IL (Interleukin)-1 antagonism decreases blood pressure in obese individuals. The underlying mechanisms are unknown. Based on experimental data, we hypothesized an effect of IL-1 antagonism via modulation of the renin-angiotensin-aldosterone system. In this explorative study, we examined shorter- (2 days) and longer-term effects (4 weeks) of IL-1 antagonism (anakinra/Kineret) on renin-angiotensin system peptide profiles and on hemodynamic parameters assessed by noninvasive measurement in obese (body mass index ≥30 kg/m2) individuals from 2 interventional trials (a prospective interventional trial [n=73] and a placebo controlled-double blinded interventional trial [n=67]). A total of 140 patients were included. Systolic blood pressure decreased after short-term (absolute difference -5.2 mm Hg [95% CI, -8.5 to -1.8]; P=0.0006) and after longer-term treatment with anakinra (absolute difference -3.9 mm Hg [95% CI, -7.59 to -0.21]; P=0.04), with no change in blood pressure in the placebo group. Upon IL-1 antagonism, equilibrium levels of Ang II (angiotensin II), Ang I, aldosterone, and renin remained unchanged. In contrast, Ang (1-7) peptide levels increased after 4 weeks (between-group difference 16.35 pmol/L [95% CI, 1.22-30.17], P=0.03), as well as the Ang (1-7)/Ang II ratio (between-group difference 0.42 [95% CI, 0.17-0.67], P=0.02) in comparison to placebo. Consistently, the stroke systemic vascular resistance index significantly decreased in the anakinra group (between-group difference of -62.65 dyn/sec per cm-5 per m2 [95% CI, -116.94 to -18.36], P=0.008, consistent with a 25% decrease). IL-1 antagonism increased the vasodilatory Ang (1-7) peptide after 4 weeks of treatment in obese individuals, paralleled by a decrease in peripheral vascular resistance. These findings point to an IL-1 mediated blood pressure-lowering mechanism via modulation of Ang (1-7). Registration- URL: https://www.clinicaltrials.gov. Unique identifiers: NCT02227420 and NCT02672592.
Keywords: aldosterone; angiotensins; blood pressure; interleukins; peptides.
Additive effects of combined angiotensin-converting enzyme inhibition and angiotensin II antagonism on blood pressure and renin release in sodium-depleted normotensives.Circulation. 1995 Aug 15;92(4):825-34. doi: 10.1161/01.cir.92.4.825. Circulation. 1995. PMID: 7641363 Clinical Trial.
Add-on angiotensin receptor blockade with maximized ACE inhibition.Kidney Int. 2001 Jun;59(6):2282-9. doi: 10.1046/j.1523-1755.2001.00745.x. Kidney Int. 2001. PMID: 11380832 Clinical Trial.
Effects of direct renin inhibition versus angiotensin II receptor blockade on angiotensin profiles in non-diabetic chronic kidney disease.Ann Med. 2017 Sep;49(6):525-533. doi: 10.1080/07853890.2017.1313447. Epub 2017 Apr 17. Ann Med. 2017. PMID: 28358246 Clinical Trial.
Blood pressure lowering efficacy of renin inhibitors for primary hypertension.Cochrane Database Syst Rev. 2017 Apr 5;4(4):CD007066. doi: 10.1002/14651858.CD007066.pub3. Cochrane Database Syst Rev. 2017. PMID: 28379619 Free PMC article. Review.
[Angiotensin II receptor blockers: current status and future prospects].Drugs. 2002;62 Spec No 1:53-64. Drugs. 2002. PMID: 12036389 Review. French.