Felodipine protects human atrial muscle from hypoxia–reoxygenation dysfunction: a force–frequency relationship study in an in vitro model of stunning

Aims: We aimed at investigating contractile changes after hypoxia–reoxygenation and dobutamine challenge in superfused human atrial pectinate muscle to see whether high versus low stimulation rate during hypoxia might account for outcome differences compatible with the definition of an in vitro model of myocardial stunning and whether pretreatment with the dihydropyridine Ca2+ entry blocker felodipine might afford protection. Methods: Human right atrial trabeculae obtained from adult patients were superfused in an organ bath with oxygenated (O2 content 16 ml/l) and modified (NaHCO3 25.7 mmol/l) Tyrodeʹs solution at 37°C. Dobutamine (1 nmol/l to 10 μmol/l) was superfused in 10 oxygenated preparations to select the optimal drug concentration to be used in another 22 which were randomized. Group (A) consisted of time-related controls (Tyrodesʹs solution for 225 min at cycle length (CL) 1600 ms and no dobutamine). There were two test groups, respectively: (B) low (1600 ms CL) and (C) high (400 ms CL) stimulation rate. After 60 min of stabilization, in groups B and C, hypoxic superfusion (O2 content 5 ml/l) lasted 60 min, then reoxygenation (60 min) and dobutamine challenge (1 μmol/l, 15 min) were performed. Analysis of variance for repeated measures with the Greenhouse–Geisser correction, and a repeated measures model with structured covariance (preparation mass, length, width and time-varying time to peak tension) matrices were used whereby grouping (G), time (T) and G•T interaction were weighted. Force–frequency relationship and post-pausal potentiation were studied after each phase. Electrophysiology, histomorphometry and electron microscopy were carried out (n=6). Felodipine (0.1 μmol/l, n=5) pretreatment (15 min before hypoxia) was given in parallel experiments. Results: Time-related controls showed 10% per hour decrease of developed tension and the Paradise test provided 80% of control values. In test groups (as compared to baseline values) contractility was decreased 65% after hypoxia–reoxygenation and it increased 25% after dobutamine (G, 0.0155