‐LCZ696, the First‐in‐Class Angiotensin Receptor Neprilysin Inhibitor, Improves Vascular Reactivity in Hypertensive Rats in the Setting of Heart Failure ‐
Authors: Trivedi Rishi K , Li Zhen , Polhemus David J , Yoo Daniel , Koiwaya Hiroshi , Goodchild Traci T , Lefer David J 
Published: November 2023

Background

LCZ696 combines an angiotensin receptor blocker (ARB) with a neprilysin inhibitor (NEPi). This inhibits RAAS over activity while simultaneously augmenting the natriuretic peptide system. LCZ696 has been shown to improve cardiovascular function in the setting of heart failure, however, its effects on vascular function have not been defined.

Methods

Male spontaneously hypertensive rats (SHRs) at 18–20 weeks of age were subjected to 45 minutes of transient LAD coronary artery ligation followed by reperfusion for 8 weeks to induce heart failure with reduced ejection fraction. At 4 weeks post‐reperfusion animals received daily oral therapy of either vehicle (VEH, n=14) or 68 mg/kg LCZ696 (LCZ, n=14). Myocardial infarct size as measured by plasma troponin levels at 4 hours post‐reperfusion were similar between the study groups. After 4 weeks of therapy, thoracic aorta was collected and evaluated for vascular reactivity in a tissue chamber apparatus connected to force transducers. Vasoreactivity was assessed for the endothelium‐dependent vasodilator acetylcholine (ACh, 0.1nM–10mM) and the direct smooth muscle vasodilator sodium nitroprusside (SNP, 0.1nM–10 mM). In addition, we also studied the vasoconstriction response to the endothelial nitric oxide synthase (eNOS) inhibitor N(omega)‐nitro‐L‐arginine methyl ester (L‐NAME, 30mM). Effects on heart function were also determined via 2‐D echocardiography and measurements of left ventricle (LV) pressures.

Results

LCZ improved LV function with a significant reduction in LV end‐diastolic pressure (3.31 ± 0.39 mmHg vs 7.86 ± 1.10mmHg; p<0.01). LCZ also attenuated the decrease in ejection fraction at 8 weeks post reperfusion (−6.1 ± 2.5% vs −14.3 ± 3.6%; p=0.06). LCZ treatment significantly improved vascular reactivity in the dose response relaxation curve for both ACh and SNP. There was a significant improvement in maximal relaxation in response to ACh (76.1 ± 3.6% vs 52.9 ± 3.6%; p<0.0001) as well as ACh EC50 (11.0 ± 4.0 nM vs 97.3 ± 9.8 nM, p<0.0001) suggesting augmented endothelium mediated vasorelaxation. Similar changes were seen in SNP maximal relaxation (90.9 ± 3.5% vs 69.1 ± 5.9%; p<0.01) and SNP EC50 (26.8 ± 4.4nM vs 125.7 ± 13.4nM, p<0.0001) suggesting improvements in vascular smooth muscle function. Lastly, there was an increased contraction in response to administration of L‐NAME following maximal relaxation by ACh suggesting the potential role of nitric oxide in the improvements seen in vascular reactivity (60 ± 6mg vs 40 ± 6mg, p=0.06).

Conclusion

LCZ696 significantly improved LV function during heart failure in the setting of hypertension with concomitant improvements in vascular reactivity. These improvements in vascular reactivity are likely a result of increased activity of eNOS and increased bioavailability of nitric oxide (NO). Studies are currently underway to evaluate eNOS function and NO levels following LCZ administration in heart failure.