Dexmedetomidine and clonidine inhibit ventricular tachyarrhythmias in a rabbit model of acquired long QT syndrome.

BACKGROUND: Agents with α-2 adrenoreceptor (AR) agonistic action have reportedly suppressed tachyarrhythmias. METHODS AND RESULTS: We hypothesized that α-2 AR agonists would have an inhibitory effect on abnormal repolarization-related ventricular tachyarrhythmias (VTs). To test this hypothesis, the effects of 2 clinically available α-2 AR agonists (dexmedetomidine and clonidine) on the occurrence of VTs were assessed in a methoxamine-sensitized rabbit model of acquired long QT syndrome (Study 1: n=45). In control rabbits, administration of methoxamine and nifekalant almost invariably caused VTs (14/15). In contrast, incidence of VT significantly decreased during the treatment with dexmedetomidine (1µg·kg(-1)·min(-1): 5/12 [P<0.01 vs. control]) or with clonidine (33.3µg·kg(-1)·min(-1): 10/18 [P<0.01]). To verify that VTs in this animal model are triggered by early afterdepolarization (EAD), the monophasic action potential on the left ventricular surface was recorded in 28 open-chest rabbits (Study 2). EAD-like hump was less frequently detected during treatment with clonidine or dexmedetomidine (2/14) than in saline-treated rabbits (9/10, P<0.005). Presence of a hump was significantly related to the advent of VTs (P<0.05). CONCLUSIONS: Agents with α-2 AR agonistic action have an inhibitory effect on VTs in a rabbit model of long QT syndrome. Alpha-2 AR agonists, especially dexmedetomidine, may be a therapeutic choice for abnormal repolarization-related VTs that are resistant to conventional treatment.

Deep anesthesia suppresses ventricular tachyarrhythmias in rabbit model of the acquired long QT syndrome.

BACKGROUND: Anesthesia sometimes suppresses ventricular tachyarrhythmias (VT) resistant to conventional pharmacological treatment. METHODS AND RESULTS: To know (1) whether deep anesthesia inhibits abnormal repolarization-related VT and (2) if α2-adrenoreceptor (AR) agonistic action is associated with the antiarrhythmic effect of anesthetics, the incidence of VT in a rabbit model of acquired long QT syndrome using different anesthetic regimen was assessed. In Study 1 (n = 30), 15 rabbits were lightly anesthetized with ketamine (123 ± 46 mg/kg) and an α2-AR agonist, xylazine (9.4±3.0mg/kg), while combination of these anesthetics at high doses were used in the other 15 rabbits (343 ± 78 mg/kg and 38.9 ± 3.0 mg/kg). Administration of α1-AR stimulant, methoxamine and nifekalant (Ikr blocker) caused VT in all lightly anesthetized rabbits. In contrast, VT was observed only in 1 of the 15 deeply anesthetized rabbits (P < 0.01). In Study 2 (n = 15), 10 rabbits were anesthetized with high-dose ketamine and low-dose xylazine. In the other 5 rabbits, low-dose ketamine and high-dose xylazine were used. QTc interval in the latter was longer than that of the former (399 ± 56 ms vs. 494 ± 57 ms, P < 0.01). Although no VT appeared in high/low-rabbits, VT occurred in 3 out of 5 low/high-rabbits (P < 0.05). CONCLUSIONS: These results suggest that (1) deep anesthesia suppresses abnormal repolarization-related VT and (2) antiarrhythmic effect of anesthesia on this type of VT is not dependent on α2-AR agonistic action.

Human atrial natriuretic peptide suppresses torsades de pointes in rabbits.

BACKGROUND: The increase in inward current, primarily L-type Ca2+ current, facilitates torsades de pointes (TdP). Because human atrial natriuretic peptide (ANP) moderates the L-type Ca2+ current, in our study it was hypothesized that ANP counteracts TdP. METHODS AND RESULTS: We tested the effect of ANP, guanosine 3', 5'-cyclic monophosphate analogue (8-bromo cGMP) and hydralazine on the occurrence of TdP in a rabbit model. In control rabbits, administration of methoxamine and nifekalant almost invariably caused TdP (14/15). In contrast, ANP (10 microg . kg(-1) . min(-1)) markedly abolished TdP (2/15), whereas hydralazine failed to show a comparable anti-arrhythmic action (10/15). TdP occurred only in 1 of 15 rabbits treated with 8-bromo cGMP. Presence of early afterdepolarization-like hump in the ventricular monophasic action potential was associated with the occurrence of TdP. CONCLUSION: Results suggest that ANP affects TdP in the rabbit model, and that this anti-arrhythmic effect of ANP is not necessarily shared by other vasodilating agents.