Purpose: We aimed to assess the effects of chronic ivabradine administration on the heart rate and blood pressure of in vivo rats and on in vitro sinus node discharge rate, both during acute parasympathetic stimulation.
Methods: Thirteen adult male Wistar rats were randomized into two groups: control (C; n=6) and treated with ivabradine (IVA; 10 mg/kg/day, for three consecutive weeks; n=7). The right vagus nerve was isolated in all rats. The intact vagus nerve was stimulated electrically at a frequency of 2, 5, 10, and 20 Hz (15 s each) with 5-min intervals between stimulations (pulse duration 0.5 ms; 20 V). The nerve was then sectioned and the distal end was stimulated using the same protocol. The heart rate and the systolic blood pressure were measured non-invasively at baseline and during each stimulation. The right atrium was then removed, placed in the Steiert organ bath, and the discharge rate of the sinus node was assessed in vitro at baseline and after applying carbamylcholine in progressively higher concentrations (10-9 to 10-6 mol/L).
Results: As expected, the two groups displayed similar baseline systolic blood pressure (p=0.95), but IVA rats presented significantly lower heart rates compared to the C rats (p=0.02). A significant, progressive decrease in systolic blood pressure was recorded during electrical stimulation of both the intact and the sectioned vagus nerves, in both the C and the IVA rats (all p<0.001). In the C rats, a significant, progressive decrease in heart rate was also recorded during electrical stimulation of both the intact and the sectioned vagus nerves (both p<0.0001). In the IVA rats, however, electrical stimulation of the intact or the sectioned vagus nerves had no effect on the heart rate (both p >0.05). A significant, progressive decrease in sinus node discharge rate was also observed in vitro, after applying progressively higher carbamylcholine concentrations, in both the C and the IVA rats (both p<0.001).
Conclusion: In rats, chronic If current blockade prevented the heart rate lowering effect of acute in vivo vagus nerve stimulation, without affecting the blood pressure response. Meanwhile, ivabradine administration had no effect on sinus node discharge rate lowering in response to direct acetylcholine receptors stimulation. These results suggest that the beneficial effects of ivabradine reported in patients with tachycardia-mediated VVS may also extend to patients with vagal hypersensitivity and excessive cardioinhibitory responses. Our data also suggest that this ‘protective’ ivabradine effect is likely to be related to an effect of ivabradine on ganglionic transmission and/or on postganglionic cholinergic fibers.