Species- and tissue-dependent effects of NO and cyclic GMP on cardiac ion channels

Abstract

Biochemical studies have established the presence of a NO pathway in the heart, including sources of NO and various effectors. Several cardiac ion channels have been shown to be modified by NO, such as L-type Ca2+, ATP-sensitive K+, and pacemaker f-channels. Some of these effects are mediated by cGMP, through the activity of three main proteins: the cGMP-dependent protein kinase (PKG), the cGMP-stimulated phosphodiesterase (PDE2) and the cGMP-inhibited PDE (PDE3). Other effects appear independent of cGMP, as for instance the NO modulation of the ryanodine receptor-Ca2+ channel. In the case of the cardiac L-type Ca2+ channel current (ICa,L), both cGMP-dependent and cGMP-independent effects have been reported, with important tissue and species specificity. For instance, in rabbit sinoatrial myocytes, NO inhibits the β-adrenergic stimulation of ICa,L through activation of PDE2. In cat and human atrial myocytes, NO potentiates the cAMP-dependent stimulation of ICa,L through inhibition of PDE3. In rabbit atrial myocytes, NO enhances ICa,L in a cAMP-independent manner through the activation of PKG. In ventricular myocytes, NO exerts opposite effects on ICa,L: an inhibition mediated by PKG in mammalian myocytes but by PDE2 in frog myocytes; a stimulation attributed to PDE3 inhibition in frog ventricular myocytes but to a direct effect of NO in ferret ventricular myocytes. Finally, NO can also regulate cardiac ion channels by a direct action on G-proteins and adenylyl cyclase.