OBJECTIVE: Evaluation of the effect of endothelin type A (ET A ) receptor blockade on the course of volume-overload heart failure in rats with angiotensin II-dependent hypertension. METHODS: Ren-2 renin transgenic rats (TGR) were used as a model of hypertension. Heart failure was induced by creating an aorto-caval fistula (ACF). Selective ET A receptor blockade was achieved by atrasentan. For comparison, other rat groups received trandolapril, an angiotensin-converting enzyme inhibitor (ACEi). Animals first underwent ACF creation and 2 weeks later the treatment with atrasentan or trandolapril, alone or combined, was applied; the follow-up period was 20 weeks. RESULTS: Eighteen days after creating ACF, untreated TGR began to die, and none was alive by day 79. Both atrasentan and trandolapril treatment improved the survival rate, ultimately to 56% (18 of 31 animals) and 69% (22 of 32 animals), respectively. Combined ACEi and ET A receptor blockade improved the final survival rate to 52% (17 of 33 animals). The effects of the three treatment regimens on the survival rate did not significantly differ. All three treatment regimens suppressed the development of cardiac hypertrophy and lung congestion, decreased left ventricle (LV) end-diastolic volume and LV end-diastolic pressure, and improved LV systolic contractility in ACF TGR as compared with their untreated counterparts. CONCLUSION: The treatment with ET A receptor antagonist delays the onset of decompensation of volume-overload heart failure and improves the survival rate in hypertensive TGR with ACF-induced heart failure. However, the addition of ET A receptor blockade did not enhance the beneficial effects beyond those obtained with standard treatment with ACEi alone.

• MeSH
• angiotensin II MeSH
• atrasentan MeSH
• endotelin-1 MeSH
• endoteliny MeSH
• hypertenze * komplikace   farmakoterapie   MeSH
• inhibitory ACE farmakologie   MeSH
• krysa rodu Rattus MeSH
• píštěle * MeSH
• potkani transgenní MeSH
• receptor angiotensinu typ 1 MeSH
• receptor endotelinu A MeSH
• srdeční selhání * farmakoterapie   etiologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• angiotensin II MeSH
• atrasentan MeSH
• endotelin-1 MeSH
• endoteliny MeSH
• inhibitory ACE MeSH
• receptor angiotensinu typ 1 MeSH
• receptor endotelinu A MeSH

AIMS: Pulmonary hypertension (PH) represents an important phenotype among the broader spectrum of patients with heart failure with preserved ejection fraction (HFpEF), but its mechanistic basis remains unclear. We hypothesized that activation of endothelin and adrenomedullin, two counterregulatory pathways important in the pathophysiology of PH, would be greater in HFpEF patients with worsening PH, and would correlate with the severity of haemodynamic derangements and limitations in aerobic capacity and cardiopulmonary reserve. METHODS AND RESULTS: Plasma levels of C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM), central haemodynamics, echocardiography, and oxygen consumption (VO2) were measured at rest and during exercise in subjects with invasively-verified HFpEF (n = 38) and controls free of HF (n = 20) as part of a prospective study. Plasma levels of CT-proET-1 and MR-proADM were highly correlated with one another (r = 0.89, P < 0.0001), and compared to controls, subjects with HFpEF displayed higher levels of each neurohormone at rest and during exercise. C-terminal pro-endothelin-1 and MR-proADM levels were strongly correlated with mean pulmonary artery (PA) pressure (r = 0.73 and 0.65, both P < 0.0001) and pulmonary capillary wedge pressure (r = 0.67 and r = 0.62, both P < 0.0001) and inversely correlated with PA compliance (r = -0.52 and -0.43, both P < 0.001). As compared to controls, subjects with HFpEF displayed right ventricular (RV) reserve limitation, evidenced by less increases in RV s' and e' tissue velocities, during exercise. Baseline CT-proET-1 and MR-proADM levels were correlated with worse RV diastolic reserve (ΔRV e', r = -0.59 and -0.67, both P < 0.001), reduced cardiac output responses to exercise (r = -0.59 and -0.61, both P < 0.0001), and more severely impaired peak VO2 (r = -0.60 and -0.67, both P < 0.0001). CONCLUSION: Subjects with HFpEF display activation of the endothelin and adrenomedullin neurohormonal pathways, the magnitude of which is associated with pulmonary haemodynamic derangements, limitations in RV functional reserve, reduced cardiac output, and more profoundly impaired exercise capacity in HFpEF. Further study is required to evaluate for causal relationships and determine if therapies targeting these counterregulatory pathways can improve outcomes in patients with the HFpEF-PH phenotype. CLINICAL TRIAL REGISTRATION: NCT01418248; https://clinicaltrials.gov/ct2/results? term=NCT01418248&Search=Search.

• Klíčová slova
• Biomarker, Exercise, Heart failure, Pulmonary circulation,
• MeSH
• arteria pulmonalis fyziologie   MeSH
• arteriální tlak fyziologie   MeSH
• atriální natriuretický faktor krev   MeSH
• cvičení fyziologie   MeSH
• echokardiografie metody   MeSH
• endotelin-1 krev   MeSH
• hemodynamika fyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• peptidové fragmenty krev   MeSH
• plicní hypertenze etiologie   metabolismus   patofyziologie   MeSH
• prospektivní studie MeSH
• průřezové studie MeSH
• senioři MeSH
• spotřeba kyslíku fyziologie   MeSH
• srdeční selhání komplikace   patofyziologie   MeSH
• studie případů a kontrol MeSH
• tepový objem fyziologie   MeSH
• tolerance zátěže fyziologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• atriální natriuretický faktor MeSH
• C-terminal proendothelin-1 MeSH Prohlížeč
• endotelin-1 MeSH
• midregional pro-atrial natriuretic peptide, human MeSH Prohlížeč
• peptidové fragmenty MeSH