Robert A Rose

Dalhousie University, Halifax, Nova Scotia, Canada

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Publications (39)204.9 Total impact

  • Motahareh Moghtadaei · Iuliia Polina · Robert A Rose
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    ABSTRACT: Natriuretic peptides (NPs) are a family of cardioprotective hormones with numerous beneficial effects in cardiovascular system. The NP family includes several peptides including atrial NP (ANP), B-type NP (BNP), C-type NP (CNP) and Dendroaspis NS (DNP). These peptides elicit their effects by binding to three distinct cell surface receptors called natriuretic peptide receptors A, B and C (NPR-A, NPR-B and NPR-C). NPR-A (which binds ANP, BNP and DNP) and NPR-B (which is selective for CNP) are particulate guanylyl cyclase (GC)-linked receptors that mediate increases in cGMP upon activation. cGMP can then target several downstream signaling molecules including protein kinase G (PKG), phosphodiesterase 2 (PDE2) and phosphodiesterase 3 (PDE3). NPR-C, which is able to bind all NPs with comparable affinity, is coupled to the activation of inhibitory G-proteins (Gi) that inhibit adenylyl cyclase (AC) activity and reduce cAMP levels. NPs are best known for their ability to regulate blood volume and fluid homeostasis. More recently, however, it has become apparent that NPs are essential regulators of cardiac electrophysiology and arrhythmogenesis. Evidence for this comes from numerous studies of the effects of NPs on cardiac electrophysiology and ion channel function in different regions and cell types within the heart, as well as the identification of mutations in the NP system that cause atrial fibrillation in humans. Despite the strong evidence that NPs regulate cardiac electrophysiology different studies have reported varying effects of NPs. The reasons for disparate observations are not fully understood, but likely occur as a result of several factors, including the fact that NP signaling can be highly complex and involve multiple receptors and/or downstream signaling molecules which may be differentially activated in different conditions. The goal of this review is to provide a comprehensive summary of the different effects of NPs on cardiac electrophysiology that have been described and to provide rationale and explanation for why different results may be obtained in different studies.
    No preview · Article · Dec 2015 · Progress in Biophysics and Molecular Biology
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    ABSTRACT: -Atrial natriuretic peptide (ANP) is a hormone with numerous beneficial cardiovascular effects. Recently, a mutation in the atrial natriuretic peptide (ANP) gene, which results in the generation of a mutant form of ANP (mANP), was identified and shown to cause atrial fibrillation (AF) in people. The mechanism(s) through which mANP causes AF are unknown. Our objective was to compare the effects of wildtype ANP and mANP on atrial electrophysiology in mice and humans. -Action potentials (APs), L-type Ca(2+) currents (ICa,L) and Na(+) current (INa) were recorded in atrial myocytes from wildtype or natriuretic peptide receptor C knockout (NPR-C(-/-)) mice. In mice ANP and mANP (10 - 100 nM) had opposing effects on atrial myocyte action potential (AP) morphology and ICa,L. ANP increased AP upstroke velocity (Vmax), AP duration, and ICa,L similarly in wildtype and NPR-C(-/-) myocytes. In contrast mANP decreased Vmax, AP duration and ICa,L and these effects were completely absent in NPR-C(-/-) myocytes. ANP and mANP also had opposing effects on ICa,L in human atrial myocytes. In contrast, neither ANP nor mANP had any effect on INa in mouse atrial myocytes. Optical mapping studies in mice demonstrate that ANP sped electrical conduction in the atria whereas mANP did the opposite and slowed atrial conduction. Atrial pacing in the presence of mANP induced arrhythmias in 62.5% of hearts while treatment with ANP completely prevented the occurrence of arrhythmias. -These findings provide mechanistic insight into how mANP causes AF and demonstrate that wildtype ANP is antiarrhythmic.
    No preview · Article · Jul 2015 · Circulation Arrhythmia and Electrophysiology
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    ABSTRACT: Cardiovascular autonomic neuropathy (CAN) is a serious complication of diabetes mellitus that impairs autonomic regulation of heart rate (HR). This has been attributed to damage to the nerves that modulate spontaneous pacemaker activity in the sinoatrial node (SAN). Our objective was to test the hypothesis that impaired parasympathetic regulation of HR in diabetes is due to reduced responsiveness of the SAN to parasympathetic agonists. We used the Akita mouse model of type 1 diabetes to study the effects of the parasympathetic agonist carbachol (CCh) on SAN function using intracardiac programmed stimulation, high resolution optical mapping and patch-clamping of SAN myocytes. CCh decreased HR by 30% and increased corrected SAN recovery time (cSNRT) by 123% in wildtype mice. In contrast, CCh only decreased HR by 12%, and only increased cSNRT by 37% in Akita mice. These alterations were due to smaller effects of CCh on SAN electrical conduction and spontaneous action potential firing in isolated SAN myocytes. Voltage clamp experiments demonstrate that the acetylcholine-activated K(+) current (IKACh) is reduced in Akita SAN myocytes due to enhanced desensitization and faster deactivation kinetics. These IKACh alterations were normalized by treating Akita SAN myocytes with PI(3,4,5)P3 or an inhibitor of regulator of G-protein signaling 4 (RGS4). There was no difference in the effects of CCh on the hyperpolarization-activated current (If) between wildtype and Akita mice. Our study demonstrates that Akita diabetic mice demonstrate impaired parasympathetic regulation of HR and SAN function due to reduced responses of the SAN to parasympathetic agonists. Our experiments demonstrate a key role for insulin-dependent phosphoinositide 3-kinase (PI3K) signaling in the parasympathetic dysfunction seen in the SAN in diabetes. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Mar 2015 · Journal of Molecular and Cellular Cardiology
  • Hailey J. Jansen · Robert A. Rose
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    ABSTRACT: The mammalian heart contains numerous cell types with cardiac fibroblasts accounting for the majority of cells. These fibroblasts play essential roles in the heart including the synthesis and remodeling of the extracellular matrix (ECM), which is the component of the heart that includes interstitial collagens. In the setting of heart disease, including heart failure (HF), abnormal fibroblast proliferation and deposition of collagens leads to adverse structural remodeling, which is a major contributing factor to the progression of heart disease. Structural remodeling of the ECM in HF can increase stiffness of the myocardium leading to impaired cardiac performance and also increase the occurrence of cardiac arrhythmias due to impaired electrical conduction. Natriuretic peptides (NPs) are a family of cardioprotective hormones with numerous effects in the cardiovascular system. Included among these is the ability to prevent fibroblast proliferation and abnormal collagen deposition in the ECM. Nps elicit their effects by binding to three NP receptors denoted NPR-A, NPR-B and NPR-C. Npr-A and NPR-B are guanylyl cyclase-linked NPRs that elicit their effects by increasing cGMP levels. Npr-C is linked to the activation of inhibitory G-proteins (Gi). All three NPRs are expressed in cardiac fibroblasts and each has been shown to play a role in the ability of NPs to protect against adverse structural remodeling in the heart. The purpose of this chapter is to provide an overview of NPs and how they affect remodeling of the ECM in HF.
    No preview · Article · Jan 2015
  • Robert A. Rose · Peter H. Backx

    No preview · Chapter · Dec 2014
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    ABSTRACT: Natriuretic peptides (NPs) are critical regulators of the cardiovascular system that are currently viewed as possible therapeutic targets for the treatment of heart disease. Recent work demonstrates potent NP effects on cardiac electrophysiology, including in the sinoatrial node (SAN) and atria. NPs elicit their effects via three NP receptors (NPR-A, NPR-B and NPR-C). Amongst these receptors, NPR-C is poorly understood. Accordingly, the goal of this study was to determine the effects of NPR-C ablation on cardiac structure and arrhythmogenesis. Cardiac structure and function were assessed in wildtype (NPR-C+/+) and NPR-C knockout (NPR-C−/−) mice using echocardiography, intracardiac programmed stimulation, patch-clamping, high resolution optical mapping, quantitative PCR and histology. These studies demonstrate that NPR-C−/− mice display SAN dysfunction, as indicated by a prolongation (30%) of corrected sinoatrial node recovery time, as well as an increased susceptibility to atrial fibrillation (6% in NPR-C+/+ vs. 47% in NPR-C−/−). There were no differences in SAN or atrial action potential morphology in NPR-C−/− mice; however, increased atrial arrhythmogenesis in NPR-C−/− mice was associated with reductions in SAN (20%) and atrial (15%) conduction velocity, as well as increases in expression and deposition of collagen in the atrial myocardium. No differences were seen in ventricular arrhythmogenesis or fibrosis in NPR-C−/− mice. This study demonstrates that loss of NPR-C results in SAN dysfunction and increased susceptibility to atrial arrhythmias in association with structural remodeling and fibrosis in the atrial myocardium. These findings indicate a critical protective role for NPR-C in the heart.This article is protected by copyright. All rights reserved
    Full-text · Article · Dec 2014 · The Journal of Physiology
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    ABSTRACT: The changes that occur in the microbiome of aging individuals are unclear, especially in light of the imperfect correlation of frailty with age. Studies in older human subjects have reported subtle effects, but these results may be confounded by other variables that often change with age such as diet and place of residence. To test these associations in a more controlled model system, we examined the relationship between age, frailty, and the gut microbiome of female C57BL/6 J mice. The frailty index, which is based on the evaluation of 31 clinical signs of deterioration in mice, showed a near-perfect correlation with age. We observed a statistically significant relationship between age and the taxonomic composition of the corresponding microbiome. Consistent with previous human studies, the Rikenellaceae family, which includes the Alistipes genus, was the most significantly overrepresented taxon within middle-aged and older mice. The functional profile of the mouse gut microbiome also varied with host age and frailty. Bacterial-encoded functions that were underrepresented in older mice included cobalamin (B12) and biotin (B7) biosynthesis, and bacterial SOS genes associated with DNA repair. Conversely, creatine degradation, associated with muscle wasting, was overrepresented within the gut microbiomes of the older mice, as were bacterial-encoded β-glucuronidases, which can influence drug-induced epithelial cell toxicity. Older mice also showed an overabundance of monosaccharide utilization genes relative to di-, oligo-, and polysaccharide utilization genes, which may have a substantial impact on gut homeostasis. We have identified taxonomic and functional patterns that correlate with age and frailty in the mouse microbiome. Differences in functions related to host nutrition and drug pharmacology vary in an age-dependent manner, suggesting that the availability and timing of essential functions may differ significantly with age and frailty. Future work with larger cohorts of mice will aim to separate the effects of age and frailty, and other factors.
    Full-text · Article · Dec 2014
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    ABSTRACT: Previous studies have shown that ventricular myocytes from female rats have smaller contractions and Ca2+ transients than males. As cardiac contraction is regulated by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway, we hypothesized that sex differences in cAMP contribute to differences in Ca2+ handling. Ca2+ transients (fura-2) and ionic currents were measured simultaneously (37°C, 2Hz) in ventricular myocytes from adult male and female C57BL/6 mice. Under basal conditions, diastolic Ca2+, sarcoplasmic reticulum (SR) Ca2+ stores, and L-type Ca2+ current did not differ between the sexes. However, female myocytes had smaller Ca2+ transients (26% smaller), Ca2+ sparks (6% smaller), and excitation-contraction coupling gain in comparison to males (23% smaller). Interestingly, basal levels of intracellular cAMP were lower in female myocytes (0.7±0.1 vs. 1.7±0.2fmol/μg protein; p<0.001). Importantly, PKA inhibition (2μM H-89) eliminated male-female differences in Ca2+ transients and gain, as well as Ca2+ spark amplitude. Western blots showed that PKA inhibition also reduced the ratio of phospho:total RyR2 in male hearts, but not in female hearts. Stimulation of cAMP production with 10μM forskolin abolished sex differences in cAMP levels, as well as differences in Ca2+ transients, sparks, and gain. To determine if the breakdown of cAMP differed between the sexes, phosphodiesterase (PDE) mRNA levels were measured. PDE3 expression was similar in males and females, but PDE4B expression was higher in female ventricles. The inhibition of cAMP breakdown by PDE4 (10μM rolipram) abolished differences in Ca2+ transients and gain. These findings suggest that female myocytes have lower levels of basal cAMP due, in part, to higher expression of PDE4B. Lower cAMP levels in females may attenuate PKA phosphorylation of Ca2+ handling proteins in females, and may limit positive inotropic responses to stimulation of the cAMP/PKA pathway in female hearts.
    Full-text · Article · Jul 2014 · Journal of Molecular and Cellular Cardiology
  • John Azer · Rui Hua · Pooja S Krishnaswamy · Robert A Rose
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    ABSTRACT: Natriuretic peptides, including 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 ~30% 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 (ISO; 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 (~15% reduction) indicating that BNP and CNP activate multiple NPRs. In support of this, the inhibitory effects of BNP were absent in NPR-C knockout mice, where BNP instead elicited a further increase (~25%) in CV. Measurements in externally paced atrial preparations demonstrate that the effects of NPs 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.
    No preview · Article · Dec 2013 · The Journal of Physiology

  • No preview · Article · Oct 2013 · The Canadian journal of cardiology
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    ABSTRACT: We previously quantified frailty in aged mice with frailty index (FI) that used specialized equipment to measure health parameters. Here we developed a simplified, noninvasive method to quantify frailty through clinical assessment of C57BL/6J mice (5-28 months) and compared the relationship between FI scores and age in mice and humans. FIs calculated with the original performance-based eight-item FI increased from 0.06±0.01 at 5 months to 0.36±0.06 at 19 months and 0.38±0.04 at 28 months (n = 14). By contrast, the increase was graded with a 31-item clinical FI (0.02±0.005 at 5 months; 0.12±0.008 at 19 months; 0.33±0.02 at 28 months; n = 14). FI scores calculated from 70 self-report items from the first wave of the Survey of Health, Ageing and Retirement in Europe were plotted as function of age (n = 30,025 people). The exponential relationship between FI scores and age (normalized to 90% mortality) was similar in mice and humans for the clinical FI but not the eight-item FI. This noninvasive FI based on clinical measures can be used in longitudinal studies to quantify frailty in mice. Unlike the performance-based eight-item mouse FI, the clinical FI exhibits key features of the FI established for use in humans.
    Full-text · Article · Sep 2013 · The Journals of Gerontology Series A Biological Sciences and Medical Sciences
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    ABSTRACT: This study determined whether deficiency of ovarian estrogen starting very early in life promoted age-associated Ca(2+) dysregulation and contractile dysfunction in isolated ventricular myocytes. Myocytes were isolated from anesthetized C57BL/6 female mice. Animals received an ovariectomy or sham-operation at one month and were aged to ~24 months. Excitation-contraction coupling parameters were compared in fura-2 loaded myocytes (37°C). While Ca(2+) transients were larger and faster in field-stimulated myocytes from ovariectomized mice, ovariectomy had no effect on peak fractional shortening. Similarly, ovariectomy had no effect on fractional shortening measured in vivo by echocardiography (values were 60.5 ± 2.9 vs. 60.3 ± 2.5% in sham and ovariectomized, respectively; n=5 mice/group). Ovariectomy did decrease myofilament Ca(2+) sensitivity, as evidenced by a 26% increase in the Ca(2+) required to activate actomyosin MgATPase in ovariectomized hearts. Larger Ca(2+) transients were attributable to a 48% increase in peak Ca(2+) current, along with an increase in the amplitude, width and frequency of Ca(2+) sparks measured in fluo-4 loaded myocytes. These changes in Ca(2+) handling were not due to increased expression of Ca(2+) channels (Cav1.2), sarcoplasmic reticulum Ca(2+) ATPase (SERCA2) or Na(+)-Ca(2+) exchanger in ovariectomized hearts. However, ovariectomy increased sarcoplasmic reticulum Ca(2+) stores by ~90% and promoted spontaneous Ca(2+) release from the sarcoplasmic reticulum when compared to sham controls. These observations demonstrate that long-term ovariectomy promotes intracellular Ca(2+) dysregulation, reduces myofilament Ca(2+) sensitivity and increases spontaneous Ca(2+) release in the aging female heart.
    Full-text · Article · Sep 2013 · PLoS ONE
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    ABSTRACT: Aged hearts are particularly vulnerable to ischemia-reperfusion injury. Our objective was to determine if del Nido cardioplegia, which contains lidocaine, less blood, and less calcium than our standard cardioplegia, provides superior protection for aged hearts. We also sought to determine if the lidocaine in del Nido cardioplegia is adequate to prevent Na(+) influx via the window current. Sodium channel kinetics were measured in rat cardiomyocytes with and without lidocaine. Recovery after 60 minutes of cardioplegic arrest was assessed in isolated working senescent rat hearts. Del Nido cardioplegia was delivered as a single dose (n = 8) because it is used clinically, and standard cardioplegia was delivered as an induction dose with re-dosing every 20 minutes (n = 8). After 20 minutes of reperfusion, hearts were switched to working mode for 60 minutes. Flows were indexed to ventricular dry weight. Troponin release was assayed. Sodium channel kinetics indicated that the lidocaine concentration in del Nido cardioplegia minimizes the potential for Na+ influx via the window current. Spontaneous contractions occurred in fewer hearts arrested with del Nido cardioplegia (88% vs 13%; P = .01), and troponin release was reduced (0.24 vs 0.89 ng/mL; P = .017). Cardiac output was approximately 90% of baseline in the del Nido group compared with approximately 50% in the standard group (173 ± 14 vs 86 ± 22 mL · min(-1) · g(-1); P = .0008). Stroke work was higher in the del Nido group (93 ± 6 vs 41 ± 10 mL · mm Hg · g(-1); P = .0002). Del Nido cardioplegia prevents spontaneous contractions during arrest, reduces troponin release, and results in superior myocardial function in isolated aged hearts. Del Nido cardioplegia has the potential to provide superior myocardial protection for older patients undergoing cardiac surgery.
    No preview · Article · Aug 2013 · The Journal of thoracic and cardiovascular surgery
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    ABSTRACT: The mechanisms by which statins are beneficial are incompletely understood. While the lowering of low-density lipoprotein concentration is associated with regression of atherosclerosis, the observed benefit of statin therapy begins within months after its initiation, making regression an unlikely cause. Although LDL-C lowering is the main mechanism by which statin therapy reduces cardiovascular events, evidence suggests that at least some of the beneficial actions of statins may be mediated by their pleiotropic effects. Thus, statins may modulate the function of cardiovascular cells and key signalling proteins, including small G-proteins, to ultimately exert their pleiotropic effects. Sphingosine-1-phosphate (S1P) is a naturally occurring bioactive lysophospholipid that regulates diverse physiological functions in a variety of different organ systems. Within the cardiovascular system, S1P mediates cardioprotection following ischemia/reperfusion injury, anti-inflammatory response, improvement of endothelial function, increased mobilization and differentiation of endothelial progenitor cells, inhibition of oxidation, and anti-atherogenic and anti-thrombotic actions. Early evidence suggests that the pleiotropic effects of statins may be related to an increase in S1P signalling. This review focuses on S1P signalling as the potential mechanism underlying the pleiotropic effects of statins. An improved understanding of this mechanism may be vital for establishing the clinical relevance of statins and their importance in the treatment and prevention of coronary artery disease.
    Full-text · Article · May 2013 · Critical Reviews in Clinical Laboratory Sciences

  • No preview · Article · Oct 2012 · Circulation
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    ABSTRACT: Phosphodiesterases (PDEs) are critical regulators of cyclic nucleotides in the heart. In ventricular myocytes, the L-type Ca(2+) current (I(Ca,L)) is a major target of regulation by PDEs, particularly members of the PDE2, PDE3 and PDE4 families. Conversely, much less is known about the roles of PDE2, PDE3 and PDE4 in the regulation of action potential (AP) properties and I(Ca,L) in the sinoatrial node (SAN) and the atrial myocardium, especially in mice. Thus, the purpose of our study was to measure the effects of global PDE inhibition with Isobutyl-1-methylxanthine (IBMX) and selective inhibitors of PDE2, PDE3 and PDE4 on AP properties in isolated mouse SAN and right atrial myocytes. We also measured the effects of these inhibitors on I(Ca,L) in SAN and atrial myocytes in comparison to ventricular myocytes. Our data demonstrate that IBMX markedly increases spontaneous AP frequency in SAN myocytes and AP duration in atrial myocytes. Spontaneous AP firing in SAN myocytes was also increased by the PDE2 inhibitor erythro-9-[2-hydroxy-3-nonyl] adenine (EHNA), the PDE3 inhibitor milrinone (Mil) and the PDE4 inhibitor rolipram (Rol). In contrast, atrial AP duration was increased by EHNA and Rol, but not by Mil. IBMX also potently, and similarly, increased I(Ca,L) in SAN, atrial and ventricular myocytes; however, important differences emerged in terms of which inhibitors could modulate I(Ca,L) in each myocyte type. Consistent with our AP measurements, EHNA, Mil and Rol each increased I(Ca,L) in SAN myocytes. Also, EHNA and Rol, but not Mil, increased atrial I(Ca,L). In complete contrast, no selective PDE inhibitors increased I(Ca,L) in ventricular myocytes when given alone. Thus, our data show that the effects of selective PDE2, PDE3 and PDE4 inhibitors are distinct in the different regions of the myocardium indicating important differences in how each PDE family constitutively regulates ion channel function in the SAN, atrial and ventricular myocardium.
    Preview · Article · Oct 2012 · PLoS ONE
  • John Azer · Rui Hua · Kimberly Vella · Robert A Rose
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    ABSTRACT: Natriuretic peptides, including BNP and CNP, elicit their effects via two guanylyl cyclase-linked receptors denoted NPR-A and NPR-B as well as a third receptor, NPR-C. The relative contributions of these receptors to the overall effects of NPs on heart rate (HR) and sinoatrial node (SAN) function are very poorly understood. The effects of BNP and CNP (10-500nM) on HR and SAN myocyte spontaneous action potential (AP) firing were studied using wildtype mice and mice lacking functional NPR-C receptors (NPR-C(-/-)). In basal conditions and 10nM doses of the β-adrenergic receptor (β-AR) agonist isoproterenol (ISO) BNP and CNP increased HR and AP firing in SAN myocytes. The NPR-C selective agonist cANF (10-500nM) had no effects in basal conditions, but decreased HR and SAN AP frequency in the presence of ISO. These effects of cANF were completely absent in NPR-C(-/-) mice. Strikingly, in the presence of 1μM doses of ISO, BNP and CNP switched to causing decreases in HR and SAN AP frequency. These decreases were not as large as those elicited by cANF and were absent in NPR-C(-/-) hearts, where BNP instead elicited a further increase in HR. Inhibition of NPR-A with A71915, in the presence of 1μM ISO, enabled BNP to signal exclusively through NPR-C and to decrease HR as effectively as cANF. Together these data demonstrate that BNP and CNP affect HR and SAN function by activating multiple receptor subtypes. NPR-A/B mediate increases in HR and SAN function, but these effects are opposed by NPR-C, which plays an increasingly important signaling role in the presence of β-AR stimulation.
    No preview · Article · Aug 2012 · Journal of Molecular and Cellular Cardiology
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    ABSTRACT: 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.
    No preview · Article · Feb 2012 · Journal of Molecular and Cellular Cardiology
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    Robert A Rose

    Preview · Article · Nov 2011 · Experimental physiology
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    ABSTRACT: Rapid electrical conduction in the His-Purkinje system tightly controls spatiotemporal activation of the ventricles. Although recent work has shed much light on the regulation of early specification and morphogenesis of the His-Purkinje system, less is known about how transcriptional regulation establishes impulse conduction properties of the constituent cells. Here we show that Iroquois homeobox gene 3 (Irx3) is critical for efficient conduction in this specialized tissue by antithetically regulating two gap junction-forming connexins (Cxs). Loss of Irx3 resulted in disruption of the rapid coordinated spread of ventricular excitation, reduced levels of Cx40, and ectopic Cx43 expression in the proximal bundle branches. Irx3 directly represses Cx43 transcription and indirectly activates Cx40 transcription. Our results reveal a critical role for Irx3 in the precise regulation of intercellular gap junction coupling and impulse propagation in the heart.
    Full-text · Article · Aug 2011 · Proceedings of the National Academy of Sciences

Publication Stats

715 Citations
204.90 Total Impact Points

Institutions

  • 2010-2015
    • Dalhousie University
      • Department of Physiology and Biophysics
      Halifax, Nova Scotia, Canada
  • 2011
    • University Health Network
      • Department of Cardiology
      Toronto, Ontario, Canada
  • 2008-2011
    • University of Toronto
      • Department of Medicine
      Toronto, Ontario, Canada
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 2003-2007
    • The University of Calgary
      • Faculty of Medicine
      Calgary, Alberta, Canada