The natriuretic peptides BNP and CNP increase heart rate and electrical conduction by stimulating ionic currents in the sinoatrial node and atrial myocardium following activation of guanylyl cyclase-linked natriuretic peptide receptors.
Natriuretic peptides (NPs) are best known for their ability to regulate blood vessel tone and kidney function whereas their electrophysiological effects on the heart are less clear. Here, we measured the effects of BNP and CNP on sinoatrial node (SAN) and atrial electrophysiology in isolated hearts as well as isolated SAN and right atrial myocytes from mice. BNP and CNP dose-dependently increased heart rate and conduction through the heart as indicated by reductions in R-R interval, P wave duration and P-R interval on ECGs. In conjunction with these ECG changes BNP and CNP (100 nM) increased spontaneous action potential frequency in isolated SAN myocytes by increasing L-type Ca(2+) current (I(Ca,L)) and the hyperpolarization-activated current (I(f)). BNP had no effect on right atrial myocyte APs in basal conditions; however, in the presence of isoproterenol (10nM), BNP increased atrial AP duration and I(Ca,L). Quantitative gene expression and immunocytochemistry data show that all three NP receptors (NPR-A, NPR-B and NPR-C) are expressed in the SAN and atrium. The effects of BNP and CNP on SAN and right atrial myocytes were maintained in mutant mice lacking functional NPR-C receptors and blocked by the NPR-A antagonist A71915 indicating that BNP and CNP function through their guanylyl cyclase-linked receptors. Our data also show that the effects of BNP and CNP are completely absent in the presence of the phosphodiesterase 3 inhibitor milrinone. Based on these data we conclude that NPs can increase heart rate and electrical conduction by activating the guanylyl cyclase-linked NPR-A and NPR-B receptors and inhibiting PDE3 activity.
Department of Physiology and Biophysics, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
Jeremy
J
Springer
John
J
Azer
Rui
R
Hua
Courtney
C
Robbins
Andrew
A
Adamczyk
Sarah
S
McBoyle
Mary Beth
MB
Bissell
Robert A
RA
Rose
D000200:Action Potentials; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D016275:Atrial Function; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D004553:Electric Conductivity; D006162:Guanylate Cyclase / Q000378:metabolism*; D006325:Heart Atria / Q000166:cytology; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020105:Milrinone / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D020097:Natriuretic Peptide, Brain / Q000494:pharmacology / Q000502:physiology*; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology; D017461:Receptors, Atrial Natriuretic Factor / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012849:Sinoatrial Node / Q000166:cytology / Q000502:physiology*; D013268:Stimulation, Chemical; D044005:Tetrahydroisoquinolines / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D010446:Peptide Fragments; D058987:Phosphodiesterase 3 Inhibitors; D044005:Tetrahydroisoquinolines; D020097:Natriuretic Peptide, Brain; D020098:Natriuretic Peptide, C-Type; C078792:A 71915; D009320:Atrial Natriuretic Factor; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C073616:atrial natriuretic factor receptor C; D020105:Milrinone; D007545:Isoproterenol