impairs vascular function. However, little, if anything, is known about responses to ONOO in the hindlimb circulation of the cat. To better understand the effects of ONOO on responses to vasoactive agonists and the mechanism by which ONOO induces vasodilation, the effects of short-term exposure to ONOO were investigated under constant-flow conditions in the hindlimb vascular bed of the cat.In these studies, direct intraarterial injections of ONOO produced dose-dependent decreases in hindquarters perfusion pressure. The vasodilator responses to ONOO were rapid in onset, were short in duration, and could be repeated without exhibiting tachyphylaxis. Vasodilator responses to ONOO were not changed in the presence of inhibitors of nitric-oxide synthase, cyclooxygenase, or K-ATP (adenosine triphosphate-sensitive potassium) channels. Furthermore, responses to ONOO were enhanced in duration by the type 5-cGMP (cyclic guanosine monophosphate) phosphodiesterase inhibitor zaprinast, whereas rolipram, a type 4-cGMP phosphodiesterase inhibitor, was without effect. Repeated administration of ONOO had no significant effect on responses to vasoconstrictor or to vasodilator agents including acetylcholine. These results show that ONOO has significant vasodilator activity in the hindlimb vascular bed of the cat and suggest that the response is mediated by a cGMP- dependent mechanism.The results of experiments with repeated injections of ONOO indicate that ONOO does not impair vasoconstrictor and endothelium-dependent or endothelium-independent vasodilator responses. Furthermore, tolerance did not develop with repeated short-term exposure to ONOO. Moreover, the results of experiments with inhibitors suggest that responses to ONOO are not dependent on K-ATP (adenosine triphosphate-sensitive potassium) channel activation, increased NOS activity, or the formation of products in the cyclooxygenase pathway. The results of these studies are consistent with the hypothesis that ONOO is rapidly converted in the hindlimb circulation to a substance that has the properties of an NO donor. These studies suggest that under physiologic conditions, the cytotoxic effects of ONOO on a short-term basis may have been overemphasized.

Original languageEnglish (US)
Pages (from-to)358-366
Number of pages9
JournalJournal of Cardiovascular Pharmacology
Volume50
Issue number4
DOIs
StatePublished - Oct 2007
Externally publishedYes

Fingerprint

Peroxynitrous Acid
Hindlimb
Vasodilator Agents
Blood Vessels
Cats
Vasoconstrictor Agents
Adenosine Triphosphate
Potassium Channels
Prostaglandin-Endoperoxide Synthases
Endothelium
Phosphodiesterase 4 Inhibitors
Rolipram
Tachyphylaxis
Intra-Arterial Injections
Phosphodiesterase Inhibitors
Nitric Oxide Donors
Cyclic GMP
Reperfusion Injury
Sulfhydryl Compounds
Vasodilation

Keywords

  • Hindlimb vascular bed
  • Nitricoxide donor
  • Peroxynitrite
  • Vasoconstrictor responses
  • Vasodilator responses

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Analysis of vasodilator responses to peroxynitrite in the hindlimb vascular bed of the cat. / Nossaman, Bobby D.; Bivalacqua, Trinity; Champion, Hunter C.; Baber, Syed R.; Kadowitz, Philip J.

In: Journal of Cardiovascular Pharmacology, Vol. 50, No. 4, 10.2007, p. 358-366.

Research output: Contribution to journalArticle

Nossaman, Bobby D. ; Bivalacqua, Trinity ; Champion, Hunter C. ; Baber, Syed R. ; Kadowitz, Philip J. / Analysis of vasodilator responses to peroxynitrite in the hindlimb vascular bed of the cat. In: Journal of Cardiovascular Pharmacology. 2007 ; Vol. 50, No. 4. pp. 358-366.
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