Role of central mineralocorticoid receptors in cardiovascular disease

Gómez-Sánchez, Celso E.; Gómez-Sánchez, Elise P.

doi:10.1007/s11906-001-0049-z

Cited by 18 publications

(6 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Aldosterone synthase immunoreactivity is found in these areas (unpublished observation) and in the hippocampus and cerebellum (29). Synthesis of aldosterone in or near cells expressing MR would increase the ratio of aldosterone to corticosterone concentrations just as destruction of corticosterone would (11,22).…”

Section: Discussionmentioning

confidence: 84%

Effect of 3β-hydroxysteroid dehydrogenase inhibition by trilostane on blood pressure in the Dahl salt-sensitive rat

Gómez-Sánchez¹,

Samuel

Vergara

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

View full text Add to dashboard Cite

The brains of rats and humans express the enzymes required for the synthesis of aldosterone from cholesterol, including the 3␤-steroid dehydrogenase that catalyzes the conversion of pregnenolone to progesterone in the pathway of adrenal steroid synthesis. Salt-induced hypertension in the Dahl inbred salt-sensitive (SS/jr) rat is associated with normal to low levels of circulating aldosterone, yet it is abrogated by the central infusion of mineralocorticoid receptor antagonists. To test the hypothesis that de novo synthesis of aldosterone in the brain has a pathophysiological role in the salt-induced hypertension of the SS rat, the 3␤-steroid dehydrogenase antagonist trilostane was infused continuously intracerebroventricularly or subcutaneously in two different cohorts of Dahl SS/jr rats, one female, the other male, during and after the development of salt-induced hypertension. The doses of trilostane used had no effect on blood pressure when infused subcutaneously. Animals receiving vehicle intracerebroventricularly experienced a 30-to 45-mmHg increase in systolic blood pressure measured by tail cuff. The intracerebroventricular, but not subcutaneous, infusion of 0.3 g/h trilostane effectively blocked the increase in systolic blood pressure and reversed the hypertension produced by drinking 0.9% saline. Trilostane was equally effective in female and male rats. Weight gain, serum aldosterone and corticosterone concentrations, and behavior assessed subjectively and by elevated plus maze were unchanged by the trilostane treatment. These studies suggest that the synthesis in the brain of a mineralocorticoid receptor agonist, probably aldosterone, is responsible in part for the salt-induced hypertension of the inbred Dahl SS/jr rat. hypertension; aldosterone synthesis; 11␤-hydroxylase; corticosterone; brain ALL OF THE ENZYMES REQUIRED for the synthesis of adrenal corticosteroids from cholesterol are expressed in specific anatomic areas of the rat brain, albeit in very small amounts (7,12,31,32). The mRNAs for these enzymes have also been demonstrated in human brain (46).

show abstract

Section: Discussionmentioning

confidence: 84%

Effect of 3β-hydroxysteroid dehydrogenase inhibition by trilostane on blood pressure in the Dahl salt-sensitive rat

Gómez-Sánchez¹,

Samuel

Vergara

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

View full text Add to dashboard Cite

show abstract

“…Clinical studies indicate that mineralocorticoid receptor (MR) blockade exerts beneficial effects on cardiovascular events beyond those predicted by its blood pressure (BP)-lowering actions 1-4. Experimental evidence further suggests that aldosterone exerts direct adverse effects on the vasculature, contributing to vascular injury and remodeling 5-8.…”

Section: Introductionmentioning

confidence: 99%

Mineralocorticoid Receptor Antagonism Attenuates Vascular Apoptosis and Injury via Rescuing Protein Kinase B Activation

et al. 2009

View full text Add to dashboard Cite

Abstract-Emerging evidence indicates that mineralocorticoid receptor (MR) blockade reduces the risk of cardiovascular events beyond those predicted by its blood pressure-lowering actions; however, the underlying mechanisms remain unclear. To investigate whether protection elicited by MR blockade is through attenuation of vascular apoptosis and injury, independently of blood pressure lowering, we administered a low dose of the MR antagonist spironolactone or vehicle for 21 days to hypertensive transgenic Ren2 rats with elevated plasma aldosterone levels. Although Ren2 rats developed higher systolic blood pressures compared with Sprague-Dawley littermates, low-dose spironolactone treatment did not reduce systolic blood pressure compared with untreated Ren2 rats. Ren2 rats exhibited vascular injury as evidenced by increased apoptosis, hemidesmosome-like structure loss, mitochondrial abnormalities, and lipid accumulation compared with Sprague-Dawley rats, and these abnormalities were attenuated by MR antagonism. Protein kinase B activation is critical to vascular homeostasis via regulation of cell survival and expression of apoptotic genes. Protein kinase B serine 473 phosphorylation was impaired in Ren2 aortas and restored with MR antagonism. In vivo MR antagonist treatment promoted antiapoptotic effects by increasing phosphorylation of BAD serine 136 and expression of Bcl-2 and Bcl-xL, decreasing cytochrome c release and BAD expression, and suppressing caspase-3 activation. Furthermore, MR antagonism substantially reduced the elevated NADPH oxidase activity and lipid peroxidation, expression of angiotensin II, angiotensin type 1 receptor, and MR in Ren2 vasculature. These results demonstrate that MR antagonism protects the vasculature from aldosterone-induced vascular apoptosis and structural injury via rescuing protein kinase B activation, independent of blood pressure effects.

show abstract

“…In excess, mineralocorticoids produce hypertension. Ablation studies and selective infusions of antagonists and agonists implicate MR in circumventricular organs, especially those of the floor of the third ventricle, and the amygdala in the increase in central sympathetic drive, release of arginine vasopressin and salt appetite, and the decrease in baroreceptor sensitivity, that contribute to the hypertension of mineralocorticoid–salt excess (Gomez‐Sanchez, 1986; Janiak & Brody, 1988; Gomez‐Sanchez et al 1990 a ; Janiak et al 1990; Brody et al 1991; Gomez‐Sanchez & Gomez‐Sanchez, 1994, 2001). As expected, MR antagonists reduce hypertension and end‐organ pathology in humans with hyperaldosteronism.…”

mentioning

confidence: 99%

Aldosterone synthesis in the brain contributes to Dahl salt‐sensitive rat hypertension

Gómez-Sánchez

Gomez-Sanchez

Plonczynski

et al. 2009

Experimental Physiology

Self Cite

View full text Add to dashboard Cite

The enzymes required for aldosterone synthesis from cholesterol are expressed in rat and human brains. The hypertension of Dahl salt-sensitive (SS) rats is mitigated by the intracerebroventricular (i.c.v.) infusion of antagonists of the mineralocorticoid receptor (MR) and downstream effectors of mineralocorticoid action, as well as ablations of brain areas that also abrogate mineralocorticoid–salt excess hypertension in normotensive rats. We used real time RT-PCR to measure mRNA of aldosterone synthase and 11β-hydroxylase, the requisite enzymes for the last step in the synthesis of aldosterone and corticosterone, respectively, MR and the determinants of MR ligand specificity, 11β-hydroxysteroid dehydrogenase types 1 and 2 (11β-HSD1&2) and hexose-6-phosphate dehydrogenase (H6PDH). A combination of extraction and ELISA was used to measure aldosterone concentrations in tissue and urine of SS and Sprague–Dawley (SD) rats. Aldosterone synthase mRNA expression was higher in the brains and lower in the adrenal glands of SS compared with SD rats. The amounts of mRNA for MR, 11β-hydroxylase, 11β-HSD1&2 and H6PD were similar. Aldosterone concentrations were greater in brains of SS than SD rats, yet, in keeping with the literature, the circulating and total aldosterone production of aldosterone in SS rats were not. The selective inhibitor of aldosterone synthase, FAD286, was infused i.c.v. or subcutaneously in a cross-over blood pressure study in hypertensive SS rats further challenged by a high-salt diet. The i.c.v. infusion of FAD286, at a dose that had no effect systemically, significantly and reversibly lowered blood pressure in SS rats. Aldosterone synthesis in brains of SS rats is greater than in SD rats and is important in the genesis of their salt-sensitive hypertension.

show abstract

Role of central mineralocorticoid receptors in cardiovascular disease

Cited by 18 publications

References 81 publications

Effect of 3β-hydroxysteroid dehydrogenase inhibition by trilostane on blood pressure in the Dahl salt-sensitive rat

Effect of 3β-hydroxysteroid dehydrogenase inhibition by trilostane on blood pressure in the Dahl salt-sensitive rat

Mineralocorticoid Receptor Antagonism Attenuates Vascular Apoptosis and Injury via Rescuing Protein Kinase B Activation

Aldosterone synthesis in the brain contributes to Dahl salt‐sensitive rat hypertension

Contact Info

Product

Resources

About