Beneficial effects of milrinone and enalapril on long-term survival of rats with healed myocardial infarction

Sweet, Charles S.; Ludden, C. T.; Stabilito, Inez I.; Emmert, Scott E.; Heyse, Joseph F.

doi:10.1016/0014-2999(88)90630-9

Cited by 50 publications

(9 citation statements)

References 15 publications

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“…To determine whether sustained elevations of intracellular cAMP content could also regulate NOS3 mRNA in vivo, adult rats were treated for 3 d with the type III phosphodiesterase inhibitor milrinone added to their drinking water, as previously described by Sweet et al (18). As expected, milrinone increased the total heart cAMP content in treated rats over levels in control, untreated animals over a 3-d period (0.9Ϯ0.26 vs 7.2Ϯ1.55 pmol/mg protein, n ϭ 3 for each condition, P Ͻ 0.01).…”

Section: Resultsmentioning

confidence: 99%

“…In some experiments, 300-g Sprague-Dawley rats were treated with milrinone (M4856; Sigma Chemical Co.) as described by Sweet et al (18) with minor modifications. Rats received 4 mg/kg milrinone in the drinking water for the first 24 h, and 2 mg/kg/d for an additional 48 h, and then were killed at 72 h. Fresh ventricular myocyte primary isolates were prepared as described above.…”

Section: Methodsmentioning

confidence: 99%

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Nitric oxide synthase (NOS3) and contractile responsiveness to adrenergic and cholinergic agonists in the heart. Regulation of NOS3 transcription in vitro and in vivo by cyclic adenosine monophosphate in rat cardiac myocytes.

Belhassen

Kelly²,

Smith³

et al. 1996

J. Clin. Invest.

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Cardiac myocytes express the nitric oxide synthase isoform originally identified in constitutive nitric oxide synthase cells (NOS3), which mediates the attenuation by muscarinic cholinergic agonists of ␤ -adrenergic stimulation of L-type calcium current and contractility in these cells. However, the reciprocal regulation of NOS3 activity in myocytes by agents that elevate cAMP has not been reported. In this study, we show that NOS3 and mRNA and protein levels in cardiac myocytes are reduced both in vitro after treatment with cAMP elevating drugs, and in vivo after 3 d of treatment with milrinone, a type III cAMP phosphodiesterase inhibitor. This effect on NOS3 activity by cAMP is cell type specific because treatment of cardiac microvascular endothelial cells in vitro or in vivo did not decrease NOS3 mRNA or protein in these cells. NOS3 downregulation in myocytes appeared to be at the level of transcription since there was no modification of NOS3 mRNA half-life by agents that increase intracellular cAMP. To determine the functional effects of NOS3 downregulation, we examined the contractile responsiveness of isolated electrically paced ventricular myocytes, isolated from animals that had been treated in vivo with milrinone, to the ␤ -adrenergic agonist isoproterenol and the muscarinic cholinergic agonist carbamylcholine. There was no difference in baseline contractile function in cells that had been pretreated with cAMP elevating agents compared to controls, but cells exposed to milrinone in vivo exhibited an accentuation in their contractile responsiveness to isoproterenol compared to controls and a loss of responsiveness to carbamylcholine. Downregu-

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Nitric oxide synthase (NOS3) and contractile responsiveness to adrenergic and cholinergic agonists in the heart. Regulation of NOS3 transcription in vitro and in vivo by cyclic adenosine monophosphate in rat cardiac myocytes.

Belhassen

Kelly²,

Smith³

et al. 1996

J. Clin. Invest.

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“…Blockade of 5‐HT receptors by various agents including SAR has also been reported to decrease cardiac hypertrophy in heart failure [40, 41]. Although this is a first study which has shown antihypertrophic effect of CIL, other PDE‐III inhibitors, such as amrinone and milri‐none have been reported to reduce cardiac hypertrophy in the failing heart [42, 43, 44]. While the exact mechanisms of the antihy‐pertrophic action of both SAR and CIL in the failing heart remain to be established, afterload reduction as a consequence of decreased peripheral resistance in heart failure by these agents may play an important role in this regard.…”

Section: Discussionmentioning

confidence: 99%

Antiplatelet therapy attenuates subcellular remodelling in congestive heart failure

Sanganalmath

Babick

Barta

et al. 2008

J Cellular Molecular Medi

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Antiplatelet agents, sarpogrelate (SAR), a 5-HT2A receptor antagonist, and cilostazol (CIL), a phosphodiesterase III (PDE-III) inhibitor, are used for the treatment of peripheral vascular disease. We tested whether these agents affect cardiac function and subcellular remodelling in congestive heart failure (CHF) induced by myocardial infarction (MI). Three weeks after MI, rats were treated daily with 5 mg/kg SAR or CIL as well as vehicle for 5 weeks. Sham-operated animals served as controls. At end of the treatment period, haemodynamic measurements were performed and the left ventricle was processed for the determination of sarcoplasmic reticulum (SR) Ca2+-uptake and -release activities, and expression of SR Ca2+-pump, phospholamban and ryanodine receptors, as well as myofibrillar ATPase activities, expression of α- and β-myosin heavy chain (MHC) isoforms, and phosphorylation of phospholamban and cardiac troponin-I (c Tn-I). Marked haemodynamic changes in the MI-induced CHF were associated with depressions in SR Ca +-uptake and -release activities as well as in protein content and gene expression for SR proteins. Furthermore, myofibrillar Ca2+-stimulated ATPase activity, as well as protein content and gene expression for α-MHC were decreased whereas those for β-MHC were increased in the failing heart. Also, phosphorylation levels of phospholamban and cTn-I were reduced in failing hearts. The MI-associated changes in cardiac function, SR and myofibillar activities, as well as SR and myofibrillar protein and gene expression were attenuated by treatment with SAR or CIL. The results suggest that SAR and CIL improve cardiac function by ameliorating subcellular remodelling in the failing heart and indicate the potential therapy of CHF with antiplatelet agents.

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“…The utility of the rat for modeling the chronic cardiac response to severe MI and for forecasting therapeutic effects of ACE inhibitors is well established. For instance, this model reproduces the effect of enalapril and captopril in humans with HF, namely restoring filling pressures and contractility [25,26], attenuating the progressive LV enlargement and dysfunction [27,28], and prolonging survival [27,29,30].…”

Section: Small Animal Modelsmentioning

confidence: 98%

Guidelines for Translational Research in Heart Failure

Lara‐Pezzi

Menasché

Trouvin

et al. 2015

J. of Cardiovasc. Trans. Res.

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Heart failure (HF) remains a major cause of death and hospitalization worldwide. Despite medical advances, the prognosis of HF remains poor and new therapeutic approaches are urgently needed. The development of new therapies for HF is hindered by inappropriate or incomplete preclinical studies. In these guidelines, we present a number of recommendations to enhance similarity between HF animal models and the human condition in order to reduce the chances of failure in subsequent clinical trials. We propose different approaches to address safety as well as efficacy of new therapeutic products. We also propose that good practice rules are followed from the outset so that the chances of eventual approval by regulatory agencies increase. We hope that these guidelines will help improve the translation of results from animal models to humans and thereby contribute to more successful clinical trials and development of new therapies for HF.

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Beneficial effects of milrinone and enalapril on long-term survival of rats with healed myocardial infarction

Cited by 50 publications

References 15 publications

Nitric oxide synthase (NOS3) and contractile responsiveness to adrenergic and cholinergic agonists in the heart. Regulation of NOS3 transcription in vitro and in vivo by cyclic adenosine monophosphate in rat cardiac myocytes.

Nitric oxide synthase (NOS3) and contractile responsiveness to adrenergic and cholinergic agonists in the heart. Regulation of NOS3 transcription in vitro and in vivo by cyclic adenosine monophosphate in rat cardiac myocytes.

Antiplatelet therapy attenuates subcellular remodelling in congestive heart failure

Guidelines for Translational Research in Heart Failure

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