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

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-[gamma] (IFN-[gamma]), IL-17A, tumor necrosis factor-[alpha] (TNF-[alpha]), IL-6, IL-1[beta] 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-[gamma] and IL-6 IL-17A, TNF-[alpha], IL-1[beta] 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-[gamma], 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-[alpha], IL-6, IL-1[beta] and IL-10 levels. Conclusion The antihypertensive action of spironolactone in resistant hypertensive patients is associated with suppressed IFN-[gamma] and IL-6 and not IL-17A. Spironolactone exerts anti-inflammatory actions in vivo on macrophages and T-cells.