Cardiac electrophysiological effects of ibuprofen in dog and rabbit ventricular preparations: Possible implication to enhanced proarrhythmic risk

Ibuprofen is a widely used non-steroidal anti-inflammatory drug, which has recently been associated with increased cardiovascular risk, but its electrophysiological effects have not yet been properly studied in isolated cardiac preparations. We studied the effects of ibuprofen on action potential characteristics and several transmembrane ionic currents using the conventional microelectrode technique and the whole-cell configuration of the patch-clamp technique on cardiac preparations and enzymatically isolated ventricular myocytes. In dog (200 µM; n=6) and rabbit (100 µM; n=7) papillary muscles, ibuprofen moderately but significantly prolonged repolarization at 1 Hz stimulation frequency. In dog Purkinje fibers, repolarization was abbreviated, and maximal rate of depolarization was depressed in a frequency-dependent manner. Levofloxacin (40 µM) alone did not alter repolarization, but augmented the ibuprofen-evoked repolarization lengthening in rabbit preparations (n=7). In dog myocytes, ibuprofen (250 µM) did not significantly influence IK1, but decreased the amplitude of Ito and IKr potassium currents by 28.2% (60 mV) and 15.2% (20 mV) respectively. Ibuprofen also depressed INaL and ICa currents by 19.9% and 16.4%. We conclude that ibuprofen seems to be free from effects on AP parameters at lower concentrations. However, at higher concentrations it may alter repolarization reserve, contributing to the observed proarrhythmic risk in patients.

Enhanced in vivo and in vitro contractile responses to β2-adrenergic receptor stimulation in dogs susceptible to lethal arrhythmias

The response to β-adrenergic receptor (β-AR) stimulation was evaluated in both isolated cardiomyocytes (video edge detection) and the intact animal (echocardiography) in dogs either susceptible (S) or resistant (R) to ventricular fibrillation induced by a 2-min coronary occlusion during the last minute of exercise. In the intact animal, velocity of circumferential fiber shortening (Vcf) was evaluated both before ( n = 27, S = 12 and R = 15) and after myocardial infarction. Before infarction, increasing doses of isoproterenol provoked similar contractile and heart rate responses in each group of dogs. Either β1-AR (bisoprolol) or β2-AR (ICI-118551) antagonists reduced the isoproterenol response, with a larger reduction noted after the β1-AR blockade. In contrast, after infarction, isoproterenol induced a significantly larger Vcf and heart rate response in the susceptible animals that was eliminated by β2-AR blockade. The single-cell isotonic shortening response to isoproterenol (100 nM) was also larger in cells obtained from susceptible compared with resistant dogs and was reduced to a greater extent by β2-AR blockade in the susceptible dog myocytes (S, −48%, n= 6; R, −15%, n = 9). When considered together, these data suggest that myocardial infarction provoked an enhanced β2-AR response in susceptible, but not resistant, animals.

Excitation–contraction coupling in isolated adult ventricular myocytes from the rat, dog, and rabbit: effects of various inotropic interventions in the presence of ryanodine

Enzymatically isolated ventricular cells from rats, dogs, and rabbits were electrically stimulated and their membrane potentials were recorded simultaneously with their contractions. Specific pharmacological interventions were used to assess the relative roles of transsarcolemmal Ca2+ entry and the Ca2+ release by the sarcoplasmic reticulum in activating contractions, in these myocytes. We used ryanodine and caffeine to influence Ca2+ release by the sarcoplasmic reticulum, BAY K 8644 and epinephrine to increase Ca2+ entry through Ca2+ channels, and veratridine, ouabain, and monensin to increase Ca2+ entry through Na+–Ca2+ exchange. Ryanodine (1 μM) completely inhibited the shortenings in rat and dog myocytes, but the contractions in rabbit myocytes were much less sensitive to this alkaloid. Similar inhibitory effects of ryanodine were observed in the presence of various inotropic agents with two exceptions: caffeine's effect on the dog myocytes was relatively insensitive to ryanodine and the long-lasting tonic contractions that veratridine triggered in the myocytes of all three species remained completely unaffected by ryanodine. The data indicate that contractile activation in rat and dog ventricular cells is strongly dependent on Ca2+ release from the sarcoplasmic reticulum, while contractility in rabbit myocytes seems to be more dependent on Ca2+ entry through the sarcolemma. The ryanodine-resistant tonic contractions triggered in the myocytes of all three species in the presence of veratridine may be activated by an increased Ca2+ entry via Na+–Ca2+ exchange.