DUAL AT1 RECEPTOR/NEPRILYSIN INHIBITION ('ARNI') IN HYPERTENSION: AN IMPROVEMENT VERSUS AT1 RECEPTOR BLOCKADE?
A.H. Jan Danser, M.D., Erasmus Medical Center, Rotterdam, The Netherlands
Neprilysin inhibitors (NEPi) prevent natriuretic peptide breakdown, thereby promoting vasodilation and natriuresis. On the other hand, they increase angiotensin and endothelin-1 (ET-1). The combined NEP/ACE inhibitor omapatrilat displayed potent effects in hypertension and heart failure, but these were accompanied by the occurrence of angioedema due to bradykinin accumulation. This should not occur when combining an ARB with a NEPi. This study evaluated the benefit of ARNI vs. ARB in renin-overexpressing hypertensive TGR(mREN2)27 rats. TGR(mREN2)27 rats were treated for three weeks with vehicle, the ARB irbesartan (IRB) or IRB + the NEPi thiorphan (0.1 and 1.0 mg per kg per day; TH0.1 and TH1.0). Hemodynamics were measured by telemetry. Vascular reactivity was determined in mesenteric arteries. Baseline MAP was 168+3 mmHg. All treatments lowered MAP by maximally 50 mmHg around day 4. After 7 days, MAP started to increase again in the IRB and IRB+TH1.0 groups, to 141+10 mmHg and 133+10 mmHg, respectively, on day 21. The MAP of rats treated with IRB+TH0.1 remained low at 104+5 mmHg on day 21. Heart-to-body weight ratio, cardiac ANP expression and myocyt size decreased only in the IRB+TH0.1 group. Urinary ET-1 increased by TH0.1 and TH1.0 versus IRB alone, indicating increased ET-1 production during ARNI treatment. Vasodilation to acetylcholine (endothelium-dependent) or the NO donor SNAP (endothelium-independent) were unaffected by all treatments. ET-1-induced constriction was diminished in the IRB+TH0.1 group, and studies with the ET-1 type B receptor (ETBR) antagonist BQ788 revealed that this was possibly due to an upregulation of ETBR. In conclusion, TH0.1 enhanced the blood pressure-lowering effects of irbesartan and diminished cardiac hypertrophy. Higher doses of thiorphan did not exert such effects, possibly because NEPi-induced ET-1 accumulation now counteracted its beneficial effects on natriuretic peptides. Upregulation of vasodilatory ETBR may have occurred to prevent the hypertensive effects of ET-1 accumulation.