Dataset Information

Cyclic AMP-dependent inotropic effects are differentially regulated by muscarinic G(i)-dependent constitutive inhibition of adenylyl cyclase in failing rat ventricle.

ABSTRACT:

Background and purpose

?-Adrenoceptor (?-AR)-mediated inotropic effects are attenuated and G(i) proteins are up-regulated in heart failure (HF). Muscarinic receptors constitutively inhibit cAMP formation in normal rat cardiomyocytes. We determined whether constitutive activity of muscarinic receptors to inhibit adenylyl cyclase (AC) increases in HF and if so, whether it modifies the reduced ?-AR- or emergent 5-HT?-mediated cAMP-dependent inotropic effects.

Experimental approach

Contractility and AC activity were measured and related to each other in rat ventricle with post-infarction HF and sham-operated (Sham) controls with or without blockade of muscarinic receptors by atropine and inactivation of G(i) protein by pertussis toxin (PTX).

Key results

Isoprenaline-mediated inotropic effects were attenuated and basal, isoprenaline- and forskolin-stimulated AC activity was reduced in HF compared with Sham. Atropine or PTX pretreatment increased forskolin-stimulated AC activity in HF hearts. ?-AR-stimulated AC and maximal inotropic response were unaffected by atropine in Sham and HF. In HF, the potency of serotonin (5-HT) to evoke an inotropic response was increased in the presence of atropine with no change in the maximal inotropic response. Interestingly, PTX pretreatment reduced the potency of 5-HT to evoke inotropic responses while increasing the maximal inotropic response.

Conclusions and implications

Although muscarinic constitutive inhibition of AC is increased in HF, it does not contribute to the reduced ?-AR-mediated inotropic effects in rat ventricle in HF. The data support the hypothesis that there are differences in the functional compartmentation of 5-HT? and ?-AR AC signalling in myocardium during HF.

SUBMITTER: Hussain RI

PROVIDER: S-EPMC3042201 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Publications

Cyclic AMP-dependent inotropic effects are differentially regulated by muscarinic G(i)-dependent constitutive inhibition of adenylyl cyclase in failing rat ventricle.

Hussain R I RI Afzal F F Mørk H K HK Aronsen J M JM Sjaastad I I Osnes J-B JB Skomedal T T Levy F O FO Krobert K A KA

British journal of pharmacology 20110201 4

<h4>Background and purpose</h4>β-Adrenoceptor (β-AR)-mediated inotropic effects are attenuated and G(i) proteins are up-regulated in heart failure (HF). Muscarinic receptors constitutively inhibit cAMP formation in normal rat cardiomyocytes. We determined whether constitutive activity of muscarinic receptors to inhibit adenylyl cyclase (AC) increases in HF and if so, whether it modifies the reduced β-AR- or emergent 5-HT₄-mediated cAMP-dependent inotropic effects.<h4>Experimental approach</h4>Co ...[more]

PMID: 21039419

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Project description:Background and purposePDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3-selective inhibitor cilostamide (0.3-1 ?M) or PDE4 inhibitor rolipram (1-10 ?M) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium.Experimental approachRight and left ventricular trabeculae from freshly explanted hearts of 5 non-?-blocker-treated and 15 metoprolol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through ?? adrenoceptors (?? adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through ?? adrenoceptors (?? adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of PDE inhibitors. Catecholamine potencies were estimated from -logEC??s.Key resultsCilostamide did not significantly potentiate the inotropic effects of the catecholamines in non-?-blocker-treated patients. Cilostamide caused greater potentiation (P = 0.037) of the positive inotropic effects of (-)-adrenaline (0.78 ± 0.12 log units) than (-)-noradrenaline (0.47 ± 0.12 log units) in metoprolol-treated patients. Lusitropic effects of the catecholamines were also potentiated by cilostamide. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline on right and left ventricular trabeculae from metoprolol-treated patients.Conclusions and implicationsMetoprolol induces a control by PDE3 of ventricular effects mediated through both ?? and ?? adrenoceptors, thereby further reducing sympathetic cardiostimulation in patients with terminal heart failure. Concurrent therapy with a PDE3 blocker and metoprolol could conceivably facilitate cardiostimulation evoked by adrenaline through ?? adrenoceptors. PDE4 does not appear to reduce inotropic and lusitropic effects of catecholamines in failing human ventricle.

Dataset Information

Cyclic AMP-dependent inotropic effects are differentially regulated by muscarinic G(i)-dependent constitutive inhibition of adenylyl cyclase in failing rat ventricle.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Cyclic AMP-dependent inotropic effects are differentially regulated by muscarinic G(i)-dependent constitutive inhibition of adenylyl cyclase in failing rat ventricle.

Similar Datasets

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