The role of cGMP‐dependent nitric oxide signalling on cardiac repolarisation

Abstract

Recently, roles for nitric oxide (NO) signalling pathways have been linked with regulation of cardiac repolarisation and protection from arrhythmias. In this study, cGMP‐dependent regulation of repolarisation was investigated using BAY 60–2770, a novel NO and haem‐independent soluble guanylyl cyclase (sGC) activator. Action potentials (AP) were recorded from isolated guinea‐pig ventricular myocytes using the perforated‐patch clamp technique. Cellular cGMP was quantified by radioimmunoassay. 1 μM BAY 60–2770 increased cellular cGMP by 2.1 ± 0.2 (n=5) fold on its own, by 7.9 ± 0.7 (n=4) fold in the presence of 100 μM IBMX a non‐selective phosphodiesterase (PDE) inhibitor, and by 38.7 ± 0.2 (n=2) fold in the presence of ODQ (which strongly potentiates the action of BAY 60–2770 on sGC). Despite substantial increases in cellular cGMP, changes in AP duration were modest. BAY 60–2770 shortened AP duration from 223.3 ± 8.1 ms in basal conditions to 213.0 ± 7.4 ms (n=6, P<0.001) ms and ODQ + BAY 60–2770 caused no further shortening. Importantly, when cGMP hydrolysis was blocked by IBMX, BAY 60–2770 prolonged APs by 19.5 ± 5.6 ms (p < 0.01, n = 8). Overall, these findings demonstrate the complex interplay between cGMP and cAMP mediated effects on cardiac repolarisation. Our results further demonstrate that PDEs limit cGMP accumulation close to ion channels in the sarcolemma, thus compartmentalising cGMP signalling.KEB is supported by a British Heart Foundation Fellowship and REC by a University of Leicester PhD studentship