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Tumor necrosis factor-alpha impairs contraction but not relaxation in carotid arteries from iNOS-deficient mice
C A Gunnett1, D D Heistad, A Loihl
1Departments of Internal Medicine and Pharmacology, and Cardiovascular Center, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
Abstract:
We used mice deficient in expression of inducible NO synthase (iNOS -/-) to directly examine the role of iNOS in impaired vasoconstrictor responses following tumor necrosis factor-alpha (TNF-alpha). In iNOS +/+ mice, contraction of carotid arteries in response to prostaglandin F(2alpha) (PGF(2alpha)) was impaired following TNF-alpha (100 microg/kg ip)(n = 10, P < 0.01). In contrast to responses in wild-type mice, contraction to low concentrations of PGF(2alpha) were normal, but maximum contraction to PGF(2alpha) was impaired in arteries from iNOS -/- mice treated with TNF-alpha [0.35 +/-.0.02 g (n = 8) following vehicle and 0.25 +/- 0.02 g (n = 7) following TNF-alpha (P < 0.05)]. Aminoguanidine, a relatively selective inhibitor of iNOS, partially restored contraction to PGF(2alpha) in vessels from iNOS +/+ mice but had no effect in iNOS -/- mice injected with TNF-alpha, suggesting that a mechanism(s) other than iNOS contributes to impaired responses. In contrast to contractile responses, relaxation of the carotid artery in response to acetylcholine and nitroprusside was not altered following TNF-alpha in iNOS +/+ or iNOS -/-mice. Responses of carotid arteries from iNOS -/- mice and effects of aminoguanidine suggest that both iNOS-dependent and iNOS-independent mechanisms contribute to impaired contractile responses following TNF-alpha.
Insights
Tumor necrosis factor-alpha (TNF-alpha) impairs vasoconstrictor responses in mice. Inducible nitric oxide synthase (iNOS) plays a role, but other mechanisms also contribute to these impaired vascular functions.
Area of Science:
- Physiology
- Pharmacology
- Immunology
Background:
- Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine implicated in vascular dysfunction.
- Inducible nitric oxide synthase (iNOS) produces nitric oxide, influencing vascular tone.
- Understanding the specific roles of iNOS in TNF-alpha-induced vascular impairment is crucial.
Purpose of the Study:
- To investigate the direct role of inducible nitric oxide synthase (iNOS) in impaired vasoconstrictor responses following TNF-alpha administration.
- To differentiate between iNOS-dependent and iNOS-independent mechanisms contributing to vascular dysfunction induced by TNF-alpha.
Main Methods:
- Utilized mice genetically deficient in iNOS expression (iNOS -/-) and wild-type (iNOS +/+) littermates.
- Administered TNF-alpha and measured carotid artery contractile responses to prostaglandin F(2alpha) (PGF(2alpha)).
- Assessed the effects of aminoguanidine, a selective iNOS inhibitor, on vascular responses.
Main Results:
- TNF-alpha impaired PGF(2alpha)-induced contraction in wild-type mouse carotid arteries.
- In iNOS -/- mice, TNF-alpha still impaired maximum PGF(2alpha) contraction, indicating iNOS-independent effects.
- Aminoguanidine partially restored responses in wild-type mice but not in iNOS -/- mice treated with TNF-alpha.
- Vascular relaxation responses to acetylcholine and nitroprusside remained unaltered by TNF-alpha in both genotypes.
Conclusions:
- Both iNOS-dependent and iNOS-independent pathways contribute to TNF-alpha-induced impairment of vasoconstrictor responses.
- iNOS plays a significant role, but other mechanisms are also involved in this vascular dysfunction.
- TNF-alpha does not appear to affect endothelium-dependent or independent vasodilation in this model.
