Effects of natriuretic peptides on electrical conduction in the sinoatrial node and atrial myocardium of the heart

Abstract

Key pointsr Natriuretic peptides are powerful regulators of the cardiovascular system, but their direct electrophysiological effects in the heart are poorly understood.r We have used optical mapping techniques to determine the effects of B-type and C-type natriuretic peptide (BNP and CNP) as well as their receptors (NPR-A, NPR-B and NPR-C) on electrical conduction in the sinoatrial node and atrial myocardium.r In basal conditions, BNP and CNP speed conduction within the sinoatrial node (SAN) and into the atrial myocardium in association with shifts in the initial exit site by activating NPR-A and NPR-B.r In the presence of isoproterenol, BNP and CNP have the opposite effect whereby conduction in the SAN and atria is slowed. These inhibitory effects are due to the activation of NPR-C as well as NPR-A/B.r We conclude that natriuretic peptides have potent effects on electrical conduction in the heart. These effects are complex and can involve multiple natriuretic peptide receptors.Abstract Natriuretic peptides, including B-type and C-type natriuretic peptide (BNP and CNP), are powerful regulators of the cardiovascular system; however, their electrophysiological effects in the heart, particularly in the sinoatrial node (SAN), are incompletely understood. We have used high-resolution optical mapping to measure the effects of BNP and CNP, and the roles of natriuretic peptide receptors (NPR-A, NPR-B and NPR-C), on electrical conduction within the SAN and atrial myocardium. In basal conditions BNP and CNP (50-500 nM) increased conduction velocity (CV) within the SAN by ß30% at the high dose and shifted the initial exit site superiorly. These effects sped conduction from the SAN to the surrounding atrial myocardium and were mediated by the NPR-A and NPR-B receptors. In the presence of isoproterenol (1 μM) the NPR-C receptor made a major contribution to the effects of BNP and CNP in the heart. In these conditions BNP, CNP and the NPR-C agonist cANF each decreased SAN CV and shifted the initial exit site inferiorly. The effects of cANF (30% reduction) were larger than BNP or CNP (ß15% reduction), indicating that BNP and CNP activate multiple natriuretic peptide receptors. In support of this, the inhibitory effects of BNP were absent in NPR-C knockout mice, where BNP instead elicited a further increase (ß25%) in CV. Measurements in externally paced atrial preparations demonstrate that the effects of natriuretic peptides on CV are partially independent of changes in cycle length. These data provide detailed novel insight into the complex effects of natriuretic peptides and their receptors on electrical conduction in the heart.

Effects of Wild-Type and Mutant Forms of Atrial Natriuretic Peptide on Atrial Electrophysiology and Arrhythmogenesis

“…Representative activation maps are presented in control conditions, after application of isoproterenol (10 nmol/L) and following subsequent application of ANP or mANP in the presence of isoproterenol ( Figure 7A). These activation maps demonstrate that the first electric breakthrough occurs in the right atrial posterior wall, which corresponds to the location of the sinoatrial node, 17 and that conduction propagates from this site into the right and left atrial appendages. As expected, isoproterenol sped conduction time throughout the atrial preparation (fewer isochrones with more space between successive isochrones in the presence of isoproterenol).…”

“…These studies were performed in an isolated atrial preparation 17,34,35 ( Figure X in the Data Supplement) and used an intermediate dose of ANP (50 nmol/L) and mANP (50 nmol/L). Representative activation maps are presented in control conditions, after application of isoproterenol (10 nmol/L) and following subsequent application of ANP or mANP in the presence of isoproterenol ( Figure 7A).…”

“…To further quantify the effects of ANP and mANP (in the presence of isoproterenol) on electrical conduction, we measured local conduction velocity (CV) in the right and left atrial appendages using a previously described approach 17 (Methods). Initially, CV was measured in atrial preparations in sinus rhythm where the cycle length was free to change.…”

“…17,28,29 Optical mapping was done using the voltage sensitive dye di-4-ANEPPS (10 μmol/L) and blebbistatin (10 μmol/L) to suppress contractile activity. All analyses were performed using custom software.…”

“…13 We have also shown that wild-type NPs (BNP and CNP) can potently increase electrical conduction in the sinoatrial node and atrial myocardium. 17 Wild-type ANP is able to elicit its physiological effects by binding to 2 NP receptors (NPRs) called NPR-A and NPR-C. 10,18,19 NPR-A is a particulate guanylyl cyclase receptor. When bound to ANP, NPR-A increases guanylyl cyclase activity and the production of cyclic GMP, which can modulate several downstream signaling proteins, including protein kinase G and phosphodiesterases.…”