Cardiac PDEs and crosstalk between cAMP and cGMP signalling pathways in the regulation of contractility

Levy, Finn Olav

doi:10.1007/s00210-013-0874-z

Cited by 21 publications

(11 citation statements)

References 67 publications

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“…Further, PDE3 and, at least in the rat ventricle, PDE4 activity (Fig. 4A,B; [41]) normally degrades low basal levels of cAMP, maintaining basal contractile force. These data highlight the necessity to remove the tonic inhibition of G i upon AC prior to PDE inhibition to allow for the enhanced cAMP signal to be transduced into a functional response.…”

Section: Discussionmentioning

confidence: 98%

Gi Proteins Regulate Adenylyl Cyclase Activity Independent of Receptor Activation

et al. 2014

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Background and purposeDespite the view that only β2- as opposed to β1-adrenoceptors (βARs) couple to Gi, some data indicate that the β1AR-evoked inotropic response is also influenced by the inhibition of Gi. Therefore, we wanted to determine if Gi exerts tonic receptor-independent inhibition upon basal adenylyl cyclase (AC) activity in cardiomyocytes.Experimental approachWe used the Gs-selective (R,R)- and the Gs- and Gi-activating (R,S)-fenoterol to selectively activate β2ARs (β1AR blockade present) in combination with Gi inactivation with pertussis toxin (PTX). We also determined the effect of PTX upon basal and forskolin-mediated responses. Contractility was measured ex vivo in left ventricular strips and cAMP accumulation was measured in isolated ventricular cardiomyocytes from adult Wistar rats.Key resultsPTX amplified both the (R,R)- and (R,S)-fenoterol-evoked maximal inotropic response and concentration-dependent increases in cAMP accumulation. The EC50 values of fenoterol matched published binding affinities. The PTX enhancement of the Gs-selective (R,R)-fenoterol-mediated responses suggests that Gi regulates AC activity independent of receptor coupling to Gi protein. Consistent with this hypothesis, forskolin-evoked cAMP accumulation was increased and inotropic responses to forskolin were potentiated by PTX treatment. In non-PTX-treated tissue, phosphodiesterase (PDE) 3 and 4 inhibition or removal of either constitutive muscarinic receptor activation of Gi with atropine or removal of constitutive adenosine receptor activation with CGS 15943 had no effect upon contractility. However, in PTX-treated tissue, PDE3 and 4 inhibition alone increased basal levels of cAMP and accordingly evoked a large inotropic response.Conclusions and implicationsTogether, these data indicate that Gi exerts intrinsic receptor-independent inhibitory activity upon AC. We propose that PTX treatment shifts the balance of intrinsic Gi and Gs activity upon AC towards Gs, enhancing the effect of all cAMP-mediated inotropic agents.

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Section: Discussionmentioning

confidence: 98%

Gi Proteins Regulate Adenylyl Cyclase Activity Independent of Receptor Activation

et al. 2014

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“…The effects of CNP in the heart are complex, as we previously showed increased b 1 -adrenergic receptor-induced, cAMP-mediated inotropic responses in the presence of CNP (Qvigstad et al, 2010), a potentially harmful effect. Thus, when evaluating new drugs that target NP signaling, direct effects on the heart should be taken into consideration (Levy, 2013;Bach et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Different Compartmentation of Responses to Brain Natriuretic Peptide and C-Type Natriuretic Peptide in Failing Rat Ventricle

Moltzau

Aronsen

Meier

et al. 2014

J Pharmacol Exp Ther

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We previously found a negative inotropic (NIR) and positive lusitropic response (LR) to C-type natriuretic peptide (CNP) in the failing heart ventricle. In this study, we investigated and compared the functional responses to the natriuretic peptides (NPs), brain (BNP) and C-type natriuretic peptide (CNP), and relate them to cGMP regulation and effects on downstream targets. Experiments were conducted in left ventricular muscle strips and ventricular cardiomyocytes from Wistar rats with heart failure 6 weeks after myocardial infarction. As opposed to CNP, BNP did not cause an NIR or LR, despite increasing cGMP levels. The BNP-induced cGMP elevation was mainly and markedly regulated by phosphodiesterase (PDE) 2 and was only marginally increased by PDE3 or PDE5 inhibition. Combined PDE2, -3, and -5 inhibition failed to reveal any functional responses to BNP, despite an extensive cGMP elevation. BNP decreased, whereas CNP increased, the amplitude of the Ca 21 transient. BNP did not increase phospholamban (PLB) or troponin I (TnI) phosphorylation, Ca 21 extrusion rate constant, or sarcoplasmatic reticulum Ca 21 load, whereas CNP did. Both BNP and CNP reduced the peak of the L-type Ca 21 current. Cyclic GMP elevations by BNP and CNP in cardiomyocytes were additive, and the presence of BNP did not alter the NIR to CNP or the CNP-induced PLB and TnI phosphorylation. However, a small increase in the LR to maximal CNP was observed in the presence of BNP. In conclusion, different responses to cGMP generated by BNP and CNP suggest different compartmentation of the cGMP signal and different roles of the two NPs in the failing heart.

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“…In analogy to the cAMP signalling cascade, the cGMP‐dependent protein kinase occurs in cardiomyocytes, and phosphorylation of phospholamban in response to CNP has been reported (Frantz et al, ). In addition to the activation of cGMP‐dependent protein kinase I, cGMP has been proposed to increase cAMP by inhibiting PDE3 (Kirstein et al, ; Kojda & Kottenberg, ) or to decrease cAMP by activating PDE2 (Levy, ; Vandecasteele, Verde, Rücker‐Martin, Donzeau‐Gouge, & Fischmeister, ). Generally, two GCs, that is, the membrane‐bound receptor‐coupled GC activated by the natriuretic peptides ANP, BNP, and CNP and the NO‐sensitive GC (NO–GC) acting as receptor for NO, are considered to be able to increase cGMP in cardiac myocytes (Stangherlin et al, ).…”

Section: Introductionmentioning

confidence: 99%

Mind the gap (junction): cGMP induced by nitric oxide in cardiac myocytes originates from cardiac fibroblasts

Menges

Krawutschke

Füchtbauer

et al. 2019

British J Pharmacology

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Background and Purpose: The intracellular signalling molecule cGMP, formed by NO-sensitive GC (NO-GC), has an established function in the vascular system.Despite numerous reports about NO-induced cGMP effects in the heart, the underlying cGMP signals are poorly characterized.Experimental Approach: Therefore, we analysed cGMP signals in cardiac myocytes and fibroblasts isolated from knock-in mice expressing a FRET-based cGMP indicator.Key Results: Whereas in cardiac myocytes, none of the known NO-GC-activating substances (NO, GC activators, and GC stimulators) increased cGMP even in the presence of PDE inhibitors, they induced substantial cGMP increases in cardiac fibroblasts.As cardiac myocytes and fibroblasts are electrically connected via gap junctions, we asked whether cGMP can take the same route. Indeed, in cardiomyocytes cocultured on cardiac fibroblasts, NO-induced cGMP signals were detectable, and two groups of unrelated gap junction inhibitors abolished these signals. Conclusion and Implication:We conclude that NO-induced cGMP formed in cardiac fibroblasts enters cardiac myocytes via gap junctions thereby turning cGMP into an intercellular signalling molecule. The findings shed new light on NO/cGMP signalling in the heart and will potentially broaden therapeutic opportunities for cardiac disease.Abbreviations: % CER, % change of emission ratio; 8MMX, 8-methoxymethyl-IBMX; Ang II, angiotensin II; ANP, atrial natriuretic peptide; BAY60, BAY60-7550; BNP, brain natriuretic peptide; CNP, C-type natriuretic peptide; ES cells, embryonic stem cells; GSNO, Snitrosoglutathione; NO-GC, NO-sensitive GC; ROI, region of interest; α/βGlycA, 18-α/βglycyrrhetinic acid

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Cardiac PDEs and crosstalk between cAMP and cGMP signalling pathways in the regulation of contractility

Cited by 21 publications

References 67 publications

Gi Proteins Regulate Adenylyl Cyclase Activity Independent of Receptor Activation

Gi Proteins Regulate Adenylyl Cyclase Activity Independent of Receptor Activation

Different Compartmentation of Responses to Brain Natriuretic Peptide and C-Type Natriuretic Peptide in Failing Rat Ventricle

Mind the gap (junction): cGMP induced by nitric oxide in cardiac myocytes originates from cardiac fibroblasts

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