3.2 Cardiovascular system 
	3.2.1 In-vitro 
Tapentadol reduced the rapid component of the delayed rectifying potassium current (IKr) in CHO cells expressing the hERG channel only at very high concentrations (IC50 = 36 μM, corresponding to 7956 ng/mL) (SP21). The effect was reversible after washout. 
In isolated papillary muscles of rabbits, tapentadol significantly prolonged the action potential duration at 100 μM (22100 ng/mL) (SP70). Tapentadol at the concentrations tested neither exerted reverse-use dependence nor induced early after-depolarizations. The minor effect of tapentadol on action potential duration was in concordance with its low activity at hERG channels. In isolated guinea pig papillary muscles, tapentadol slightly shortened the action potential at concentrations of 10 μM (2210 ng/mL) and 100 μM. At 100 μM, a reduction of upstroke velocity was observed (SP122). 
The potential effects of tapentadol on the electrocardiogram (ECG) were assessed in-vitro in spontaneously beating guinea pig Langendorff heart preparations. At concentrations of 3 μM (663 ng/mL) and 30 μM (6630 ng/mL, the most prominent effect was a concentration-dependent bradycardia accompanied by slowing of atrioventricular conduction and ventricular depolarization. These effects were completely reversible following washout. QTc time was not affected ≤30 μM of tapentadol (SP154). 
Effects on inotropy and chronotropy were studied in guinea pig isolated atrial and papillary muscle preparations. At high cumulative concentrations of ≤1000 μM, tapentadol induced concentration-dependent negative chronotropic and inotropic effects. The effects were weak with IC50-values of about 400 μM, 88400 ng/mL) in the atrium (chronotropy) and 500 μM (110500 ng/mL) in the papillary muscle (inotropy) (PH379). 
In K+-depolarized rat aortic preparations, in which Na+-channels were blocked by lidocaine, tapentadol reduced isometric aortic contractions. This activity was weak with an IC50-value of 153 μM (33813 ng/mL) (SP220).