Abstract
We sought to delineate contributions of nitric oxide (NO) and other mechanisms to impairment of contraction and endothelium-dependent relaxation following prolonged in vitro incubation, endotoxin and interleukin-1 exposure in isolated rat aorta. Responses from freshly-dissected (control) rings ±endothelium were compared with those from rings incubated in sterile, antibiotic containing medium ± E. Coli endotoxin (LPS, 100 μg/ml) ± interleukin-1 (IL-1, 40 ng/ml) at 37°C for 20-24 h. In some experiments, medium included dexamethasone (DEX, 1 μg/ml), cycloheximide (10 μg/ml), or NG-nitro-L-arginine (NNLA, 10-4M). After incubation, medium nitrite was measured. Incubation alone, without addition of inflammatory mediators, impaired contraction in an agonist-specific manner, by both NO-dependent and NO-independent mechanisms. Either LPS or IL-1 diminished contraction further, in a similarly heterogeneous manner. For example, contractions were changed in LPS-incubated endothelium-intact rings (vs. fresh controls) by -85%, +115%, -15%, -96%, and -37% for phenylephrine (PE), serotonin, prostaglandin F2α, angiotensin II, and U46619, respectively. NO synthase inhibition with NNLA either following, or during LPS incubation only partially normalized subsequent PE contractions, an effect which was smaller than that of DEX. Nitrite accumulation was inversely proportional to PE response, even though NO was not the sole mediator of LPS-impaired contraction. LPS and IL-1 nearly abolished ACh-induced relaxation, which was only mildly impaired by incubation alone. We conclude that prolonged incubation impaired vasoconstriction via both NO synthase induction and NO-independent mechanisms. LPS or IL-1 incubation impaired vasoconstriction further, primarily by NO-independent mechanisms. Moreover, vasoconstrictor responses following LPS varied with the agonist's ability to modulate endothelial NO release. These results are in accord with the failure of NO synthase inhibition to fully restore systemic vascular resistance indices in experimental endotoxemia or in hyperdynamic septic patients.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 455-467 |
| Number of pages | 13 |
| Journal | Life Sciences |
| Volume | 69 |
| Issue number | 4 |
| DOIs | |
| State | Published - Jun 15 2001 |
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Keywords
- Endothelium
- Endotoxin
- Nitric oxide
- Vascular
- Vasoconstriction
- Vasorelaxation
ASJC Scopus subject areas
- Pharmacology
Cite this
Nitric oxide dependent and independent effects of in vitro incubation or endotoxin on vascular reactivity in rat aorta. / Wylam, Mark; Metkus, Andrea P.; Umans, Jason G.
In: Life Sciences, Vol. 69, No. 4, 15.06.2001, p. 455-467.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Nitric oxide dependent and independent effects of in vitro incubation or endotoxin on vascular reactivity in rat aorta
AU - Wylam, Mark
AU - Metkus, Andrea P.
AU - Umans, Jason G.
PY - 2001/6/15
Y1 - 2001/6/15
N2 - We sought to delineate contributions of nitric oxide (NO) and other mechanisms to impairment of contraction and endothelium-dependent relaxation following prolonged in vitro incubation, endotoxin and interleukin-1 exposure in isolated rat aorta. Responses from freshly-dissected (control) rings ±endothelium were compared with those from rings incubated in sterile, antibiotic containing medium ± E. Coli endotoxin (LPS, 100 μg/ml) ± interleukin-1 (IL-1, 40 ng/ml) at 37°C for 20-24 h. In some experiments, medium included dexamethasone (DEX, 1 μg/ml), cycloheximide (10 μg/ml), or NG-nitro-L-arginine (NNLA, 10-4M). After incubation, medium nitrite was measured. Incubation alone, without addition of inflammatory mediators, impaired contraction in an agonist-specific manner, by both NO-dependent and NO-independent mechanisms. Either LPS or IL-1 diminished contraction further, in a similarly heterogeneous manner. For example, contractions were changed in LPS-incubated endothelium-intact rings (vs. fresh controls) by -85%, +115%, -15%, -96%, and -37% for phenylephrine (PE), serotonin, prostaglandin F2α, angiotensin II, and U46619, respectively. NO synthase inhibition with NNLA either following, or during LPS incubation only partially normalized subsequent PE contractions, an effect which was smaller than that of DEX. Nitrite accumulation was inversely proportional to PE response, even though NO was not the sole mediator of LPS-impaired contraction. LPS and IL-1 nearly abolished ACh-induced relaxation, which was only mildly impaired by incubation alone. We conclude that prolonged incubation impaired vasoconstriction via both NO synthase induction and NO-independent mechanisms. LPS or IL-1 incubation impaired vasoconstriction further, primarily by NO-independent mechanisms. Moreover, vasoconstrictor responses following LPS varied with the agonist's ability to modulate endothelial NO release. These results are in accord with the failure of NO synthase inhibition to fully restore systemic vascular resistance indices in experimental endotoxemia or in hyperdynamic septic patients.
AB - We sought to delineate contributions of nitric oxide (NO) and other mechanisms to impairment of contraction and endothelium-dependent relaxation following prolonged in vitro incubation, endotoxin and interleukin-1 exposure in isolated rat aorta. Responses from freshly-dissected (control) rings ±endothelium were compared with those from rings incubated in sterile, antibiotic containing medium ± E. Coli endotoxin (LPS, 100 μg/ml) ± interleukin-1 (IL-1, 40 ng/ml) at 37°C for 20-24 h. In some experiments, medium included dexamethasone (DEX, 1 μg/ml), cycloheximide (10 μg/ml), or NG-nitro-L-arginine (NNLA, 10-4M). After incubation, medium nitrite was measured. Incubation alone, without addition of inflammatory mediators, impaired contraction in an agonist-specific manner, by both NO-dependent and NO-independent mechanisms. Either LPS or IL-1 diminished contraction further, in a similarly heterogeneous manner. For example, contractions were changed in LPS-incubated endothelium-intact rings (vs. fresh controls) by -85%, +115%, -15%, -96%, and -37% for phenylephrine (PE), serotonin, prostaglandin F2α, angiotensin II, and U46619, respectively. NO synthase inhibition with NNLA either following, or during LPS incubation only partially normalized subsequent PE contractions, an effect which was smaller than that of DEX. Nitrite accumulation was inversely proportional to PE response, even though NO was not the sole mediator of LPS-impaired contraction. LPS and IL-1 nearly abolished ACh-induced relaxation, which was only mildly impaired by incubation alone. We conclude that prolonged incubation impaired vasoconstriction via both NO synthase induction and NO-independent mechanisms. LPS or IL-1 incubation impaired vasoconstriction further, primarily by NO-independent mechanisms. Moreover, vasoconstrictor responses following LPS varied with the agonist's ability to modulate endothelial NO release. These results are in accord with the failure of NO synthase inhibition to fully restore systemic vascular resistance indices in experimental endotoxemia or in hyperdynamic septic patients.
KW - Endothelium
KW - Endotoxin
KW - Nitric oxide
KW - Vascular
KW - Vasoconstriction
KW - Vasorelaxation
UR - http://www.scopus.com/inward/record.url?scp=0035876327&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035876327&partnerID=8YFLogxK
U2 - 10.1016/S0024-3205(01)01137-7
DO - 10.1016/S0024-3205(01)01137-7
M3 - Article
C2 - 11459436
AN - SCOPUS:0035876327
VL - 69
SP - 455
EP - 467
JO - Life Sciences
JF - Life Sciences
SN - 0024-3205
IS - 4
ER -