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.
Aims/hypothesis Angiotensin II is well-recognised to be a key mediator in driving the pathological events of diabetesassociated atherosclerosis via signalling through its angiotensin II type 1 receptor (AT 1 R) subtype. However, its actions via the angiotensin II type 2 receptor (AT 2 R) subtype are still poorly understood. This study is the first to investigate the role of the novel selective AT 2 R agonist, Compound 21 (C21) in an experimental model of diabetes-associated atherosclerosis (DAA). Methods Streptozotocin-induced diabetic Apoe-knockout mice were treated with vehicle (0.1 mol/l citrate buffer), C21 (1 mg/kg per day), candesartan cilexetil (4 mg/kg per day) or C21 + candesartan cilexetil over a 20 week period. In vitro models of DAA using human aortic endothelial cells and monocyte cultures treated with C21 were also performed. At the end of the experiments, assessment of plaque content and markers of oxidative stress, inflammation and fibrosis were conducted.Results C21 treatment significantly attenuated aortic plaque deposition in a mouse model of DAA in vivo, in association with a decreased infiltration of macrophages and mediators of inflammation, oxidative stress and fibrosis. On the other hand, combination therapy with C21 and candesartan (AT 1 R antagonist) appeared to have a limited additive effect in attenuating the pathology of DAA when compared with either treatment alone. Similarly, C21 was found to confer profound antiatherosclerotic actions at the in vitro level, particularly in the setting of hyperglycaemia. Strikingly, these atheroprotective actions of C21 were completely blocked by the AT 2 R antagonist PD123319. Conclusions/interpretation Taken together, these findings provide novel mechanistic and potential therapeutic insights into C21 as a monotherapy agent against DAA.
Atrial fibrillation (AF) is prevalent in diabetes mellitus (DM); however, the basis for this is unknown. This study investigated AF susceptibility and atrial electrophysiology in type 1 diabetic Akita mice using in vivo intracardiac electrophysiology, high-resolution optical mapping in atrial preparations, and patch clamping in isolated atrial myocytes. qPCR and western blotting were used to assess ion channel expression. Akita mice were highly susceptible to AF in association with increased P-wave duration and slowed atrial conduction velocity. In a second model of type 1 DM, mice treated with streptozotocin (STZ) showed a similar increase in susceptibility to AF. Chronic insulin treatment reduced susceptibility and duration of AF and shortened P-wave duration in Akita mice. Atrial action potential (AP) morphology was altered in Akita mice due to a reduction in upstroke velocity and increases in AP duration. In Akita mice, atrial Na+current (INa) and repolarizing K+current (IK) carried by voltage gated K+(Kv1.5) channels were reduced. The reduction in INaoccurred in association with reduced expression ofSCN5aand voltage gated Na+(NaV1.5) channels as well as a shift in INaactivation kinetics. Insulin potently and selectively increased INain Akita mice without affecting IK. Chronic insulin treatment increased INain association with increased expression of NaV1.5. Acute insulin also increased INa, although to a smaller extent, due to enhanced insulin signaling via phosphatidylinositol 3,4,5-triphosphate (PIP3). Our study reveals a critical, selective role for insulin in regulating atrial INa, which impacts susceptibility to AF in type 1 DM.
Heart rate (HR) and sinoatrial node (SAN) function are modulated by the autonomic nervous system. HR regulation by the parasympathetic nervous system (PNS) is impaired in diabetes mellitus (DM), which is denoted cardiovascular autonomic neuropathy. Whether blunted PNS effects on HR in type 2 DM are related to impaired responsiveness of the SAN to PNS agonists is unknown. This was investigated in type 2 diabetic db/db mice in vivo and in isolated SAN myocytes. The PNS agonist carbachol (CCh) had a smaller inhibitory effect on HR, while HR recovery time after CCh removal was accelerated in db/db mice. In isolated SAN myocytes CCh reduced spontaneous action potential firing frequency but this effect was reduced in db/db mice due to blunted effects on diastolic depolarization slope and maximum diastolic potential. Impaired effects of CCh occurred due to enhanced desensitization of the acetylcholine-activated K+ current (IKACh) and faster IKACh deactivation. IKACh alterations were reversed by inhibition of regulator of G-protein signaling 4 (RGS4) and by the phospholipid PIP3. SAN expression of RGS4 was increased in db/db mice. Impaired PNS regulation of HR in db/db mice occurs due to reduced responsiveness of SAN myocytes to PNS agonists in association with enhanced RGS4 activity.
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