Carbon monoxide modulates electrical activity of murine myocardium via cGMP-dependent mechanisms

Abstract

Carbon monoxide (CO) is critical in cell signaling, and inhalation of gaseous CO can impact cardiovascular physiology. We have investigated electrophysiological effects of CO and their potential cGMP-dependent mechanism in isolated preparations of murine myocardium. The standard microelectrode technique was used to record myocardial action potentials (APs). Exogenous CO (0.96 × 10(-4)-4.8 × 10(-4) M) decreased AP duration in atrial and ventricular tissue and accelerated pacemaking activity in sinoatrial node. Inhibitors of heme oxygenases (zinc and tin protoporphyrin IX), which are responsible for endogenous CO production, induced the opposite effects. Inhibitor of soluble guanylate cyclase (sGC), ODQ (10(-5) M) halved CO-induced AP shortening, while sGC activator azosidnone (10(-5) M-3 × 10(-4) M) and cGMP analog BrcGMP (3 × 10(-4) M) induced the same effects as CO. To see if CO effects are attributed to differential regulation of phosphodiesterase 2 (PDE2) and 3 (PDE3), we used inhibitors of these enzymes. Milrinone (2 × 10(-6) M), selective inhibitor of cGMP-downregulated PDE3, blocked CO-induced rhythm acceleration. EHNA(2 × 10(-6) M), which inhibits cGMP-upregulated PDE2, attenuated CO-induced AP shortening, but failed to induce any positive chronotropic effect. Our findings indicate that PDE2 activity prevails in working myocardium, while PDE3 is more active in sinoatrial node. The results suggest that cardiac effects of CO are at least partly attributed to activation of sGC and subsequent elevation of cGMP intracellular content. In sinoatrial node, this leads to PDE3 inhibition, increased cAMP content, and positive chronotropy, while it also causes PDE2 stimulation in working myocardium, thereby enhancing cAMP degradation and producing AP shortening. Thus, CO induces significant alterations of cardiac electrical activity via cGMP-dependent mechanism and should be considered as a novel regulator of cardiac electrophysiology.

Evidence for a role of heme oxygenase-1 in the control of cardiac function in zebrafish (Danio rerio) larvae exposed to hypoxia

“…These results clearly indicate a tonic inhibitory role of the HO-1/CO system on cardiac frequency in developing zebrafish. These findings are in contrast to the positive chronotropic effects reported in mammals (Abramochkin, 2013;Abramochkin et al, 2015). Based on the present study, the inhibitory effects of CO do not appear to persist under hypoxic conditions because there was no further increase in f H when HO-1-deficient larvae were exposed to hypoxia.…”

“…Previous studies demonstrated that exogenous application of CO to mouse sinoatrial node preparations caused an accelerated sinus rhythm, demonstrating a direct effect of CO on f H (Abramochkin, 2013). A positive chronotropic effect of CO also was observed in the working myocardium of mouse, providing further evidence that CO is involved in controlling cardiac frequency (Abramochkin et al, 2015). The constitutively expressed form of HO, HO-2, also is present in interstitial cells of Cajal (ICC) which act as pacemaker cells in the gastrointestinal tracts of mammals (Farrugia and Szurszewski, 1999).…”

“…Because it is so readily diffusible across membranes, CO may act quickly in either an autocrine or paracrine manner to affect cells within the vicinity of the cell in which it was synthesized. CO readily binds to heme-containing proteins and, among them, soluble guanylyl cyclase is one of the most well studied and is essential for the vasodilatory effects of CO (Wilkinson and Kemp, 2011;Abramochkin et al, 2015). In fish, the HO-1/CO pathway plays a dilatory role in blood vessels via a CO-mediated increase in cGMP (Dombkowski et al, 2009).…”

Phosphodiesterases 3 and 4 Differentially Regulate the Funny Current, If, in Mouse Sinoatrial Node Myocytes

“…Meanwhile, a role for cGMP is suggested by the observation of high levels of soluble guanylyl cyclase and cGMP in the sinoatrial node [ 48 ]. Indeed, cGMP-mediated inhibition of PDE3 has been suggested to increase cAMP concentration and accelerate AP firing rate in mouse sinoatrial nodes [ 49 ]. cGMP-mediated inhibition of PDE3 has also been shown to modulate cAMP levels in subcellular compartments involved in βAR signaling in ventricular myocytes [ 50 ].…”

Effects of exogenous nicotinamide adenine dinucleotide (NAD+) in the rat heart are mediated by P2 purine receptors

“…P2Y stimulation leads to increase in NO production, following stimulation of sGC and rise of intracellular cGMP content. cGMP stimulates phosphodiesterase 2, which is one of the prevalent phosphodiesterase isoforms in working myocardium of rabbit [ 43 ] and mouse [ 44 ], and therefore reduces intracellular cAMP content. Decrease of cAMP level leads to attenuation of I CaL and subsequent AP shortening (see [ 45 ] for review).…”