Carvedilol blockade of α1- and β-adrenoceptor induced inotropic responses in rats with congestive heart failure

Qvigstad, Eirik; Sjaastad, Ivar; Bøkenes, Janny; Schiander, I.; Solberg, L E; Sejersted, Ole M.; Osnes, Jan‐Bjørn; Skomedal, Tor

doi:10.1016/j.ejphar.2005.04.027

Cited by 9 publications

(10 citation statements)

References 24 publications

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“…[18][19][20] Our findings were consistent with previous studies, which have shown that isoproterenol induces an increase in heart rate and FS. In animals, isoproterenol has been shown to enhance LV cardiac systolic and diastolic function and heart rate.…”

Section: Discussionsupporting

confidence: 92%

Doxycycline Attenuates Isoproterenol-Induced Myocardial Fibrosis and Matrix Metalloproteinase Activity in Rats

Hori

Kunihiro

Sato

et al. 2009

Biological & Pharmaceutical Bulletin

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Congestive heart failure is associated with extracellular matrix (ECM) remodeling resulting from an imbalance in the synthesis and degradation of ECM collagen.1,2) Severe degrees of cardiac remodeling are associated with an increased risk of heart failure, morbidity, and mortality in patients with heart failure. 3,4) Neurohumoral activation plays a key role in compensatory mechanisms and myocardial remodeling in patients with heart disease, and is accompanied by the expression of matrix metalloproteinases (MMPs). 2,3,5,6) The MMPs compose a family of enzymes that contribute to ECM remodeling in several disease states, by promoting ECM degradation. Interestingly, several studies have shown that increased MMP expression and activation are involved in myocardial remodeling processes associated with several heart diseases. 4,[7][8][9] In addition, animal models of heart disease showed increases in MMP activity and left ventricular (LV) remodeling. [10][11][12] Likewise, MMP inhibition and deletion are reported to prevent LV remodeling and dysfunction, suggesting the potential usefulness of MMP inhibitors (MMPi) in patients with heart failure. Spontaneously hypertensive rats showed increased collagen accumulation and MMP activation, which were reversed after treatment with an MMPi. 6) MMP knockout mice showed preserved cardiac function and decreased myocardial fibrosis in myocardial infarction. 13,14) Furthermore, the MMPi doxycycline was reported to prevent cardiac hypertrophy, MMP activity, and myocardial fibrosis in rats with myocardial ischemia. 15) However, few studies have examined the effects of doxycycline on b-agonist-induced myocardial fibrosis. Therefore, we investigated the effects of doxycycline on isoproterenol-induced myocardial fibrosis and MMP expression. MATERIALS AND METHODSFour-week-old Wistar-Kyoto rats (nϭ42) were obtained from a commercial laboratory (Charles River, Yokohama, Japan). The rats were housed individually in an air-conditioned room with a 12-h dark-light cycle and were given a standard diet with ad libitum access to tap water. The rats were divided into 3 groups: control (CTL), isoproterenol (ISO), and isoproterenol with doxycycline (ISOϩDOX). This study was approved by the Institutional Laboratory Animal Care and Use Committee of the School of Veterinary Medicine of Kitasato University, Japan.Study 1 Four-week-old rats (nϭ18; body weight, 90-110 g) were divided into 3 groups: control (nϭ6), ISO (nϭ 6), and ISOϩDOX (nϭ6). Animals were anesthetized with an intraperitoneal injection of pentobarbital (50 mg/kg). A 3Fr catheter was implanted into the jugular vein and the drug was administered with an infusion pump (Nihon Kohden, Tokyo, Japan). The rats were stabilized for 15 min and placed in the prone position above an ultrasound standoff pad (3M Health Care Ltd., Tokyo). Control rats were infused 0.9% saline alone. L-Isoproterenol (Sigma-Aldrich Co., St. Louis, MO, U.S.A.) was infused at 0.5 and 1.0 mg/kg/min for 5 min. In ISOϩDOX rats, doxycycline hydrochloride was infused at 17-18 m...

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Section: Discussionsupporting

confidence: 92%

Doxycycline Attenuates Isoproterenol-Induced Myocardial Fibrosis and Matrix Metalloproteinase Activity in Rats

Hori

Kunihiro

Sato

et al. 2009

Biological & Pharmaceutical Bulletin

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“…Accordingly, we also show that the responsiveness to b1-adrenoceptors is reduced in HF compared with Sham ( Figure 4A). However, there is an increase in the sensitivity of b1-adrenoceptor-mediated PIR in HF compared with Sham ( Figures 3C and 7D) which is in accordance with our previous reports using both (-)-noradrenaline and isoprenaline as b-adrenoceptor agonists (Sjaastad et al, 2003;Qvigstad et al, 2005). A possible explanation for this leftward shift of the concentration-response curve might be the reduced activity of PDE4 in HF compared with Sham which is consistent with the observation that PDE4 inhibition does not further sensitize the b1-adrenoceptor-mediated PIR in HF.…”

Section: B 1 -And B 2 -Adrenoceptor Responsiveness In Hfsupporting

confidence: 92%

“…Thus, as a whole the b 1-adrenoceptor-mediated maximal LR was preserved in HF compared with Sham. This corresponds essentially to findings in our previous reports (Sjaastad et al, 2003;Qvigstad et al, 2005) that the LR to non-selective b-adrenoceptor stimulation by isoprenaline was unchanged in postinfarction HF compared with Sham. The b2-adrenoceptor-mediated LR was significantly increased in HF compared with Sham, both in the absence and in the presence of Cil/Rol.…”

Section: B 1 -And B 2 -Adrenoceptor Responsiveness In Hfsupporting

confidence: 91%

Differential regulation of β₂‐adrenoceptor‐mediated inotropic and lusitropic response by PDE3 and PDE4 in failing and non‐failing rat cardiac ventricle

Afzal¹,

Aronsen

Moltzau³

et al. 2010

British J Pharmacology

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BACKGROUND AND PURPOSEb-Adrenoceptors play a major role in regulating myocardial function through cAMP-dependent pathways. Different phosphodiesterases (PDEs) regulate intracellular cAMP-pools and thereby contribute to the compartmentalization of cAMP-dependent effects. We explored the involvement of PDEs in limiting the b2 adrenoceptor-mediated positive inotropic (PIR) and lusitropic (LR) responses in sham-operated (Sham) and failing rat hearts. EXPERIMENTAL APPROACHExtensive myocardial infarctions were induced by coronary artery ligation in Wistar rats. Rats developing heart failure were studied 6 weeks after surgery. Contractility was measured in left ventricular strips from failing and Sham hearts. cAMP was quantified by RIA. KEY RESULTSIn ventricular strips, stimulation of b2-adrenoceptors with (-)-adrenaline (300 nM CGP20712A present) exerted a small PIR and LR. In Sham hearts, b2-adrenoceptor-mediated as well as b1-adrenoceptor-mediated PIR and LR were increased by selective inhibition of either PDE3 (1 mM cilostamide) or PDE4 (10 mM rolipram). In failing rat hearts, PDE3 inhibition enhanced PIR and LR to both b1-and b2-adrenoceptor stimulation while PDE4 inhibition had no effect on these responses despite a significant increase in cAMP levels. Combined PDE3/4 inhibition further enhanced the PIR and LR of b2-and b1-adrenoceptor activation both in Sham and failing hearts, compared with PDE3 inhibition alone. PDE4 enzyme activity was reduced in failing hearts. CONCLUSIONS AND IMPLICATIONSBoth PDE3 and PDE4 attenuated b2-and b1-adrenoceptor-mediated contractile responses in Sham hearts. In failing hearts, these responses are attenuated solely by PDE3 and thus even selective PDE3 inhibitors may provide a profound enhancement of b-adrenoceptor-mediated responses in heart failure. AbbreviationsEHNA, erythro-9-(2-hydroxy-3-nonyl) adenine; HF, heart failure; LR, lusitropic response; PIR, positive inotropic response; RT, relaxation time BJP British Journal of Pharmacology

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“…Posterior left ventricular papillary muscles and left ventricle strips (diameter ∼1.0 mm) were prepared, mounted in 31°C organ baths containing physiological salt solution with 1.8 mM Ca 2+ , equilibrated and field‐stimulated at 1 Hz (Skomedal et al ., 1982; 1997). Contraction–relaxation cycles were recorded and analysed as previously described (Sjaastad et al ., 2003; Qvigstad et al ., 2005b). Maximal development of force (dF/dt) max , time to peak force (TPF), time to 80% relaxation (TR80) and relaxation time (RT; RT = TR80‐TPF) were measured.…”

Section: Methodsmentioning

confidence: 99%

Cyclic AMP‐dependent inotropic effects are differentially regulated by muscarinic G_i‐dependent constitutive inhibition of adenylyl cyclase in failing rat ventricle

Afzal

et al. 2011

British J Pharmacology

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BACKGROUND AND PURPOSEb-Adrenoceptor (b-AR)-mediated inotropic effects are attenuated and Gi 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 b-AR-or emergent 5-HT4-mediated cAMP-dependent inotropic effects. EXPERIMENTAL APPROACHContractility 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 Gi protein by pertussis toxin (PTX). KEY RESULTSIsoprenaline-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. b-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 IMPLICATIONSAlthough muscarinic constitutive inhibition of AC is increased in HF, it does not contribute to the reduced b-AR-mediated inotropic effects in rat ventricle in HF. The data support the hypothesis that there are differences in the functional compartmentation of 5-HT4 and b-AR AC signalling in myocardium during HF.

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Carvedilol blockade of α1- and β-adrenoceptor induced inotropic responses in rats with congestive heart failure

Cited by 9 publications

References 24 publications

Doxycycline Attenuates Isoproterenol-Induced Myocardial Fibrosis and Matrix Metalloproteinase Activity in Rats

Doxycycline Attenuates Isoproterenol-Induced Myocardial Fibrosis and Matrix Metalloproteinase Activity in Rats

Differential regulation of β₂‐adrenoceptor‐mediated inotropic and lusitropic response by PDE3 and PDE4 in failing and non‐failing rat cardiac ventricle

Cyclic AMP‐dependent inotropic effects are differentially regulated by muscarinic G_i‐dependent constitutive inhibition of adenylyl cyclase in failing rat ventricle

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Carvedilol blockade of α1- and β-adrenoceptor induced inotropic responses in rats with congestive heart failure

Cited by 9 publications

References 24 publications

Doxycycline Attenuates Isoproterenol-Induced Myocardial Fibrosis and Matrix Metalloproteinase Activity in Rats

Doxycycline Attenuates Isoproterenol-Induced Myocardial Fibrosis and Matrix Metalloproteinase Activity in Rats

Differential regulation of β2‐adrenoceptor‐mediated inotropic and lusitropic response by PDE3 and PDE4 in failing and non‐failing rat cardiac ventricle

Cyclic AMP‐dependent inotropic effects are differentially regulated by muscarinic Gi‐dependent constitutive inhibition of adenylyl cyclase in failing rat ventricle

Contact Info

Product

Resources

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Differential regulation of β₂‐adrenoceptor‐mediated inotropic and lusitropic response by PDE3 and PDE4 in failing and non‐failing rat cardiac ventricle

Cyclic AMP‐dependent inotropic effects are differentially regulated by muscarinic G_i‐dependent constitutive inhibition of adenylyl cyclase in failing rat ventricle