Urocortin induces positive inotropic effect in rat heart

Calderón-Sánchez, Eva; Delgado, Carmen; Ruiz‐Hurtado, Gema; Domínguez-Rodríguez, Alejandro; Cachofeiro, Victoria; Rodríguez-Moyano, María; Gómez, Ana M.; Ordóñez, Antonio; Smani, Tarik

doi:10.1093/cvr/cvp161

Cited by 36 publications

(36 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It is also widely acknowledged that NO, by targeting soluble guanylyl cyclase, and thus protein kinase G, negatively affects contractility by reducing L-type Ca 2ϩ current in many tissues, including rat ventricular myocytes (Pellegrino et al 2009). Furthmore, cAMP, protein kinase A, Epac pathway, and mitogen-activated protein kinase pathway are reportedly involved in the drug-induced positive inotropism in the rat heart (Calderón-Sanchez et al 2009). It would be interesting to see whether any of the above targets are involved in the inotropic and chronotropic activity of doxazosin and its enantiomers in the isolated heart tissues of the rat and rabbit, thus more experimental work is needed.…”

Section: Discussionmentioning

confidence: 99%

Chiral recognition of doxazosin enantiomers in 3 targets for therapy as well as adverse drug reactions in animal experiments

ZhaoDing

DuanLi-Hua

WangFeng-Yu

et al. 2012

Can. J. Physiol. Pharmacol.

View full text Add to dashboard Cite

Doxazosin used in benign prostatic hyperplasia has the side effects of causing hypotension and the risk of heart failure. The 3 targets of α(1A)-adrenoceptors (in the prostate), α(1D)-adrenoceptors (in the aorta), and an unknown mechanism (in the heart) are involved, respectively. We hypothesized that there is a chiral recognition of doxazosin enantiomers in the 3 targets. Using isolated rat aorta (α(1D)-adrenoceptors) and rabbit prostate (α(1A)-adrenoceptors), we examined pA(2) and pK(B) values of doxazosin enantiomers. We observed chronotropic and inotropic effects of doxazosin enantiomers in isolated rat and rabbit heart tissues. (-)Doxazosin and (+)doxazosin produced a shift to the right of concentration-contraction curves for noradrenalin (aorta) and phenylephrine (prostate smooth muscle). The pA(2) value of (-)doxazosin (8.625 ± 0.053) was smaller than (+)doxazosin (9.503 ± 0.051) in rat aorta, but their pK(B) values in rabbit prostate were the same. In rat and rabbit heart tissues, (+)doxazosin (3-30 µmol·L(-1)) significantly decreased atrial rate, and produced negative inotropic effects; however, (-)doxazosin did not affect the atrial rate, and produced positive inotropic effects in the atria. Thus, the chiral carbon atom of doxazosin does not affect its activity at the therapeutic target of α(1A)-adrenoceptors in the prostate, but significantly changes its blocking activity against α(1D)-adrenoceptors in the aorta, and produces opposite inotropic effects in the atria via an α(1)-adrenoceptor-independent mechanism.

show abstract

Section: Discussionmentioning

confidence: 99%

Chiral recognition of doxazosin enantiomers in 3 targets for therapy as well as adverse drug reactions in animal experiments

ZhaoDing

DuanLi-Hua

WangFeng-Yu

et al. 2012

Can. J. Physiol. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…Rap1 activity was determined by using a Rap1 activation kit (Upstate Biotechnology). Briefly, porcine CASMCs were treated with G-1 (1 μM) between 2 and 15 min with or without ARF-GEF inhibitor, brefeldin A (BFA, 50 μM), a potential Epac inhibitor [18] and 007 (50 μM) for 5 min. Cell lysates were equally split into two microfuge tubes, then incubated with GTPγS (1 mM) in one tube and GDP (1mM) in the other tube.…”

Section: Methodsmentioning

confidence: 99%

Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA

Zhang

Zhao

et al. 2017

PLoS ONE

View full text Add to dashboard Cite

Previously, we reported that cAMP/PKA signaling is involved in GPER-mediated coronary relaxation by activating MLCP via inhibition of RhoA pathway. In the current study, we tested the hypothesis that activation of GPER induces coronary artery relaxation via inhibition of RhoA/Rho kinase pathway by cAMP downstream targets, exchange proteins directly activated by cAMP (Epac) as well as PKA. Our results show that Epac inhibitors, brefeldin A (BFA, 50 μM), or ESI-09 (20 μM), or CE3F4 (100 μM), all partially inhibited porcine coronary artery relaxation response to the selective GPER agonist, G-1 (0.3–3 μM); while concurrent administration of BFA and PKI (5 μM), a PKA inhibitor, almost completely blocked the relaxation effect of G-1. The Epac specific agonist, 8-CPT-2Me-cAMP (007, 1–100 μM), induced a concentration-dependent relaxation response. Furthermore, the activity of Ras-related protein 1 (Rap1) was up regulated by G-1 (1 μM) treatment of porcine coronary artery smooth muscle cells (CASMCs). Phosphorylation of vasodilator-stimulated phosphoprotein (p-VASP) was elevated by G-1 (1 μM) treatment, but not by 007 (50 μM); and the effect of G-1 on p-VASP was blocked by PKI, but not by ESI-09, an Epac antagonist. RhoA activity was similarly down regulated by G-1 and 007, whereas ESI-09 restored most of the reduced RhoA activity by G-1 treatment. Furthermore, G-1 decreased PGF2α-induced p-MYPT1, which was partially reversed with either ESI-09 or PKI; whereas, concurrent administration of ESI-09 and PKI totally prevented the inhibitory effect of G-1. The inhibitory effects of G-1 on p- MLC levels in CASMCs were mostly restored by either ESI-09 or PKI. These results demonstrate that activation of GPER induces coronary artery relaxation via concurrent inhibition of RhoA/Rho kinase by Epac/Rap1 and PKA. GPER could be a potential drug target for preventing and treating cardiovascular diseases.

show abstract

“…PKA, in turn, elevated L‐type Ca 2+ current and sarcoplasmic reticulum (SR) Ca 2+ content via increased SR‐Ca 2+ ‐ATPase (SERCA) activity to augment intracellular Ca 2+ concentration ([Ca 2+ ] i ) transients and enhance cardiomyocyte contractility (Yang et al ., 2006). Similarly, a recent study in rat ventricular myocytes observed Ca 2+ ‐dependent positive inotropic and lusitropic effects induced by urocortin 1 (Calderon‐Sanchez et al ., 2009). Urocortin 1 also increased PKA activity in rat cardiac myocytes.…”

Section: Introductionmentioning

confidence: 99%

“…However, unlike rabbit cardiac myocytes, in rat cardiac myocytes, this increased PKA activity did not appear to underlie the positive inotropic and lusitropic effects. Rather the exchange protein activated by cAMP (Epac), protein kinase C (PKC) and mitogen‐activated protein kinase (MAPK) signalling pathways contributed to the positive inotropic and lusitropic effects of urocortin 1 (Calderon‐Sanchez et al ., 2009). These findings suggest that, in cardiac myocytes, urocortins may act via multiple signalling pathways to elicit inotropic and lusitropic effects and, in addition, that the relative contribution of these signalling pathways to the inotropic and lusitropic effects may be species‐dependent.…”

Section: Introductionmentioning

confidence: 99%

cAMP‐ and Ca²⁺/calmodulin‐dependent protein kinases mediate inotropic, lusitropic and arrhythmogenic effects of urocortin 2 in mouse ventricular myocytes

Yang

Kockskämper

Khan

et al. 2010

British J Pharmacology

View full text Add to dashboard Cite

BACKGROUND AND PURPOSE Urocortin 2 is beneficial in heart failure, but the underlying cellular mechanisms are not completely understood. Here we have characterized the functional effects of urocortin 2 on mouse cardiomyocytes and elucidated the underlying signalling pathways and mechanisms. EXPERIMENTAL APPROACH Mouse ventricular myocytes were field‐stimulated at 0.5 Hz at room temperature. Fractional shortening and [Ca2+]i transients were measured by an edge detection and epifluorescence system respectively. Western blots were carried out on myocyte extracts with antibodies against total phospholamban (PLN) and PLN phosphorylated at serine‐16. KEY RESULTS Urocortin 2 elicited time‐ and concentration‐dependent positive inotropic and lusitropic effects (EC50: 19 nM) that were abolished by antisauvagine‐30 (10 nM, n= 6), a specific antagonist of corticotrophin releasing factor (CRF) CRF2 receptors. Urocortin 2 (100 nM) increased the amplitude and decreased the time constant of decay of the underlying [Ca2+]i transients. Urocortin 2 also increased PLN phosphorylation at serine‐16. H89 (2 µM) or KT5720 (1 µM), two inhibitors of protein kinase A (PKA), as well as KN93 (1 µM), an inhibitor of Ca2+/calmodulin‐dependent protein kinase II (CaMKII), suppressed the urocortin 2 effects on shortening and [Ca2+]i transients. In addition, urocortin 2 also elicited arrhythmogenic events consisting of extra cell shortenings and extra [Ca2+]i increases in diastole. Urocortin 2‐induced arrhythmogenic events were significantly reduced in cells pretreated with KT5720 or KN93. CONCLUSIONS AND IMPLICATIONS Urocortin 2 enhanced contractility in mouse ventricular myocytes via activation of CRF2 receptors in a cAMP/PKA‐ and Ca2+/CaMKII‐dependent manner. This enhancement was accompanied by Ca2+‐dependent arrhythmogenic effects mediated by PKA and CaMKII.

show abstract

Urocortin induces positive inotropic effect in rat heart

Abstract: Our results show that Ucn evokes potent positive inotropic and lusitropic effects mediated, at least in part, by an increase in I(CaL) and [Ca(2+)](i) transient amplitude. These effects may involve the activation of Epac, PKC, and MAPK signalling pathways.

Cited by 36 publications

References 42 publications

Chiral recognition of doxazosin enantiomers in 3 targets for therapy as well as adverse drug reactions in animal experiments

Chiral recognition of doxazosin enantiomers in 3 targets for therapy as well as adverse drug reactions in animal experiments

Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA

cAMP‐ and Ca²⁺/calmodulin‐dependent protein kinases mediate inotropic, lusitropic and arrhythmogenic effects of urocortin 2 in mouse ventricular myocytes

Contact Info

Product

Resources

About

Urocortin induces positive inotropic effect in rat heart

Abstract: Our results show that Ucn evokes potent positive inotropic and lusitropic effects mediated, at least in part, by an increase in I(CaL) and [Ca(2+)](i) transient amplitude. These effects may involve the activation of Epac, PKC, and MAPK signalling pathways.

Cited by 36 publications

References 42 publications

Chiral recognition of doxazosin enantiomers in 3 targets for therapy as well as adverse drug reactions in animal experiments

Chiral recognition of doxazosin enantiomers in 3 targets for therapy as well as adverse drug reactions in animal experiments

Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA

cAMP‐ and Ca2+/calmodulin‐dependent protein kinases mediate inotropic, lusitropic and arrhythmogenic effects of urocortin 2 in mouse ventricular myocytes

Contact Info

Product

Resources

About

cAMP‐ and Ca²⁺/calmodulin‐dependent protein kinases mediate inotropic, lusitropic and arrhythmogenic effects of urocortin 2 in mouse ventricular myocytes