Efficacy of angiotensin receptor neprilysin inhibitor in Asian patients with refractory hypertension

Background Angiotensin receptor neprilysin inhibitor, concomitantly inhibits neprilysin and angiotensin type 1 receptor shown an effect of reducing blood pressure. We aimed to study whether it can be used as an antihypertensive agent in patients with resistant hypertension who has already been treated. Methods This is a multiple center prospective study. Thirty-five Chinese patients with refractory hypertension were enrolled. Resistant hypertension was defined as on the basis of improved lifestyle when the application of the three reasonable and tolerable dose of antihypertensive drugs including thiazide diuretics at least four weeks after treatment, the inadequate control of BP is confirmed by ambulatory BP monitoring, or at least four drugs are needed to achieve the BP standard. Refractory hypertensive patient received sacubitil/valsartan 200 mg instead of their angiotensin type 1 receptor blocker while other agents were continued. If blood pressure was uncontrolled, the sacubitil/valsartan dose was increased to 400 mg after 4 weeks. ABPM were evaluated at 8 weeks follow up. Results Reductions in office SBP/DBP at week 8 were 37/17 mmHg. the average baseline ABPM were 154/90 mmHg of 24-h, and daytime BP and nighttime BP were 157/92 mmHg and 145/83 mmHg respectively. he average endpoint ABPM were 134/80 mmHg of 24-h, and daytime BP and nighttime BP were 136/82 mmHg and 125/73 mmHg respectively. Reductions in 24-h ABPM at week 8 were 20/9 mmHg while 20/10 mmHg in daytime and 20/9 mmHg in nighttime. Conclusion The sacubitil/valsartan provided a strategy therapy for refractory hypertension in Chinese patients in reducing SBP and DBP. FUNDunding Acknowledgement Type of funding sources: None.

Relaxin attenuates organ fibrosis via an angiotensin-type 2 receptor mechanism in aged hypertensive female rats

Background: The anti-fibrotic effects of recombinant human relaxin (RLX) in the kidney are dependent on an interaction between its cognate receptor (RXFP1) and the angiotensin type 2 receptor (AT2R) in male models of disease. Whether RLX has therapeutic effects, which are also mediated via the AT2R, in hypertensive adult and aged/reproductively senescent females is unknown. Thus, we determined whether treatment with RLX provides cardiorenal protection, via an AT2R-dependent mechanism, in adult and aged female stroke prone-spontaneously hypertensive rats (SHRSP). Methods: In 6- (6MO) and 15-month-old (15MO; reproductively senescent) female SHRSP, systolic blood pressure (SBP), glomerular filtration rate (GFR) and proteinuria were measured before and after 4 weeks treatment with vehicle (Veh), RLX (0.5 mg/kg/day s.c.) or RLX+PD123319 (AT2R antagonist; 3 mg/kg/day s.c.). Aortic endothelium-dependent relaxation and fibrosis of the kidney, heart and aorta were assessed. Results: In 6MO SHRSP, RLX significantly enhanced GFR by ~25% (P=0.001) and reduced cardiac fibrosis (P=0.01) as compared to vehicle-treated counterparts. These effects were abolished or blunted by PD123319 co-administration. In 15MO females, RLX reduced interstitial renal (P=0.02) and aortic (P=0.003) fibrosis, and lowered SBP (13±3 mmHg; P=0.04) relative to controls. These effects were also blocked by PD123319 co-treatment (all p<0.05 versus RLX treatment alone). RLX also markedly improved vascular function by ~40% (P<0.0001) in 15MO SHRSP, but this was not modulated by PD123319 co-treatment. Conclusion: The anti-fibrotic and organ-protective effects of RLX, when administered to a severe model of hypertension, conferred cardiorenal protection in adult and reproductively senescent female rats, to a great extent via an AT2R-mediated mechanism.

Covid-19-induced pulmonary hypertension in children, and the use of phosphodiesterase-5 inhibitors

Respiratory tract infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first occurred in Wuhan, China, in December 2019 and was declared as a pandemic by WHO. The interaction between the 2019 coronavirus disease (COVID-19) and pulmonary hypertension (PH) in children is not widely known. Phosphodiesterase-5 inhibitors (PDEI), one class of drugs used to treat PH, including sildenafil, can suppress angiotensin type I (AT-1) receptor expression. Furthermore, it reduces proinflammatory cytokines and infiltrates the alveolar, inhibits endothelial and smooth muscle transition, mesenchymal cells in the pulmonary artery, and prevents clotting and thrombosis complications. Sildenafil has shown positive effects by diverting the blood flow to the lungs in such a way that ventilation is adequate and can also be anti-inflammatory.

In Aged Females, the Enhanced Pressor Response to Angiotensin II Is Attenuated By Estrogen Replacement via an Angiotensin Type 2 Receptor-Mediated Mechanism

Loss of ovarian hormones following menopause contributes to the rise in cardiovascular risk with age. Estrogen plays a protective role against hypertension and end-organ damage by modulating the depressor actions of the AT 2 R (angiotensin type 2 receptor). Our aim was to determine whether estrogen replacement in aged female mice can lower arterial pressure, improve endothelial function, and reduce organ fibrosis via an AT 2 R-mediated mechanism. Mean arterial pressure was measured via radiotelemetry in ovary-intact adult (3–4-month-old), aged (16–18-month-old; reproductively senescent) and aged–17β-estradiol (E 2 )–treated (3 µg/day SC) female mice, which were administered vehicle, Ang II (angiotensin II; 600 ng/[kg·min] SC) or Ang II+PD123319 (AT 2 R antagonist; 3 mg/[kg·day SC). On day 21 of treatment, aortic endothelium-dependent relaxation and cardiac and renal tissue (fibrosis and gene expression) were analyzed. Basal mean arterial pressure was lower in E 2 -treated aged mice (89±1 mm Hg, n=20) relative to aged controls (94±1 mm Hg; n=18, P =0.002). The Ang II pressor response was enhanced by ≈20 mm Hg in aged compared with adult females ( P =0.01). E 2 -treatment reduced the Ang II pressor response in aged females ( P =0.002), an effect that was reversed by PD123319 in the aged E 2 –Ang II group ( P =0.0009). E 2 -treatment increased renal AT 2 R (≈6-fold; P <0.0001) and MasR (Mas oncoreceptor; 2–3-fold, P <0.05) gene expression in aged females. However, neither Ang II–induced endothelial dysfunction nor the age-related increase in renal and cardiac fibrosis was restored by E 2 -treatment in aged female mice. In conclusion, estrogen replacement in aged females may reduce arterial pressure to levels observed in adult females, via an AT 2 R-mediated renal mechanism.