Impact of phosphodiesterases PDE3 and PDE4 on 5-hydroxytryptamine receptor4-mediated increase of cAMP in human atrial fibrillation.

Atrial fibrillation (AF)-associated remodeling includes contractile dysfunction whose reasons are only partially resolved. Serotonin (5-HT) increases contractile force and causes arrhythmias in atrial trabeculae from patients in sinus rhythm (SR). In persistent atrial fibrillation (peAF), the force responses to 5-HT are blunted and arrhythmic effects are abolished.

Phosphodiesterase PDE2 activity, increased by isoprenaline, does not reduce β-adrenoceptor-mediated chronotropic and inotropic effects in rat heart.

Myocardial PDE2 activity increases in terminal human heart failure and after isoprenaline infusion in rat heart. PDE2 inhibitors do not potentiate the murine sinoatrial tachycardia produced by noradrenaline. We investigated whether isoprenaline infusion induces PDE2 to decrease the chronotropic and inotropic effects of catecholamines in rat heart.

The β -adrenoceptor agonist mirabegron increases human atrial force through β -adrenoceptors: an indirect mechanism?

Background And Purpose: Mirabegron has been classified as a β -adrenoceptor agonist approved for overactive bladder syndrome. We investigated possible cardiac effects of mirabegron in the absence or presence of β-adrenoceptor subtype antagonists. In view of its phenylethanolamine structure, we investigated whether mirabegron has indirect sympathomimetic activity by using neuronal uptake blockers.

In permanent atrial fibrillation, PDE3 reduces force responses to 5-HT, but PDE3 and PDE4 do not cause the blunting of atrial arrhythmias.

Background And Purpose: 5-HT increases force and L-type Ca(2) (+) current (ICa,L ) and causes arrhythmias through 5-HT4 receptors in human atrium. In permanent atrial fibrillation (peAF), atrial force responses to 5-HT are blunted, arrhythmias abolished but ICa,L responses only moderately attenuated. We investigated whether, in peAF, this could be due to an increased function of PDE3 and/or PDE4, using the inhibitors cilostamide (300 nM) and rolipram (1 μM) respectively.

Inhibitors of phosphodiesterases PDE2, PDE3, and PDE4 do not increase the sinoatrial tachycardia of noradrenaline and prostaglandin PGE₁ in mice.

Phosphodiesterases PDE2, PDE3, and PDE4 are expressed in murine sinoatrial cells. PDE3 and/or PDE4 reduce heart rate but apparently do not influence the tachycardia mediated through sinoatrial β1- and β2-adrenoceptors despite the high content of sinoatrial cAMP. The function of PDE2 is, however, uncertain.

Mucosa of murine detrusor impairs β2 -adrenoceptor-mediated relaxation.

Aims: To investigate the role of the mucosa in (-)-isoprenaline-induced relaxation of mouse detrusor muscle and to characterize the β-adrenoceptor subtypes involved.

Methods: Isolated intact and mucosa-denuded muscle strips from the urinary bladder of male C57BL6 mice were pre-contracted with KCl (40 mM) and were relaxed with increasing concentrations of the β-adrenoceptor (β-AR) agonist (-)-isoprenaline and forskolin in the presence and absence of the subtype-selective β-AR blockers CGP20712A (β1 -ARs), ICI118,551 (β2 -ARs), and L748,337 (β3 -ARs).

Results: Force development in response to KCl was larger in mucosa-denuded than in intact preparations and was almost completely relaxed with increasing concentrations of (-)-isoprenaline.

Carvedilol induces greater control of β2- than β 1-adrenoceptor-mediated inotropic and lusitropic effects by PDE3, while PDE4 has no effect in human failing myocardium.

The β-blockers carvedilol and metoprolol provide important therapeutic strategies for heart failure treatment. Therapy with metoprolol facilitates the control by phosphodiesterase PDE3, but not PDE4, of inotropic effects of catecholamines in human failing ventricle. However, it is not known whether carvedilol has the same effect.

Mucosa of human detrusor impairs contraction and β-adrenoceptor-mediated relaxation.

Objectives: To elucidate the impact of the mucosa on detrusor muscle function by investigating force of contraction under various stimulatory conditions and during subsequent relaxation using catecholamines.

Patients And Methods: Detrusor tissue was obtained from patients who had undergone cystectomy for bladder cancer and strips of intact or mucosa-denuded muscle were set up for force measurement. Preparations were precontracted with KCl, carbachol or electric-field stimulation (EFS).

PDE3, but not PDE4, reduces β₁ - and β₂-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients.

Background And Purpose: PDE3 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 μM) or PDE4 inhibitor rolipram (1-10 μM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium.

Phosphodiesterases reduce spontaneous sinoatrial beating but not the 'fight or flight' tachycardia elicited by agonists through Gs-protein-coupled receptors.

Cyclic AMP (cAMP) steers the generation of basal heart beat in the sinoatrial node. It also induces sinoatrial tachycardia and increased cardiac force, elicited through activation of Gs-protein-coupled receptors (GsPCRs). Phosphodiesterases (PDEs) hydrolyse cAMP.

Homology model and docking studies on porcine β₂ adrenoceptor: description of two binding sites.

The affinity of the classical β(2) adrenoceptor-selective inverse agonist ICI118,551 is notoriously lower for porcine β(2) adrenoceptors (p(2)βAR) than for human β(2) adrenoceptors (hβ(2)AR) but molecular mechanisms for this difference are still unclear. Homology 3-D models of pβ(2)AR can be useful in predicting similarities and differences, which might in turn increase the comparative understanding of ligand interactions with the hβ(2)AR. In this work, the pβ(2)AR amino acid sequence was used to carry out homology modeling.

Human atrial β(1L)-adrenoceptor but not β₃-adrenoceptor activation increases force and Ca(2+) current at physiological temperature.

Background And Purpose: It has been proposed that BRL37344, SR58611 and CGP12177 activate β₃-adrenoceptors in human atrium to increase contractility and L-type Ca(2+) current (I(Ca-L)). β₃-adrenoceptor agonists are potentially beneficial for the treatment of a variety of diseases but concomitant cardiostimulation would be potentially harmful. It has also been proposed that (-)-CGP12177 activates the low affinity binding site of the β₁-adrenoceptor in human atrium.

Function of cardiac beta1- and beta2-adrenoceptors of newborn piglets: role of phosphodiesterases PDE3 and PDE4.

The structures of porcine and human beta(2)-adrenoceptors differ but the repercussions for porcine cardiac function are unknown. We investigated the function of porcine beta(2)-adrenoceptors in 3 cardiac regions, sinoatrial node, left atrium and right ventricle of newborn piglets. Both (-)-noradrenaline and (-)-adrenaline caused sinoatrial tachycardia: 60+/-10% and 62+/-7% of the maximum response (E(max)) to (-)-noradrenaline (-logEC(50)=9.

Phosphodiesterases do not limit beta1-adrenoceptor-mediated sinoatrial tachycardia: evidence with PDE3 and PDE4 in rabbits and PDE1-5 in rats.

The mammalian heart expresses at least five phosphodiesterases (PDE1-5). Catecholamines produce surges of inotropically relevant cAMP through beta(1)-adrenoceptor stimulation. cAMP is mainly hydrolysed by PDE3 and/or PDE4 thereby blunting contractility.

Ontogenic changes of the control by phosphodiesterase-3 and -4 of 5-HT responses in porcine heart and relevance to human atrial 5-HT(4) receptors.

Background And Purpose: Atrial inotropic responses to 5-HT mediated through 5-HT(4) receptors fade, presumably through phosphodiesterase (PDE) activity. We investigated the influence of a selective inhibitor of PDE3 (cilostamide) or of PDE4 (rolipram) on the fade of 5-HT responses in atrial muscle.

Experimental Approach: 5-HT responses were compared, ex vivo, on sinoatrial beating rate of newborn piglets, porcine atrial and ventricular force, and human atrial force.

Inotropy and L-type Ca2+ current, activated by beta1- and beta2-adrenoceptors, are differently controlled by phosphodiesterases 3 and 4 in rat heart.

Background And Purpose: beta(1)- and beta(2)-adrenoceptors coexist in rat heart but beta(2)-adrenoceptor-mediated inotropic effects are hardly detectable, possibly due to phosphodiesterase (PDE) activity. We investigated the influence of the PDE3 inhibitor cilostamide (300 nmol x L(-1)) and the PDE4 inhibitor rolipram (1 micromol x L(-1)) on the effects of (-)-catecholamines.

Experimental Approach: Cardiostimulation evoked by (-)-noradrenaline (ICI118551 present) and (-)-adrenaline (CGP20712A present) through beta(1)- and beta(2)-adrenoceptors, respectively, was compared on sinoatrial beating rate, left atrial and ventricular contractile force in isolated tissues from Wistar rats.

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

Acting through a low-affinity site of the beta(1)-adrenoceptor (beta(1L)AR), CGP12177 causes sinoatrial tachycardia and positive inotropic effects in left atrium but not in the ventricle of the rat. However, inhibition of either PDE3 or PDE4 also uncovers positive inotropic effects of CGP12177 in ventricle, but whether these phosphodiesterases also control the atrial agonist effects of CGP12177 was unknown. We, therefore, investigated the effects of the PDE3-selective inhibitor cilostamide (300 nM) and PDE4 inhibitor rolipram (1 microM) on the (-)-CGP12177-evoked increases of sinoatrial beating rate and force of paced left atria of the rat.

Catecholamines relax detrusor through beta 2-adrenoceptors in mouse and beta 3-adrenoceptors in man.

(-)-Isoproterenol [4-[1-hydroxy-2-[(1-methylethyl)amino]ethyl]-1,2-benzene diol hydrochloride] relaxes murine detrusor through beta-adrenoceptors (ARs); however, the beta-AR subtypes involved are unknown. beta(2)-ARs have been associated with caveolae, plasma-lemmal scaffolding domains that are absent in caveolin-1 (cav-1) knockout (KO) mice. Here, we studied detrusor responses in the absence and presence of beta-AR subtype-selective antagonists in wild-type (WT) and cav-1 KO mice.

The low-affinity site of the beta1-adrenoceptor and its relevance to cardiovascular pharmacology.

beta-Adrenoceptor blocking agents (beta-blockers) that at low concentrations antagonize cardiostimulant effects of catecholamines, but at high concentrations also cause cardiostimulation, have been appearing since the late 1960s. These cardiostimulant beta-blockers, coined non-conventional partial agonists, antagonize the effects of catecholamines through a high-affinity site (beta(1H)AR), but cause cardiostimulation mainly through a low-affinity site (beta(1L)AR) of the myocardial beta(1)-adrenoceptor. The experimental non-conventional partial agonist (-)-CGP12177 increases cardiac L-type Ca(2+) current density and Ca(2+) transients, shortens action potential duration but augments action potential plateau, increases heart rate and force, as well as causes arrhythmic Ca(2+) transients and arrhythmic cardiocyte contractions.

(-)-Adrenaline elicits positive inotropic, lusitropic, and biochemical effects through beta2 -adrenoceptors in human atrial myocardium from nonfailing and failing hearts, consistent with Gs coupling but not with Gi coupling.

Activation of either coexisting beta1- or beta2 -adrenoceptors with noradrenaline or adrenaline, respectively, causes maximum increases of contractility of human atrial myocardium. Previous biochemical work with the beta2 -selective agonist zinterol is consistent with activation of the cascade beta2 -adrenoceptors-->Gsalpha-protein-->adenylyl cyclase-->cAMP-->protein kinase (PKA)-->phosphorylation of phospholamban, troponin I, and C-protein-->hastened relaxation of human atria from nonfailing hearts. However, in feline and rodent myocardium, catecholamines and zinterol usually do not hasten relaxation through activation of beta2 -adrenoceptors, presumably because of coupling of the receptors to Gi protein.

5-hydroxytryptamine receptors in the human cardiovascular system.

The human cardiovascular system is exposed to plasma 5-hydroxytryptamine (5-HT, serotonin), usually released from platelets. 5-HT can produce harmful acute and chronic effects. The acute cardiac effects of 5-HT consist of tachycardia (preceded on occasion by a brief reflex bradycardia), increased atrial contractility and production of atrial arrhythmias.

5-Hydroxytryptamine-induced contraction of human temporal arteries coexpressing 5-HT2A receptors and wild-type or variant (Phe124Cys) 5-HT1B receptors: increased contribution of 5-HT1B receptors to the total contractile amplitude in arteries from Phe124Cys heterozygous individuals.

Objectives: Expression studies of the rare Phe124Cys sequence variant of the human 5-HT1B receptor in HEK293 cells demonstrated that 5-hydroxytryptamine (5-HT) and sumatriptan had both three times higher binding affinity and agonist potency at the variant receptor than wild-type receptor. We examined whether in-vivo expression of the variant compared to the wild-type Phe/Phe genotype at codon 124 of the 5-HT1B receptor in human temporal arteries modifies their agonist-induced contraction.

Methods: Rings of arteries, coexpressing 5-HT1B and 5-HT2A receptors, from 98 patients undergoing neurosurgery were set up to measure contraction.

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

1.--The cardiostimulant effects of CGP12177, mediated through a beta(1)-adrenoceptor site with low affinity for (-)-propranolol, are potentiated by the nonselective PDE inhibitor IBMX but the role of PDE isoenzymes is unknown. We studied the effects of the PDE3-selective inhibitor cilostamide (300 nM) and PDE4-selective inhibitor rolipram (1 microM) on the positive inotropic and cyclic AMP-enhancing effects of CGP12177 and noradrenaline in right ventricular strips of rat.

Fading of 5-HT4 receptor-mediated inotropic responses to 5-hydroxytryptamine is caused by phosphodiesterase activity in porcine atrium.

Inotropic responses to 5-hydroxytryptamine (5-HT) in human and porcine atrium can fade, suggesting 5-HT(4) receptor desensitization. De Maeyer et al., however, show in this issue that inhibition of phosphodiesterases with isobutyl-methyl-xanthine prevents fading of 5-HT(4) receptor-mediated responses to 5-HT and the partial agonist prucalopride in porcine atrium.