RESUMEN
AIM: Sacubitril/valsartan (Sac/Val, LCZ696), the world's first angiotensin receptor-neprilysin inhibitor (ARNi), has been widely used in the treatment of heart failure. However, the use of Sac/Val in the treatment of atrial fibrillation (AF), especially AF with hypertension, has been less reported. We investigated the effect of Sac/Val on atrial remodeling and hypertension-related AF. METHODS: The AF induction rate and electrophysiological characteristics of spontaneously hypertensive rats (SHRs) treated with Sac/Val or Val were detected by rapid atrial pacing and electrical mapping/optical mapping. The whole-cell patch-clamp and Western blot were used to observe electrical/structural remodeling of atrial myocytes/tissue of rats and atrium-derived HL-1 cells cultured under 40 mmHg in vitro. RESULTS: Sac/Val was superior to Val in reducing blood pressure, myocardial hypertrophy and susceptibility of AF in SHRs. The shorten action potentials duration (APD), decreased L type calcium channel current (ICa,L) and Cav1.2, increased ultrarapid delayed rectified potassium current (Ikur) and Kv1.5 in atrial myocytes/tissue of SHRs could be better improved by Sac/Val, as well as the levels of atrial fibrosis. While the protein expression of angiotensin-converting enzyme-1 (ACE-1), angiotensin, angiotensin II type I AT1 receptor (AT1R) and neprilysin (NEP) were increased, which could be more effective ameliorated by Sac/Val than Val. Furthermore, Val + Sacubitrilat (LBQ657) (an active NEP inhibitor) was also superior to LBQ657 or Val in improving the electrical and structural remodeling of HL-1 cells through inhibiting NEP. CONCLUSION: Sac/Val can improve atrial structural and electrical remodeling induced by hypertension and reduce the AF susceptibility by inhibiting RAS and NEP. The above effects of Sac/Val were superior to Val alone.
Asunto(s)
Fibrilación Atrial , Remodelación Atrial , Hipertensión , Ratas , Animales , Fibrilación Atrial/tratamiento farmacológico , Ratas Endogámicas SHR , Neprilisina , Valsartán/farmacología , Valsartán/uso terapéutico , Compuestos de Bifenilo/farmacología , Compuestos de Bifenilo/uso terapéutico , Aminobutiratos/farmacología , Aminobutiratos/uso terapéutico , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Antihipertensivos/farmacología , Combinación de Medicamentos , Angiotensinas , Tetrazoles/farmacologíaRESUMEN
Thromboxane A2 (TXA2 ) has been implicated in the pathogenesis of vascular complications, but the underlying mechanism remains unclear. The contraction of renal arterial rings in mice was measured by a Multi Myograph System. The intracellular calcium concentration ([Ca2+ ]i ) in vascular smooth muscle cells (VSMCs) was obtained by using a fluo-4/AM dye and a confocal laser scanning microscopy. The results show that the U46619-induced vasoconstriction of renal artery was completely blocked by a TXA2 receptor antagonist GR32191, significantly inhibited by a selective phospholipase C (PI-PLC) inhibitor U73122 at 10 µmol/L and partially inhibited by a Phosphatidylcholine - specific phospholipase C (PC-PLC) inhibitor D609 at 50 µmol/L. Moreover, the U46619-induced vasoconstriction was inhibited by a general protein kinase C (PKC) inhibitor chelerythrine at 10 µmol/L, and a selective PKCδ inhibitor rottlerin at 10 µmol/L. In addition, the PKC-induced vasoconstriction was partially inhibited by a Rho-kinase inhibitor Y-27632 at 10 µmol/L and was further completely inhibited together with a putative IP3 receptor antagonist and store-operated Ca2+ (SOC) entry inhibitor 2-APB at 100 µmol/L. On the other hand, U46619-induced vasoconstriction was partially inhibited by L-type calcium channel (Cav1.2) inhibitor nifedipine at 1 µmol/L and 2-APB at 50 and 100 µmol/L. Last, U46619-induced vasoconstriction was partially inhibited by a cell membrane Ca2+ activated C1- channel blocker 5-Nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) at 50 and 100 µmol/L. Our results suggest that the U46619-induced contraction of mouse intrarenal arteries is mediated by Cav1.2 and SOC channel, through the activation of thromboxane-prostanoid receptors and its downstream signaling pathway.
Asunto(s)
Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Arterias/efectos de los fármacos , Arterias/fisiología , Vasoconstricción/efectos de los fármacos , Animales , Canales de Calcio/metabolismo , Canales de Cloruro/antagonistas & inhibidores , Riñón/irrigación sanguínea , Masculino , Ratones , Ratones Endogámicos C57BL , Fosfolipasas de Tipo C/metabolismo , Quinasas Asociadas a rho/metabolismoRESUMEN
BACKGROUND: The reproducibility of the measurement of mechanical dyssynchrony by echocardiography including Doppler tissue imaging has recently been questioned. The aim of this study was to ascertain the role of a dedicated training program to improve skills and the reproducibility of dyssynchrony assessment. METHODS: In 70 patients with heart failure, color Doppler tissue images were acquired, and the time to peak systolic velocity of each segment and several dyssynchrony indices, including the standard deviation of time to peak systolic velocity, were measured by an expert to constitute a reference standard. The same images were then assessed by two beginners, who had only basic knowledge of dyssynchrony analysis after a 1-hour lecture, and two graduates, who had received a structured hands-on training program. Both sets of results were compared with the standard. RESULTS: For the standard deviation of time to peak systolic velocity, the linear correlations between the standard and beginner 1 (r = 0.643) and beginner 2 (r = 0.532) were only modest (P < .001 for both). When referenced to the standard, interobserver variability was 18% for beginner 1 and 19% for beginner 2. Measurements with differences of ≥10 msec were found in 24% and 22% of cases by beginners 1 and 2, respectively. In contrast, the assessments made by graduates 1 and 2 were significantly improved. The correlation coefficients were 0.935 and 0.929 (P < .001 for both), and interobserver variability values were 8% and 7%. The prevalence rates of measurements with differences ≥ 10 msec were 1.5% and 3%, respectively. CONCLUSIONS: There is a learning curve for the measurement of systolic dyssynchrony using Doppler tissue imaging, but good reproducibility can be achieved by the use of a dedicated training program.