Endogenous nitric oxide signalling system and the cardiac muscarinic acetylcholine receptor‐inotropic response

Sterin‐Borda, Leonor; Echagüe, Agustina Vila; Leirós, Claudia Pérez; Genaro, Ana Marı́a; Borda, Enri

doi:10.1111/j.1476-5381.1995.tb16646.x

Cited by 61 publications

(53 citation statements)

References 30 publications

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“…The data presented here in eNOS null cardiac myocytes nevertheless support previous work using pharmacologic NOS inhibitors and͞or NO donors that implicate an important role for eNOS in mediating parasym- pathetic nervous system signaling in the heart (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). These data also support the contention that the effects of endogenously generated NO within cardiac myocytes are mediated by activation of guanylyl cyclase.…”

Section: Discussionsupporting

confidence: 88%

“…Recently, a number of studies have implicated an important role for nitric oxide (NO) generation in mediating some aspects of muscarinic cholinergic and adrenergic signaling, both in intact hearts and in isolated myocytes (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). NO, whether released by pharmacologic NO donors or generated by activation of endogenous NO synthases (NOS), has been shown to suppress the activation of voltage-sensitive Ca 2ϩ current (I Ca-L ) by ␤-adrenergic agonists (7)(8)(9)(10)(11)(12).…”

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confidence: 99%

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Muscarinic cholinergic regulation of cardiac myocyte I _Ca-L is absent in mice with targeted disruption of endothelial nitric oxide synthase

Han

Féron

Opel

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

135

121

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Cardiac myocytes have been shown to express constitutively endothelial nitric oxide synthase (eNOS) (nitric oxide synthase 3), the activation of which has been implicated in the regulation of myocyte L-type voltagesensitive calcium channel current (I Ca-L ) and myocyte contractile responsiveness to parasympathetic nervous system signaling, although this implication remains controversial. Therefore, we examined the effect of the muscarinic cholinergic agonist carbachol ( The regulation of the beating rate and force of contraction of the heart by the autonomic nervous system has been one of the most intensively studied aspects of cardiovascular pharmacology. Recently, a number of studies have implicated an important role for nitric oxide (NO) generation in mediating some aspects of muscarinic cholinergic and adrenergic signaling, both in intact hearts and in isolated myocytes (1-12). NO, whether released by pharmacologic NO donors or generated by activation of endogenous NO synthases (NOS), has been shown to suppress the activation of voltage-sensitive Ca 2ϩ current (I Ca-L ) by ␤-adrenergic agonists (7-12). Conversely, inhibition of NO generation within cardiac myocytes, including specialized pacemaker and conduction system cells, has been shown to blunt the negative inotropic and chronotropic effects of parasympathetic nerve stimulation in the mammalian heart in situ when infused with a ␤-adrenergic agonist (3-6).The enzyme responsible for the generation of NO within cardiac myocytes is the NOS originally described in endothelial cells (i.e., eNOS or NOS3). eNOS is a Ca 2ϩ -calmodulinactivated enzyme that is localized in both myocytes and endothelial cells to specialized plasmalemmal microdomains termed caveolae (15, 16). A principal target of eNOSgenerated NO is the soluble guanylyl cyclase (17-21). Indeed, agents that prevent cGMP generation have been shown to attenuate significantly the inhibitory effect of NO on I Ca-L (8)(9)(10)17).Nevertheless, the importance of endogenous NO generation in the regulation of cardiac I Ca-L , particularly in response to muscarinic cholinergic agonists, remains controversial (see refs. 16, 21, and 22 for reviews). In frog ventricular myocytes, for example, NOS inhibitors failed to modify cholinergic inhibition of I Ca-L (23). Inhibition of a cAMP-stimulated chloride current by cholinergic agonists in guinea pig ventricular myocytes also was unaffected by NOS inhibitors (24). This controversy prompted us to examine the control of I Ca-L by muscarinic cholinergic signaling in atrial and ventricular myocytes of mice with targeted disruption of eNOS (eNOS null ). We found that muscarinic cholinergic agonists significantly increased intracellular cGMP levels in wild-type (WT) but not eNOS null myocytes and that cholinergic inhibition of ␤-adrenergic agonist-stimulated I Ca-L and myocyte contractile amplitude both were impaired in myocytes lacking functional eNOS. METHODSCell Isolation. Calcium-tolerant ventricular and atrial myocytes were isolated from mice as described (2...

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Section: Discussionsupporting

confidence: 88%

mentioning

confidence: 99%

Muscarinic cholinergic regulation of cardiac myocyte I _Ca-L is absent in mice with targeted disruption of endothelial nitric oxide synthase

Han

Féron

Opel

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

135

121

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“…15 Alternative signal transduction pathways activating PKC in atrial cardiomyocytes exist via the parasympathetic/muscarinic system. 16 In this study, we investigated the regulation of IK 1 in isolated human cardiomyocytes and the regulation of a cloned inward rectifier potassium channel Kir 2.1b (hIRK) from human atrium by PKC. …”

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confidence: 99%

Human Cardiac Inwardly-Rectifying K ⁺ Channel Kir _2.1b Is Inhibited by Direct Protein Kinase C-Dependent Regulation in Human Isolated Cardiomyocytes and in an Expression System

et al. 2002

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Background-Protein kinases A (PKA) and C (PKC) are activated in ischemic preconditioning and heart failure, conditions in which patients develop arrhythmias. The native inward rectifier potassium current (IK 1 ) plays a central role in the stabilization of the resting membrane potential and the process of arrhythmogenesis. This study investigates the functional relationship between PKC and IK 1 . Methods and Results-In whole-cell patch-clamp experiments with isolated human atrial cardiomyocytes, the IK 1 was reduced by 41% when the nonspecific activator of PKC phorbol 12 myristate 13-acetate (PMA; 100 nmol/L) was applied. To investigate the effects of PKC on cloned channel underlying parts of the native IK 1 , we expressed Kir 2.1b heterologously in Xenopus oocytes and measured currents with the double-electrode voltage-clamp technique. PMA decreased the current by an average of 68%, with an IC 50 of 0.68 nmol/L. The inactive compound 4-␣-PMA was ineffective. Thymeleatoxin and 1-oleolyl-2-acetyl-sn-glycerol, 2 specific activators of PKC, produced effects similar to those of PMA. Inhibitors of PKC, ie, staurosporine and chelerytrine, could inhibit the PMA effect (1 nmol/L) significantly. After mutation of the PKC phosphorylation sites (especially S64A and T353A), PMA became ineffective. Conclusions-The human IK 1 in atrial cardiomyocytes and one of its underlying ion channels, the Kir 2.1b channel, is inhibited by PKC-dependent signal transduction pathways, possibly contributing to arrhythmogenesis in patients with structural heart disease in which PKC is activated. Key Words: ion channels Ⅲ signal transduction Ⅲ arrhythmia Ⅲ electrophysiology I n human cardiomyocytes, repolarization at the end of the action potential is caused by many different potassium currents, which can be classified as delayed outward and inward rectifiers. The inward rectifier potassium current (IK 1 ) reveals inwardly rectifying properties responsible for the terminal repolarization at the end of the cardiac action potential. The native IK 1 is composed of several different potassium channels with distinct single channel conductances of 20 pS, 35 pS and 10 pS. 1 Likewise, different gene families (Kir 2.1 , Kir 2.2 , and Kir 2.3 ) have been found in human heart encoding IK 1 . 2 The native IK 1 may be involved in arrhythmogenesis of coronary artery disease 3 and dilated cardiomyopathy. 4 Mutations of Kir 2.1 channels are associated with Anderson's syndrome, an inherited disease with an arrhythmia characterized by QT-prolongation, periodic paralysis, and dysmorphic features. 5 Within the Kir 2.1 family, several distinct channels have been cloned in chronological order. The first channel, named IRK 1 or MM-IRK 1 , was found in mouse tissue. 6 The rabbit channel RBHIK 1 revealed a 97% amino acid homology to MM-IRK 1 . 7 The human HH-IRK 1 , which has a 98% homology to MM-IRK 1 , was the first channel cloned from the human heart. 8 With the help of primers derived from IRK 1 , 2 channel sequences were identified in human atrial tissue; one was...

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“…The negative contractile effect in mammalian heart caused by the activation of mAChRs is mediated mainly by the M 2 subtype of receptors (Hosey, 1992;Sterin-Borda et al, 1995). Previously, we have determined the different signaling events involved in the M 2 mAChR-dependent inhibition of contractility in rat-isolated atria, which is associated with increased production of nitric oxide (NO).…”

Section: Introductionmentioning

confidence: 99%

“…The mechanism appears to occur secondarily to stimulation of phosphoinositide (PI) turnover, via phospholipase C (PLC) activation. This in turn triggers a further cascade of reactions involving calcium/calmodulin (CaM) and protein kinase C (PKC), leading to activation of nitric oxide synthase (NOS) and soluble guanylate cyclase activity (Sterin-Borda et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms involved in the regulation of mRNA for M₂ muscarinic acetylcholine receptors and endothelial and neuronal NO synthases in rat atria

Ganzinelli

Joensen

Borda

et al. 2007

British J Pharmacology

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Background and purpose: Agonists of the M 2 muscarinic acetylcholine receptor (mAChR) increase mRNA for this receptor and mRNA for endothelial and neuronal isoforms of NO synthase (eNOS or nNOS). Here we examine the different signalling pathways involved in such events in rat cardiac atria. Experimental approach: In isolated atria, the effects of carbachol on mRNA for M 2 receptors, eNOS and nNOS were measured along with changes in phosphoinositide (PI) turnover, translocation of protein kinase C (PKC), NOS activity and atrial contractility. Key Results: Carbachol increased mRNA for M 2 receptors, activation of PI turnover, translocation of PKC and NOS activity and decreased atrial contractility. Inhibitors of phospholipase C (PLC), calcium/calmodulin (CaM), NOS and PKC prevented the carbachol-dependent increase in mRNA for M 2 receptors. These inhibitors also attenuated the carbachol induced increase in nNOS-and eNOS-mRNA levels. Inhibition of nNOS shifted the dose response curve of carbachol on contractility to the right, whereas inhibition of eNOS shifted it to the left. Conclusions and implications: From our results, activation of M 2 receptors induced nNOS and eNOS expression and activation of NOS up-regulated M 2 receptor gene expression. The signalling pathways involved included stimulation of PI turnover via PLC activation, CaM and PKC. nNOS and eNOS mediated opposing effects on the negative inotropic effect in atria, induced by stimulation of M 2 receptors. These results may contribute to a better understanding of the effects and side effects of cholinomimetic treatment in patients with cardiac neuromyopathy.

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Endogenous nitric oxide signalling system and the cardiac muscarinic acetylcholine receptor‐inotropic response

Cited by 61 publications

References 30 publications

Muscarinic cholinergic regulation of cardiac myocyte I _Ca-L is absent in mice with targeted disruption of endothelial nitric oxide synthase

Muscarinic cholinergic regulation of cardiac myocyte I _Ca-L is absent in mice with targeted disruption of endothelial nitric oxide synthase

Human Cardiac Inwardly-Rectifying K ⁺ Channel Kir _2.1b Is Inhibited by Direct Protein Kinase C-Dependent Regulation in Human Isolated Cardiomyocytes and in an Expression System

Mechanisms involved in the regulation of mRNA for M₂ muscarinic acetylcholine receptors and endothelial and neuronal NO synthases in rat atria

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Endogenous nitric oxide signalling system and the cardiac muscarinic acetylcholine receptor‐inotropic response

Cited by 61 publications

References 30 publications

Muscarinic cholinergic regulation of cardiac myocyte I Ca-L is absent in mice with targeted disruption of endothelial nitric oxide synthase

Muscarinic cholinergic regulation of cardiac myocyte I Ca-L is absent in mice with targeted disruption of endothelial nitric oxide synthase

Human Cardiac Inwardly-Rectifying K + Channel Kir 2.1b Is Inhibited by Direct Protein Kinase C-Dependent Regulation in Human Isolated Cardiomyocytes and in an Expression System

Mechanisms involved in the regulation of mRNA for M2 muscarinic acetylcholine receptors and endothelial and neuronal NO synthases in rat atria

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Muscarinic cholinergic regulation of cardiac myocyte I _Ca-L is absent in mice with targeted disruption of endothelial nitric oxide synthase

Muscarinic cholinergic regulation of cardiac myocyte I _Ca-L is absent in mice with targeted disruption of endothelial nitric oxide synthase

Human Cardiac Inwardly-Rectifying K ⁺ Channel Kir _2.1b Is Inhibited by Direct Protein Kinase C-Dependent Regulation in Human Isolated Cardiomyocytes and in an Expression System

Mechanisms involved in the regulation of mRNA for M₂ muscarinic acetylcholine receptors and endothelial and neuronal NO synthases in rat atria