Abstract
BackgroundIncreasing evidence indicates that the rapid component of delayed rectifier potassium current (IKr) is modulated by α- and β-adrenergic stimulation. However, the role and mechanism regulating IKr through β2-adrenoreceptor (β-AR) stimulation in heart failure (HF) are unclear.Methodology/Principal FindingsIn the present study, we investigated the effects of fenoterol, a highly selective β2-AR agonist, on IKr in left ventricular myocytes obtained from control and guinea pigs with HF induced by descending aortic banding. IKr was measured by using whole cell patch clamp technique. In control myocytes, superfusion of fenoterol (10 µM) caused a 17% decrease in IKr. In HF myocytes, the same concentration of fenoterol produced a significantly greater decrease (33%) in IKr. These effects were not modified by the incubation of myocytes with CGP-20712A, a β1-AR antagonist, but were abolished by pretreatment of myocytes with ICI-118551, a β2-AR antagonist. An inhibitory cAMP analog, Rp-cAMPS and PKA inhibitor significantly attenuated fenoterol-induced inhibition of IKr in HF myocytes. Moreover, fenoterol markedly prolonged action potential durations at 90% (APD90) repolarization in HF ventricular myocytes.ConclusionsThe results indicate that inhibition of IKr induced by β2-AR stimulation is increased in HF. The inhibitory effect is likely to be mediated through a cAMP/PKA pathway in HF ventricular myocytes.
Highlights
Heart failure (HF) is associated with significant mortality, with nearly 50% of deaths occurring suddenly, primarily from ventricular tachycardia to ventricular fibrillation [1]
The inhibitory effect is likely to be mediated through a cAMP/protein kinase A (PKA) pathway in heart failure (HF) ventricular myocytes
HF Reduces Ikr Tail Current Density Ikr tail currents of guinea pig left ventricular (LV) myocyte were completely abolished by the specific Ikr blocker, dofetilide (1 mm) (Figure 1A), indicating that Ikr tail currents were measured free of contamination by other currents under the given experimental conditions
Summary
Heart failure (HF) is associated with significant mortality, with nearly 50% of deaths occurring suddenly, primarily from ventricular tachycardia to ventricular fibrillation [1]. Stimulation of bAR by 10 mM isoprenaline decreased IKr tail currents in guinea pig ventricular myocytes [7]. Recent studies have revealed that IKr tail currents are enhanced by 100 nM isoprenaline in canine ventricular myocytes [11]. Experimental studies have demonstrated that canine ventricular response to b2-agonists is increased in tachypacing failure [12]. The present study was designed to examine the role and possible mechanisms of b2-AR activation in IKr in left ventricular (LV) myocytes from HF guinea pigs using the whole cell patch clamp technique. Increasing evidence indicates that the rapid component of delayed rectifier potassium current (IKr) is modulated by a- and b-adrenergic stimulation. The role and mechanism regulating IKr through b2-adrenoreceptor (b-AR) stimulation in heart failure (HF) are unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
