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Dexamethasone lacks effect on blood pressure in mice with a disrupted endothelial NO synthase gene
Thomas Wallerath1, Axel Gödecke, Andrei Molojavyi
1Department of Pharmacology, Johannes Gutenberg University, D-55101 Mainz, Germany.
Insights
Glucocorticoids raise blood pressure by decreasing endothelial nitric oxide synthase (eNOS) expression, reducing nitric oxide (NO) production. This mechanism was confirmed in mice lacking the eNOS gene.
Area of Science:
- Cardiovascular Physiology
- Molecular Endocrinology
- Renal Physiology
Background:
- Cushing's syndrome and glucocorticoid use are linked to hypertension.
- The molecular mechanisms underlying glucocorticoid-induced hypertension are not fully understood.
- Previous studies indicated dexamethasone downregulates endothelial nitric oxide synthase (eNOS) gene expression.
Purpose of the Study:
- To investigate the role of endothelial nitric oxide synthase (eNOS) in glucocorticoid-induced hypertension.
- To determine if dexamethasone-induced hypertension is dependent on eNOS in vivo.
- To examine the effect of dexamethasone on eNOS expression and nitric oxide (NO) production in mice.
Main Methods:
- Comparison of mean arterial blood pressure changes in wild-type (eNOS+/+) and eNOS knockout (eNOS-/-) mice treated with dexamethasone.
- Administration of a nitric oxide synthase (NOS) inhibitor (ethylisothiourea) to assess its effects in eNOS+/+ and eNOS-/- mice.
- Measurement of serum nitrite/nitrate (NO2-/NO3-) levels as an indicator of NO synthesis.
- Assessment of eNOS gene expression in the heart, liver, and kidney of treated mice.
Main Results:
- Dexamethasone increased mean arterial blood pressure in eNOS+/+ mice but not in eNOS-/- mice.
- The NOS inhibitor ethylisothiourea caused hypertension in eNOS+/+ mice but not in eNOS-/- mice.
- Dexamethasone treatment led to decreased serum NO2-/NO3- levels in eNOS+/+ mice, while eNOS-/- mice showed lower baseline levels unaffected by dexamethasone.
- Dexamethasone reduced eNOS expression in the heart, liver, and kidney of wild-type mice.
Conclusions:
- The expressional downregulation of eNOS contributes to glucocorticoid-induced hypertension.
- Reduced vascular nitric oxide (NO) production is a key mechanism in steroid-induced hypertension.
- eNOS plays a critical role in mediating the hypertensive effects of glucocorticoids.
Abstract:
Cushing's syndrome and systemic administration of glucocorticoids are associated with hypertension, but the underlying molecular mechanism is only partially understood. We have shown previously that dexamethasone downregulates the expression of the endothelial NO synthase (eNOS) gene in human endothelial cells and in the rat and that this may contribute to the blood pressure-raising effect of the steroid [Proc. Natl. Acad. Sci. USA 96 (1999) 13357]. In the current communication, we demonstrated that dexamethasone increased mean arterial blood pressure in wild-type C-57 Bl6 mice (eNOS+/+ mice), but had no effect on blood pressure in mice with a disrupted eNOS gene (eNOS-/- mice) derived from the same strain. The NOS inhibitor ethylisothiourea, used for control purposes, showed a hypertensive effect in eNOS+/+ mice, but no such effect in eNOS-/- mice. Serum NO2-/NO3- levels, an indicator of total body NO synthesis, decreased significantly when eNOS+/+ mice were treated with dexamethasone. eNOS-/- mice had lower serum NO2-/NO3- levels per se, which were not changed significantly by dexamethasone. Dexamethasone decreased the expression of eNOS in three major organs of the mouse investigated, namely the heart, the liver, and the kidney. We conclude that the expressional downregulation of eNOS and the ensuing reduction in vascular NO production contributes to the hypertension caused by glucocorticoids.
