Effects of phosphodiesterase type 5 inhibition on intracellular calcium handling and its implications for cardioprotection and antiarrhythmogenesis

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Phosphodiesterase type 5A inhibition with sildenafil improves cardiac function in heart failure. In addition, sildenafil in animal models of myocardial infarction has direct cardioprotective and antiarrhythmic effects. Sildenafil reduces L-type calcium current (Ica-L) and attenuates adrenergically driven inotropism, but effects on calcium handling are largely undetermined. Isolated adult rat ventricular myocytes were voltage clamped and calcium fluorescence measured with the indicator fura-2. Cells were paced at 0·5 Hz with depolarisations from −60 mV to +10 mV. Sarcoplasmic reticulum (SR) content was determined by application of caffeine (10–20 mmol/L) and integration of inward sodium-calcium exchanger current. Rate constants for calcium extrusion from the cell (Kcaff) and calcium uptake into the SR (KSERCA) were determined by fitting first order exponentials to decay phases of the respective calcium transients. Following the initial control protocol, a therapeutically relevant dose of sidenafil (1 μM) was applied. Differences were determined with student's paired t tests. Sildenafil reduced SR content by 26·5% (n=9, p<0·01). To a lesser extent, sildenafil also reduced calcium transient amplitude (by −13·6%, n=9, p<0·05); this was not accompanied by a reduction in KSERCA (–2.3% with sildenafil, p=0·97, n=5). Peak and integrated Ica-L were also reduced with sildenafil (–9·1% and −6·0%, respectively, n=9, p<0·05). The effect on Ica-L was also seen in adult dog ventricular myocytes (reducing peak and integrated Ica-L by 15·9% and 26·4%, respectively, p<0·05 and p<0·01, n=6, 23°C). These effects cannot be attributed to run-down effects. Sildenafil substantially reduced SR content with no reduction in KSERCA, and thus may be mediated through ryanodine receptor modulation. Such reduction in SR load may reduce proarrhythmic SR calcium release, indicating a novel mechanism through which sildenafil exerts an antiarrhythmic effect. Acute reductions in calcium transient amplitude and Ica-L with sildenafil indicate acute negative inotropic effects and may contribute to our understanding of its cardioprotective effects in the setting of hyperadrenergic drive in heart failure.
Original languageEnglish
Number of pages1
JournalThe Lancet
Issue numberSpecial issue S53
Publication statusPublished - 27 Feb 2013


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