Neuronal nitric oxide synthase and its interaction with soluble guanylate cyclase is a key factor for the vascular dysfunction of experimental sepsis.

Abstract:

OBJECTIVE:Vascular dysfunction plays a central role in sepsis, and it is characterized by hypotension and hyporesponsiveness to vasoconstrictors. Nitric oxide is regarded as a central element of sepsis vascular dysfunction. The high amounts of nitric oxide produced during sepsis are mainly derived from the inducible isoform of nitric oxide synthase 2. We have previously shown that nitric oxide synthase 2 levels decrease in later stages of sepsis, whereas levels and activity of soluble guanylate cyclase increase. Therefore, we studied the putative role of other relevant nitric oxide sources, namely, the neuronal (nitric oxide synthase 1) isoform, in sepsis and its relationship with soluble guanylate cyclase. We also studied the consequences of nitric oxide synthase 1 blockade in the hyporesponsiveness to vasoconstrictors. DESIGN:Randomized controlled prospective experimental study. SETTING:Academic research laboratory. SUBJECTS:Female Wistar rats submitted to cecal ligation and puncture method. INTERVENTIONS:1) Six, 12, and 24 hours after cecal ligation and puncture, vascular reactivity to phenylephrine (3 and 30 nmol/kg) before and after 7-nitroindazole (45 μmol/kg, s.c.) or aminoguanidine (30 μmol/kg, s.c.) administration was evaluated. 2) Protein levels and interaction between nitric oxide synthase 1 and soluble guanylate cyclase were determined. 3) Six, 12, and 24 hours after cecal ligation and puncture, thoracic aorta segments were stimulated with phenylephrine in the presence or absence of 7-nitroindazole and cyclic guanosine monophosphate accumulation was determined. 4) After 24 hours of cecal ligation and puncture, norepinephrine was infused (10 μg/kg/min) in the presence or absence of 7-nitroindazole or S-methyl-L-thiocitrulline (1 μmol/kg, IV) and mean arterial pressure was registered. MEASUREMENTS AND MAIN RESULTS:1) Both nitric oxide synthase 1 and soluble guanylate cyclase are expressed in higher levels in vascular tissues during sepsis; 2) both proteins physically interact and nitric oxide synthase 1 blockade inhibits cyclic guanosine monophosphate production; 3) pharmacological blockade of nitric oxide synthase 1 using 7-nitroindazole or S-methyl-L-thiocitrulline reverts the hyporesponsiveness to phenylephrine and increases the vasoconstrictor effect of norepinephrine and phenylephrine. CONCLUSIONS:Sepsis induces increased expression and physical association of nitric oxide synthase 1/soluble guanylate cyclase and a higher production of cyclic guanosine monophosphate that together may help explain sepsis-induced vascular dysfunction. In addition, selective inhibition of nitric oxide synthase 1 restores the responsiveness to vasoconstrictors. Therefore, inhibition of nitric oxide synthase 1 (and possibly soluble guanylate cyclase) may represent a valuable alternative to restore the effectiveness of vasopressor agents during late sepsis.

journal_name

Crit Care Med

journal_title

Critical care medicine

authors

Nardi GM,Scheschowitsch K,Ammar D,de Oliveira SK,Arruda TB,Assreuy J

doi

10.1097/CCM.0000000000000301

subject

Has Abstract

pub_date

2014-06-01 00:00:00

pages

e391-400

issue

6

eissn

0090-3493

issn

1530-0293

journal_volume

42

pub_type

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