The mineralocorticoid receptor blocker spironolactone lowers plasma interferon-γ and interleukin-6 in patients with type 2 diabetes and treatment-resistant hypertension

Abstract

Background: The mineralocorticoid receptor antagonist spironolactone lowers blood pressure in patients with resistant hypertension despite antihypertensive treatment with angiotensin-converting inhibitors (ACEi) and angiotensin-II receptor blockers (ARB). In preclinical studies, spironolactone suppresses pro-hypertensive interleukin 17A (IL-17A).Objectives: Plasma samples were analysed from a randomized, double-blind placebo-controlled trial with spironolactone given to patients with type 2 diabetes mellitus (T2DM) and resistant hypertension on three antihypertensive drugs. We tested the hypothesis that spironolactone-induced antihypertensive effects are associated with suppression of IL-17A and related cytokines.Methods: Interferon-g (IFN-g), IL-17A, tumor necrosis factor-a (TNF-a), IL-6, IL-1b and IL-10 were assessed in plasma with immunoassay in samples before and after 16 weeks of treatment with placebo or spironolactone (12.5-25-50 mg/day).Results: Spironolactone significantly reduced plasma IFN-g and IL-6 while IL-17A, TNF-a, IL-1b and IL-10 were unchanged. IL-6 was more sensitive to higher doses of spironolactone. At baseline, serum aldosterone correlated positively with diastolic night blood pressure. Urine albumin/creatinine-ratios correlated positively with plasma IL-6 at baseline. There were no relations between aldosterone and cytokine concentrations at baseline; between cytokine concentration and blood pressure at baseline; and between cytokine concentration decrease and blood pressure decrease, except for IFN-g, after treatment. The spironolactone-induced elevation in plasma potassium related inversely to blood pressure but not to changes in cytokines. In macrophages in vitro, spironolactone suppressed lipopolysaccharide (LPS)-induced TNF-a, IL-6, IL-1b and IL-10 levels. Conclusion:The antihypertensive action of spironolactone in resistant hypertensive patients is associated with suppressed IFN-g and IL-6 and not IL-17A. Spironolactone exerts anti-inflammatory actions in vivo on macrophages and T-cells.

Interferon gamma in the pathogenesis of hypertension − recent insights

“…Thangaraj et al studied the immunomodulatory effects of the MR antagonist spironolactone on 119 type 2 diabetic patients with hypertension despite ongoing treatment with three or more antihypertensive drugs [ 33 ▪ ]. Administration of 25 mg of spironolactone per day to the patients resulted in significantly reduced serum T cell IFNγ -but not interleukin (IL)-17A-production that correlated with significantly reduced systolic blood pressure in the recipients [ 33 ▪ ].…”

“…Thangaraj et al studied the immunomodulatory effects of the MR antagonist spironolactone on 119 type 2 diabetic patients with hypertension despite ongoing treatment with three or more antihypertensive drugs [ 33 ▪ ]. Administration of 25 mg of spironolactone per day to the patients resulted in significantly reduced serum T cell IFNγ -but not interleukin (IL)-17A-production that correlated with significantly reduced systolic blood pressure in the recipients [ 33 ▪ ]. This double-blind placebo-controlled study also found macrophage IL-6 production was significantly reduced after 50 mg/day spironolactone therapy; however, plasma IFNγ levels were not significantly reduced at this higher dose, complicating interpretation [ 33 ▪ ].…”

“…Administration of 25 mg of spironolactone per day to the patients resulted in significantly reduced serum T cell IFNγ -but not interleukin (IL)-17A-production that correlated with significantly reduced systolic blood pressure in the recipients [ 33 ▪ ]. This double-blind placebo-controlled study also found macrophage IL-6 production was significantly reduced after 50 mg/day spironolactone therapy; however, plasma IFNγ levels were not significantly reduced at this higher dose, complicating interpretation [ 33 ▪ ]. Although somewhat inconclusive, this clinical study may suggest a relationship between the mineralocorticoid receptor, T cell IFNγ production, and macrophage IL-6 release [ 33 ▪ ].…”

“…This double-blind placebo-controlled study also found macrophage IL-6 production was significantly reduced after 50 mg/day spironolactone therapy; however, plasma IFNγ levels were not significantly reduced at this higher dose, complicating interpretation [ 33 ▪ ]. Although somewhat inconclusive, this clinical study may suggest a relationship between the mineralocorticoid receptor, T cell IFNγ production, and macrophage IL-6 release [ 33 ▪ ]. IL-6 stimulation has been found to promote T cell expansion and IFNγ production under inflammatory conditions [ 53 ], and IFNγ stimulation has been found to promote monocyte production of IL-6 [ 37 , 54 , 55 ].…”

“…Additional prudence, then, is warranted when discussing IFNγ-related mechanisms. Several recent preclinical studies have continued to uncover the molecular mechanisms by which IFNγ mediates the progression of cardiovascular diseases [ 6 ▪ , 24 ▪ , 29 ▪▪ , 30 ▪▪ , 31 ▪ , 32 ▪ ], and several recent clinical studies corroborate, at minimum, a correlation between IFNγ and elevated systolic blood pressure [ 33 ▪ , 34 ▪▪ , 35 ▪ ]. This review will highlight these recent findings from the last two years and discuss them in the context of presently understood mechanisms.…”