Wen Xiaohong | PubMed Health

PubMed2003

Deactivation of norepinephrine by peroxynitrite as a new pathogenesis in the hypotension of septic shock.

BACKGROUND: Vascular hyporeactivity to catecholamines limits successful treatment of hypotension in septic shock. Large amounts of nitric oxide (NO) and superoxide anion (O(2)(-1).) are produced in response to bacterial endotoxins and/or inflammatory cytokines. NO reacts with O(2)(-1). to form the potentially toxic NO metabolite, peroxynitrite (ONOO(-1)). The purpose of this study was to investigate whether ONOO(-1) decreases the vasocontractile activity of norepinephrine. METHODS: Norepinephrine was treated with ONOO(-1) or 3-morpholinosydonimine-N-ethyl-carbamine (SIN-1; an ONOO(-1) producer) in a 5 x 10(-2) m sodium phosphate buffer solution at pH 7.4, and absorbance of the product was measured spectrophotometrically at 295 and 370 nm. Norepinephrine pretreated with ONOO(-1) was administered to isolated rat thoracic aortas to observe contractions in functional experiments. The rate constant between norepinephrine and ONOO(-1) was determined via a competition assay with cysteine in functional experiments. Norepinephrine pretreated with ONOO(-1) was injected intravenously into anesthetized rats to measure blood pressure. RESULTS: Norepinephrine pretreated with ONOO(-1) was confirmed spectrally as oxidized norepinephrine. Norepinephrine pretreated with ONOO(-1) decreased its vasocontractile force in an ONOO(-1) (10(-6), up to 3 x 10(-4) m) concentration-dependent manner (EC(50) = 5.1 x 10(-5) m). The decrease in its force was lower at pretreatment with ONOO(-1) in a lower pH buffer. A rate constant for the ONOO(-1)-norepinephrine reaction was 6 x 10(2) m/s. Norepinephrine (10(-7) m) incubated with SIN-1 (10(-3) m) decreased its vasocontractile force in an incubation time-dependent manner. Administration of norepinephrine pretreated with ONOO(-1) to anesthetized rats caused no significant change in arterial blood pressure. CONCLUSIONS: These results indicate that norepinephrine was oxidized and deactivated by ONOO(-1). This deactivation may, at least in part, account for the hyporeactivities of vasocontraction to norepinephrine in septic shock.

Anesthesia↗

PubMed2003

Peroxynitrite decreases dopamine's vasoconstrictive activity.

UNLABELLED: Peroxynitrite (ONOO(-1)) reacts with dopamine to form an oxidized derivative. To investigate the vasoconstrictive activity of this derivative, we performed functional examinations with dopamine treated with ONOO(-1) or 3-morpholinosydonimine-N-ethyl-carbamine (SIN-1; an ONOO(-1) producer) on isolated strips of rat thoracic aorta. To exclude the direct effect of ONOO(-1), the strips were pretreated with methylene blue, a guanylyl cyclase inhibitor. Dopamine induced concentration-dependent contraction, but dopamine pretreated with ONOO(-1) decreased the contraction in an ONOO(-1)-concentration-dependent manner. Both maximum contractions and 50% effective concentration values for dopamine-induced vasocontraction were significantly decreased by pretreatment with ONOO(-1). Dopamine incubated with SIN-1 also decreased the contraction, the decrease being dependent on the incubation time. ONOO(-1) formation is a favored reaction and occurs easily when cellular production of both nitric oxide and superoxide increases, as in septic shock. These results may, at least in part, account for dopamine's limitation as a vasoconstrictor in septic shock. IMPLICATIONS: Peroxynitrite (ONOO(-1)) reacts with dopamine to form an oxidized derivative. We investigated the vasoconstrictive activity of this derivative with functional examinations using rat thoracic aorta and found the activity decreased. As ONOO(-1) formation increases in septic shock, our results may account for dopamine's limitation as a vasoconstrictor in septic shock.

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