Cardiovascular Effects Of The KCNQ Channel Opener, Retigabine, In Conscious Rats

Laurice Fretwell, Julie March, Philip Kemp, Sheila Gardiner, Jeanette Woolard. Institute of Cell Signalling, University of Nottingham, Nottingham, NG7 2UH, UK.

Retigabine activates voltage-gated Kv7.2-7.5 (KCNQ2-5) channels, which are important regulators of membrane excitability (Mackie & Byron, 2008). Kv7.2-7.5 channels were initially regarded as neuronal, but more recently a role for these channels in the control of vascular smooth muscle has emerged (Ohya et al, 2003), although there are limited in vivo data. This study measured the regional haemodynamic responses to retigabine in conscious, freely moving rats under normotensive conditions and during acute hypertension induced by angiotensin (AII) and arginine vasopressin (AVP). A possible role for sympathoadrenal activation was explored using propranolol.

Male, Sprague-Dawley rats (350-450g) were anaesthetized (fentanyl and medetomidine, 300 µg/kg i.p. of each) and implanted with pulsed Doppler flow probes, and, at least 10 days later, intravascular catheters (jugular vein, distal abdominal aorta) to measure renal (R), mesenteric (M) and hindquarters (H) vascular conductances (VC). Experiments began 24h after catheterisation and ran over 3 days. On Day 1, responses to i.v. retigabine (1 and 5 mg/kg at least 60 min apart) or vehicle (saline, 0.1 mL,) were assessed 90 min after the onset of i.v. infusion (0.4 mL/h) of saline (control), propranolol (1 mg/kg; 0.5 mg/kg/h), or AII (0.1 μg/kg/h) plus AVP (0.01 μg/kg/h). No substances were given on Day 2. On Day 3, animals given retigabine on Day 1 were given vehicle, and vice versa. Some of the results are presented in Table 1.

Table 1: Changes in haemodynamic variables following administration of retigabine (5 mg/kg). Values are mean ± SEM. *P<0.05 vs. baseline (Friedman’s test).

Under control conditions resting cardiovascular variables (mean ± SEM) were:- HR 336 ± 6 beats/min, BP 100 ± 3 mmHg, RVC 76 ± 11, MVC 77 ± 8, HVC 44 ± 5 (kHz/mmHg)103, and retigabine triggered a dose-dependent fall in BP, and renal, mesenteric and hindquarters vasodilatations and a variable HR response (Table 1). In the presence of AII+AVP, resting cardiovascular variables were HR 324 ± 14 beats/min, BP 149 ± 3 mmHg, RVC 35 ± 3, MVC 33 ± 5, HVC 30 ± 4 (kHz/mmHg)103, and retigabine caused a larger drop in BP and the renal and mesenteric vasodilatations were augmented (P<0.05 for integrated (0-60 min) responses). In the presence of propranolol, retigabine consistently caused bradycardia and its vasodilator effects were reduced (P<0.05 for integrated (0-60 min) responses) suggesting a possible involvement of sympathoadrenal activation.

Mackie AR & Byron KL. (2008) Mol Pharmacol. 74:1171-9.

Ohya et al. (2003) Circ Res. 92:1016-1023.

Research supported by a University of Nottingham-funded Career Development Fellowship (LF).