Regional differences in the negative inotropic effect of acetylcholine within the canine ventricle.

Yang, Zhaokang; Boyett, Mark R.; Janvier, N.C.; McMorn, Stephen O.; Shui, Z.; Karim, Fazlul

doi:10.1113/jphysiol.1996.sp021346

Cited by 37 publications

(51 citation statements)

References 30 publications

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“…Indeed, in two eNOS null myocytes (cells 7 and 8 in Table 1), the extent of CCh-induced inhibition of contractile responsiveness was comparable to that seen in myocytes from WT mice. These differences in responsiveness to CCh in eNOS null myocytes may be in part caused by the known heterogeneity in expression levels of I K(ACh) in different regions of ventricular muscle (40,43). It also is possible that eNOS null ventricular myocytes might exhibit an increase in expression of I K(ACh) because increased expression of K ϩ channels has been reported recently in response to hypertrophic stimuli in vitro (44).…”

Section: Discussionmentioning

confidence: 99%

“…The presence of I K(ACh) channels in ventricular cells may account in part for the demonstration of some NOindependent effects of muscarinic cholinergic agonists on myocyte contractile function (36)(37)(38)(39)(40)(41)(42). Expression of I K(ACh) in ventricular muscle may explain why there was a trend for CCh to inhibit myocyte contractile responsiveness to ISO in eNOSnull mice.…”

Section: Discussionmentioning

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

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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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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

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“…Our previous functional studies have shown that ACh has a negative inotropic effect on rat, ferret, and dog ventricle, and this was shown to be the result of the activation of the muscarinic K ϩ channel (Boyett et al 1988;McMorn et al 1993;Yang et al 1996). The muscarinic K ϩ channel is a heterotetramer of Kir3.1 and Kir3.4.…”

Section: Abundance Of Kir31 and Kir34 Proteins In Ventriclementioning

confidence: 99%

Distribution of the Muscarinic K⁺ Channel Proteins Kir3.1 and Kir3.4 in the Ventricle, Atrium, and Sinoatrial Node of Heart

Dobrzynski

Marples

Musa

et al. 2001

J Histochem Cytochem.

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The functionally important effects on the heart of ACh released from vagal nerves are principally mediated by the muscarinic K+ channel. The aim of this study was to determine the abundance and cellular location of the muscarinic K+ channel subunits Kir3.1 and Kir3.4 in different regions of heart. Western blotting showed a very low abundance of Kir3.1 in rat ventricle, although Kir3.1 was undetectable in guinea pig and ferret ventricle. Although immunofluorescence on tissue sections showed no labeling of Kir3.1 in rat, guinea pig, and ferret ventricle and Kir3.4 in rat ventricle, immunofluorescence on single ventricular cells from rat showed labeling in t-tubules of both Kir3.1 and Kir3.4. Kir3.1 was abundant in the atrium of the three species, as shown by Western blotting and immunofluorescence, and Kir3.4 was abundant in the atrium of rat, as shown by immunofluorescence. Immunofluorescence showed Kir3.1 expression in SA node from the three species and Kir3.4 expression in the SA node from rat. The muscarinic K+ channel is activated by ACh via the m2 muscarinic receptor and, in atrium and SA node from ferret, Kir3.1 labeling was co-localized with m2 muscarinic receptor labeling throughout the outer cell membrane.

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“…Assuming that Kir3 channels might be the final effectors in cardiomyocytes could have been in contradiction to the classical notion that these channels are absent from mammalian ventricle (39). In fact, ample experimental evidence has recently been accumulated that Kir3 channel density is far from negligible in mammalian tissues, including human ventricle (40)(41)(42).…”

Section: Discussionmentioning

confidence: 96%

“…We know of no other description of a GABA Bdependent activation in nonneural excitable cells, even though GABA B binding sites have been reported in rabbit oviduct and uterus (46). Kir3 channels, which were demonstrated to be present in mammalian ventricle (40)(41)(42), are likely the main effectors of the system. As their activation plays an important role in cardiac excitability, we speculate that GABA B Rs are possibly involved in this property.…”

Section: Discussionmentioning

confidence: 99%

γ-Aminobutyric acid type B receptors are expressed and functional in mammalian cardiomyocytes

Lorente

Lacampagne

Pouzeratte

et al. 2000

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

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␥-Hydroxybutyrate (GHB), an anesthetic adjuvant analog of ␥-aminobutyrate (GABA), depresses cell excitability in hippocampal neurons by inducing hyperpolarization through the activation of a prominent inwardly rectifying K ؉ (Kir3) conductance. These GABA type B (GABAB)-like effects are clearly shown at high concentrations of GHB corresponding to blood levels usually reached during anesthesia and are mimicked by the GABAB agonist baclofen. Recent studies of native GABAB receptors (GABABRs) have favored the concept that GHB is also a selective agonist. Furthermore, cloning has demonstrated that GABABRs assemble heteromeric complexes from the GABABR1 and GABABR2 subtypes and that these assemblies are activated by GHB. The surprisingly high tissue content, together with anti-ischemic and protective effects of GHB in the heart, raises the question of a possible influence of GABAB agonists on excitable cardiac cells. In the present study, we provide electrophysiological evidence that GHB activates an inwardly rectifying K ؉ current in rat ventricular myocytes. This effect is mimicked by baclofen, reversibly inhibited by GABAB antagonists, and prevented by pertussis toxin pretreatment. Both GABA BR1 and GABABR2 are detected in cardiomyocytes by Western blotting and are shown to coimmunoprecipitate. Laser scanning confocal microscopy discloses an even distribution of the two receptors in the sarcolemma and along the transverse tubular system. Hence, we conclude that GABABRs are distributed not only in neuronal tissues but also in the heart, where they can be activated and induce electrophysiological alterations through G-protein-coupled inward rectifier potassium channels.

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Regional differences in the negative inotropic effect of acetylcholine within the canine ventricle.

Cited by 37 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

Distribution of the Muscarinic K⁺ Channel Proteins Kir3.1 and Kir3.4 in the Ventricle, Atrium, and Sinoatrial Node of Heart

γ-Aminobutyric acid type B receptors are expressed and functional in mammalian cardiomyocytes

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Regional differences in the negative inotropic effect of acetylcholine within the canine ventricle.

Cited by 37 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

Distribution of the Muscarinic K+ Channel Proteins Kir3.1 and Kir3.4 in the Ventricle, Atrium, and Sinoatrial Node of Heart

γ-Aminobutyric acid type B receptors are expressed and functional in mammalian cardiomyocytes

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

Distribution of the Muscarinic K⁺ Channel Proteins Kir3.1 and Kir3.4 in the Ventricle, Atrium, and Sinoatrial Node of Heart