Abstract 494 Efficacy of different antihypertensive drug classes after renal denervation in the spontaneous hypertensive rat model

Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5
Efficacy of different antihypertensive drug classes after renal denervation in the spontaneous hypertensive rat model
M. Hohl¹, L. Lauder¹, Ö. Sevimli¹, M. Tokcan¹, W. Lea², F. Götzinger¹, C. Schneider¹, U. Hübner³, U. Lehnert¹, M. Wolf¹, M. Meyer², M. Böhm¹, F. Mahfoud¹
¹Innere Medizin III - Kardiologie, Angiologie und internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar; ²Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Department of Experimental and Clinical Toxicology, Homburg/Saar; ³Zentrallabor, Klinische Chemie und Laboratoriumsmedizin, Homburg/Saar;
Background: Catheter-based renal denervation (RDN) lowers BP in patients with uncontrolled hypertension in the absence and presence of antihypertensive medications. Objectives: To assess the effects of different antihypertensive medication on BP and maladaptive cardiac phenotypes in spontaneous hypertensive rats (SHR) following RDN. Methods: A total of 64 male SHR with implanted radiotelemetry-devices for continuous BP monitoring were randomly allocated to undergo surgical RDN or a sham-operation (SHAM). Ten days after RDN, rats of both groups were randomized to receive either no antihypertensive medication (Ctrl), amlodipine, olmesartan, hydrochlorothiazide (HCT), or eplerenone for 4 weeks. Reductions in renal norepinephrine tissue concentration and expression of renal tyrosine hydroxylase were used to quantify the extent of denervation of the kidneys. Cardiac remodeling was assessed histologically and circulating neuroendocrine markers were measured. Results: Mean arterial pressure (MAP) was significantly reduced following RDN compared with SHAM-Ctrl (-11.6±2.3 versus -0.1±1.3 mmHg; p<0.05). In SHAM animals, antihypertensive treatment with amlodipine and olmesartan but not HCT or eplerenone significantly reduced MAP compared with SHAM-Ctrl (SHAM+amlodipine: -15.8±2.1 mmHg, p<0.001; SHAM+olmesartan: -17.1±3.0 mmHg, p<0.001; SHAM+HCT: -9.1±1.5 mmHg, p=0.36; SHAM+eplerenone: 1.4±1.0 mmHg, p=0.99). In combination with RDN, all antihypertensive drugs but eplerenone significantly lowered MAP compared with SHAM-Ctrl (RDN+amlodipine: -26.9±3.9 mmHg, p<0.0001; RDN+olmesartan -32.8±3.1 mmHg, p<0.0001; RDN+HCT: -20.5±2.7 mmHg, p<0.0001; RDN+eplereonone: -11.2±2.8 mmHg, p=0.12). RDN+olmesartan proved to be the most effective combination with RDN. RDN-Ctrl was associated with significantly reduced plasma renin activity (SHAM-Ctrl: 9.17±0.12ng/ml; RDN-Ctrl: 8.65±0.15ng/ml, p<0.05) and aldosterone (SHAM-Ctrl: 283.7±43.9 pg/ml; RDN-Ctrl: 133.2±16.3pg/ml, p<0.01) concentration compared with SHAM-Ctrl. In SHAM, treatment with amlodipine, olmesartan, and HCT inhibited perivascular fibrosis formation compared with SHAM-Ctrl (SHAM-Ctrl: -52.6±4.6%; SHAM-amlodipine: -34.5±3.0%, p<0.05; SHAM+olmesartan: -36±1.0%, p<0.05. SHAM-HCT: -29.9±4.7%; p<0.001), which was further amplified only in RDN+olmesartan (31.9±1.2%; p<0.05 vs SHAM-olmesartan). Left ventricular collagen content was significantly reduced in SHAM+olmesartan (SHAM-Ctrl: 6.5±0.9% vs SHAM-olmesartan: 2.8±0.1%, p<0.05). However, the combination of RDN with olmesartan had no additional effect. Conclusion: Antihypertensive drug therapy after RDN resulted in a further decrease in blood pressure, with olmesartan showing the most pronounced additive effect. The effects of RDN in the presence of commonly used antihypertensive drugs on the activity of the renin-angiotensin-aldosterone system and cardiac remodeling highly depends on the mechanism of action of the respective drug.
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