Cilostamide potentiates more the positive inotropic effects of (−)-adrenaline through β2-adrenoceptors than the effects of (−)-noradrenaline through β1-adrenoceptors in human atrial myocardium

  title={Cilostamide potentiates more the positive inotropic effects of (−)-adrenaline through $\beta$2-adrenoceptors than the effects of (−)-noradrenaline through $\beta$1-adrenoceptors in human atrial myocardium},
  author={Torsten Christ and Andreas Engel and Ursula Ravens and Alberto Julio Kaumann},
  journal={Naunyn-Schmiedeberg's Archives of Pharmacology},
  • T. ChristA. Engel A. Kaumann
  • Published 15 November 2006
  • Biology, Medicine, Chemistry
  • Naunyn-Schmiedeberg's Archives of Pharmacology
Activation of both β1- and β2-adrenoceptors increases the contractility of human atrial myocardium through cyclic AMP-dependent pathways. Cyclic AMP is hydrolised by phosphodiesterases, but little is known about which isoenzymes catalyse inotropically relevant cyclic AMP accumulated upon stimulation of β-adrenoceptor subtypes. We have compared the positive inotropic effects of (−)-noradrenaline and (−)-adrenaline, mediated through β1- and β2-adrenoceptors, respectively, in the absence and… 

(-)-Adrenaline elicits positive inotropic, lusitropic, and biochemical effects through β2-adrenoceptors in human atrial myocardium from nonfailing and failing hearts, consistent with Gs coupling but not with Gi coupling

The hastening of relaxation caused by (-)-adrenaline together with the PKA-catalyzed phosphorylation of the three proteins involved in relaxation, indicate coupling of β2-adrenoceptors to Gs protein.

The effects of both noradrenaline and CGP12177, mediated through human β1-adrenoceptors, are reduced by PDE3 in human atrium but PDE4 in CHO cells

The role of PDE3 and PDE4 on signals through the H and L sites in human myocardium was sought to unravel and cilostamide, but not rolipram, increased the positive inotropic effects and abolished the time dependent fade of both agonists.

Phosphodiesterases PDE3 and PDE4 jointly control the inotropic effects but not chronotropic effects of (−)-CGP12177 despite PDE4-evoked sinoatrial bradycardia in rat atrium

These isoenzymes jointly reduce (−)-CGP12177-evoked increases of left atrial contractility through β1LAR and Cyclic AMP appears to maintain sinoatrial rate and PDE4 elicits bradycardia through hydrolysis of cAMP in a compartment distinct from the β1-adrenoceptor-induced cAMP compartment through which cAMP causes tachycardia.

AkrinorTM, a Cafedrine/ Theodrenaline Mixture (20:1), Increases Force of Contraction of Human Atrial Myocardium But Does Not Constrict Internal Mammary Artery In Vitro

AkinorTM increased cardiac contractile force by direct sympathomimetic actions and PDE inhibition, did not constrict A. mammaria interna rings, but shifted the noradrenaline curve rightward from -logEC50 6.18 ±0.08 to 5.23 ± 0.05 M.mam maria rings, compatible with an α-AR antagonistic effect or PDE inhibited.


Investigation of the effect of long‐term maximally tolerated carvedilol administration on left ventricular ejection fraction (LVEF) in patients with non‐ischaemic cardiomyopathy and segregation of patients into Arg389Gly‐β1‐adrenoceptors found that carveilol caused a greater increase in left vent cardiac ejection faction in patients carrying the Arg389 allele.

Atropine augments cardiac contractility by inhibiting cAMP-specific phosphodiesterase type 4

It is proposed that inhibition of PDE4 by atropine accounts, at least in part, for the induction of tachycardia and the arrhythmogenic potency of this drug.

PDE4 in the human heart – major player or little helper?

The key result is that the PDE4 inhibitor rolipram does not affect the positive inotropic effects of β1‐ or β2‐adrenoceptor stimulation, which is an important and reassuring finding.

Phosphodiesterase-4 activity: a critical modulator of atrial contractility and arrhythmogenesis.

  • David R Van WagonerBruce D Lindsay
  • Biology, Medicine
    Journal of the American College of Cardiology
  • 2012



β2-Adrenoceptor-mediated positive inotropic effect of adrenaline in human ventricular myocardium

The contribution of β1- and β2-adrenoceptors to the positive inotropic effects of adrenaline and noradrenaline cannot be inferred straightforwardly from biochemical estimates of receptor fractions and fractional adenylate cyclase stimulation.

Phosphodiesterase PDE3 blunts the positive inotropic and cyclic AMP enhancing effects of CGP12177 but not of noradrenaline in rat ventricle

Both PDE3 and PDE4 of rat ventricle appear to hydrolyse cyclic AMP generated through the low‐affinity β1‐adrenoceptor site, thereby preventing inotropic responses of CGP12177.

The affinity of (-)-propranolol for beta 1- and beta 2-adrenoceptors of human heart. Differential antagonism of the positive inotropic effects and adenylate cyclase stimulation by (-)-noradrenaline and (-)-adrenaline.

It is concluded that the concentration of physiological catecholamines at the human heart beta-adrenoceptors is limited by neuronal capture but not by extraneuronal uptake.

Carvedilol blocks beta2- more than beta1-adrenoceptors in human heart.

β2-Adrenoceptor activation by zinterol causes protein phosphorylation, contractile effects and relaxant effects through a cAMP pathway in human atrium

It is concluded that in human atrial myocardium activation of both β1AR and β2AR leads to cAMP-dependent phosphorylation of proteins involved in augmenting both contractility and relaxation.

Carvedilol blocks h 2 - more than h 1 -adrenoceptors in human heart

Carvedilol blocks human cardiac h1and h2-adrenoceptors more than h1-ad Renfrewshire, thereby conceivably contributing to the beneficial effects in heart failure.

A comparison of the effects of adrenaline and noradrenaline on human heart: the role of beta 1- and beta 2-adrenoceptors in the stimulation of adenylate cyclase and contractile force.

Unexpectedly, in atria from patients treated with the beta 1-selective antagonist atenolol, contractile responses to adrenaline are markedly and selectively augmented through activation of beta 2-adrenoceptors.

Selective beta 1-adrenoceptor blockade enhances positive inotropic responses to endogenous catecholamines mediated through beta 2-adrenoceptors in human atrial myocardium.

The results suggest that chronic blockade of beta 1-adrenoceptors causes enhanced coupling of beta 2-adreceptors to adenylate cyclase or to other mechanisms leading to increased contractile force.

Beta-2 adrenergic activation of L-type Ca++ current in cardiac myocytes.

It is concluded that beta-2 adrenergic receptor activation produces a strong increase in ICa in frog, rat and human cardiac myocytes which is due to stimulation of adenylyl cyclase and activation of cAMP-dependent phosphorylation.

Effects of (−)‐RO363 at human atrial β‐adrenoceptor subtypes, the human cloned β3‐adrenoceptor and rodent intestinal β3‐adrenoceptors

The question of β1‐adrenoceptor sensitivity is addressed by determining the inotropic potency and intrinsic activity of the β1-adrenOceptor selective partial agonist (−)‐RO363 and by carrying out both homogenate binding and quantitative β‐adRenoceptor autoradiography in atria obtained from patients treated or not treated with β‐blockers.