An obligatory role for nitric oxide in autonomic control of mammalian heart rate.

Han, Xianlin; Shimoni, Y.; Giles, Wayne R.

doi:10.1113/jphysiol.1994.sp020132

Cited by 205 publications

(140 citation statements)

References 20 publications

Supporting

Mentioning

133

Contrasting

Unclassified

Order By: Relevance

“…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: 80%

“…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). 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)(4)(5)(6).…”

mentioning

confidence: 99%

See 1 more Smart Citation

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.

137

121

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionsupporting

confidence: 80%

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.

137

121

View full text Add to dashboard Cite

show abstract

“…NO is now recognized to be an important endogenous vasodilator as well as a mediator or modulator of the myocardial response to other agents (Brady, Warren, Poole-Wilson, Williams & Harding, 1993;Han, Shimoni & Giles, 1994;. Endogenous NO has been shown to reduce the cardiotoxic properties of ET_1 in isolated hearts and attenuate the elevation of intracellular Ca¥ transients in ventricular myocytes .…”

Section: Influence Of No Generationmentioning

confidence: 99%

Differential Effects of Endothelin‐1 on Basal and Isoprenaline‐Enhanced Ca²⁺ Current in Guinea‐Pig Ventricular Myocytes

Thomas

Sims

Karmazyn

1997

The Journal of Physiology

View full text Add to dashboard Cite

We examined the effect of endothelin‐1 (ET‐1) on basal and isoprenaline‐enhanced L‐type Ca2+ current (ICa,L) in guinea‐Pig ventricular myocytes under nystatin‐perforated patch configuration. ET‐1 at concentrations of 1, 5 and 10 nM had little effect on basal ICa,L. However, ICa,L enhanced by isoprenaline (500 nM) was significantly attenuated by 5 nM ET‐1 by more than 50%. This effect was reversed upon washout. ICa,L enhanced by forskolin was also decreased by ET‐1. The inhibitory effect of ET‐1 against isoprenaline was completely blocked by the ETA receptor antagonist BQ‐123 (1 μm). In myocytes incubated with pertussis toxin (PTX, 2 μg ml−1) for 5 h, ET‐1 did not inhibit isoprenaline‐enhanced ICa,L. Although ET‐1 has been shown to activate specific protein kinase C (PKC) isoforms, a significant inhibitory effect of ET‐1 was maintained in the presence of the PKC inhibitor bisindolylmaleimide (20 nm). The nitric oxide (NO) donor SIN‐1 (10 μm) attenuated but failed to prevent the ET‐1 effect. In summary, our results demonstrate that ET‐1 is devoid of any significant effects on basal ICa,L. However, it exerts a potent inhibitory effect against isoprenaline‐enhanced ICa,L. This effect is mediated through ETA receptors coupled to PTX‐sensitive G‐proteins and occurs in the presence of PKC inhibition and NO generation.

show abstract

“…In relation to heart rate, Han, Shimoni & Giles (1994) found that NO altered spontaneous beating rhythm in isolated cultured sino-atrial node cell preparations. However, direct extrapolation of such observations to the whole animal is difficult.…”

Section: Introductionmentioning

confidence: 99%

The role of nitric oxide in the control by the vagal nerves of the heart of the ferret

Conlon

Collins

Kidd

1998

Experimental Physiology

View full text Add to dashboard Cite

SUMMARYThis study focuses on the potential role for nitric oxide on the actions of the parasympathetic innervation to the heart. Earlier, we showed that the nitric oxide synthase (NOS) inhibitor Ne-nitro-L-arginine methyl ester (L-NAME) reduced the bradycardia induced by stimulation of vagal efferent motor fibres and that these effects are reversible through administration of the NOS substrate L-arginine. In the present study, we show that D-arginine does not reverse the effects of the inhibitors and confirm that they are reversed by L-arginine. Another NOS inhibitor, N0-nitro-L-arginine (L-NOARG), produced similar effects which were not reversed by L-arginine. In an examination of the effect of increasing NO availability with the NO donor sodium nitroprusside the vagally induced bradycardia was enhanced at all frequencies tested. In a separate series, the effects of NOS inhibitors and NO donors on the dromotropic actions of the vagus were examined. The NOS inhibitor L-NAME, reduced the increase in atrio-ventricular conduction delay normally induced by efferent vagal stimulation at all frequencies tested both in the 'paced' and 'unpaced' heart. Further, sodium nitroprusside enhanced this delay. Overall the study indicates that NO has an important facilitatory role on both the chronotropic and dromotropic actions of the vagus nerve on the heart and that NO may be a rate-limiting factor in the cardiac responses to vagal stimulation.

show abstract

An obligatory role for nitric oxide in autonomic control of mammalian heart rate.

Cited by 205 publications

References 20 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

Differential Effects of Endothelin‐1 on Basal and Isoprenaline‐Enhanced Ca²⁺ Current in Guinea‐Pig Ventricular Myocytes

The role of nitric oxide in the control by the vagal nerves of the heart of the ferret

Contact Info

Product

Resources

About

An obligatory role for nitric oxide in autonomic control of mammalian heart rate.

Cited by 205 publications

References 20 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

Differential Effects of Endothelin‐1 on Basal and Isoprenaline‐Enhanced Ca2+ Current in Guinea‐Pig Ventricular Myocytes

The role of nitric oxide in the control by the vagal nerves of the heart of the ferret

Contact Info

Product

Resources

About

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

Differential Effects of Endothelin‐1 on Basal and Isoprenaline‐Enhanced Ca²⁺ Current in Guinea‐Pig Ventricular Myocytes