Effects Of Milrinone On Left Ventricular End‐Systolic Pressure–Volume Relationship Of Rat Hearts <i>In Situ</i>

Kishi, Takashi; Nakahashi, Kazuhiro; Itô, Haruo; Taniguchi, Shigeki; Takaki, Miyako

doi:10.1046/j.1440-1681.2001.03512.x

Cited by 18 publications

(39 citation statements)

References 36 publications

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“…Previous studies have revealed that the left ventricular end-systolic pressure-volume relation of isolated crosscirculated and in situ ejecting adult rat hearts have upward convex curves, even within the physiological range [15][16][17]. This convex curvature of end-systolic pressure-volume relation has also been described in mice hearts [18,19].…”

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confidence: 70%

Isoproterenol-Induced Hypertrophied Rat Hearts: Does Short-Term Treatment Correspond to Long-Term Treatment?

et al. 2008

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Abstract:In consideration of clinical implications, it is often complained that short-term experimental diseased heart models do not mimic long-term diseased hearts that are often clinically encountered. The aim of the present study was (i) to compare the left ventricular function between rat cardiac hypertrophy models treated with isoproterenol for 3 days (Iso 3d) and 7 days (Iso 7d) by pressure-volume measurements with a catheter method, and (ii) to follow up the left ventricular function in the same model treated with Iso up to 16 weeks with a less-invasive echocardiography. An infusion of either Iso (1.2 mg·kg -1 ·day -1 for 3 days-16 weeks) or vehicle (saline 24 µl·day -1 for 3 days-16 weeks; Sa group) was performed by subcutaneously implanting an osmotic minipump. There were no significant differences in the systolic pressure-volume area at midrange left ventricular volume (PVA mLVV : a mechanical work capability index) between Iso 3d and 7d groups, though PVA mLVV in both groups was significantly reduced from that in the Sa group. From echocardiography, the left ventricular function of the hypertrophy models at 3 days, 1 week, and 2 weeks was unchanged, but the model at a term longer than 4 weeks resulted in prolonged systolic failure. The results indicated that (i) no marked differences in the left ventricular mechanical work capability were found between the Iso 3d and 7d groups, and that (ii) only a 3-day Iso infusion induced the hypertrophy model similar in shape and function to that induced by a 2-week Iso infusion. We concluded that the 3-day model was sufficient.Key words: conductance catheter, echocardiography, left ventricular volumetry, systolic pressure-volume area.It is known that chronic infusions of a α, β-stimulant, norepinephrine, and a β-stimulant, isoproterenol (Iso), induce cardiac hypertrophy accompanied with enhanced fibrosis among cardiac interstitial cells [1][2][3]. Many studies on mechanisms underlying Iso-induced cardiac hypertrophy have been reported [4][5][6][7][8][9][10][11][12][13]. Cardiac oxidative stress contributes to this type of cardiac remodeling, especially in respect to wall stiffness, based on fibrogenesis in chronically Iso-infused rats (3 mg·kg -1 ·day -1 for 10 days), whereas cardiac phosphorylated MAP (mitogen-activated protein) kinases (extracellular signal related kinase; ERK1/2, c-JUN NH 2 -terminal kinase; JNK, p38) returned to normal [4]. The AT1 (type 1 angiotensin II) receptor plays a crucial role in the development of cardiac hypertrophy and oxidative stress in chronically Iso-infused mice (15 mg·kg -1 ·day -1 for 11 days) [5]. Furthermore, we have recently found that a novel histone deacetylase (HDAC) inhibitor has no effects of antihypertrophic modalities on the Iso-induced rat heart (1.2 mg·kg -1 ·day -1 for 3 days) [6]. Nevertheless, the conclusive mechanisms underlying Iso-induced cardiac hypertrophy have not yet been determined [4][5][6][7][8][9][10][11][12][13].We have previously succeeded in inducing cardiac hypertrophy by stimulating the β 1 -re...

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Isoproterenol-Induced Hypertrophied Rat Hearts: Does Short-Term Treatment Correspond to Long-Term Treatment?

et al. 2008

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“…Both of them have been approved by the United States Food and Drug Administration and are used in clinical treatment. The former is prescribed in patients with severe heart failure (Kikura and Levy, 1995; Kishi et al, 2001); the latter is used in patients with intermittent claudication (Beebe et al, 1999). The potency of inhibition of milrinone and cilostazol on PDE3A is similar, although these two drugs differ substantially in their chemical structures.…”

Section: Resultsmentioning

confidence: 99%

“…One, cilostazol, with antiplatelet, antithrombotic, and vasodilatory effects, has been approved for the treatment of patients with intermittent claudication (Dawson, 2001) and for prevention of short-and mediumterm vessel closure as well as late restenosis after intracoronary stenting (El-Beyrouty and Spinler, 2001;Tanabe et al, 2001). The other, milrinone, improves the hemodynamic status of heart failure via inotropic/vasodilatory effects attributable to the increase in cardiac intracellular cAMP level (Kishi et al, 2001). Milrinone is used for the treatment perioperative severe heart failure or marked deterioration of congestive heart failure (Kikura and Levy, 1995).…”

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Identification of Interaction Sites of Cyclic Nucleotide Phosphodiesterase Type 3A with Milrinone and Cilostazol Using Molecular Modeling and Site-Directed Mutagenesis

Zhang

Colman

2002

Mol Pharmacol

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To identify amino acid residues involved in PDE3-selective inhibitor binding, we selected eight presumed interacting residues in the substrate-binding pocket of PDE3A using a model created on basis of homology to the PDE4B crystal structure. We changed the residues to alanine using site-directed mutagenesis technique, expressed the mutants in a baculovirus/ Sf9 cell system, and analyzed the kinetic characteristics of inhibition of the mutant enzymes by milrinone and cilostazol, specific inhibitors of PDE3. The mutants displayed differential sensitivity to the inhibitors. Mutants Y751A, D950A, and F1004A had reduced sensitivity to milrinone (K i changed from 0.66 M for the recombinant PDE3A to 7.5 to 156 M for the mutants), and diminished sensitivity to cilostazol (K i of the mutants were 18-to 371-fold higher than that of the recombinant PDE3A). In contrast, the mutants T844A, F972A and Q975A showed increased K i for cilostazol but no difference for milrinone from the recombinant PDE3A. Molecular models show that the PDE3 inhibitors cilostazol and milrinone share some of common residues but interact with distinct residues at the active site, suggesting that selective inhibitors can be designed with flexible size against PDE3 active site. Our study implies that highly conserved residuals Y751, D950 and F1004 in the PDE families are key residues for binding of both substrate and inhibitors, and nonconserved T844 may be responsible for the cilostazol selectivity of PDE3A. Detailed knowledge of the structure of inhibitory sites should contribute to development of more potent and specific inhibitory drugs.

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“…23) Milrinone is considered to exert a positive inotropic action and to decrease left ventricular endsystolic pressure reflecting the decrease in left ventricular afterload. 24) However, milrinone-induced reductions in effective arterial elastance reflecting the fall in total peripheral resistance and changes in stroke volume are not significant. 24) These previous reports suggested that baroreflex control is important to obtain the inotropic effect of milrinone.…”

Section: Discussionmentioning

confidence: 98%

“…24) However, milrinone-induced reductions in effective arterial elastance reflecting the fall in total peripheral resistance and changes in stroke volume are not significant. 24) These previous reports suggested that baroreflex control is important to obtain the inotropic effect of milrinone. Another previous study suggested that BRS predicts the cases in which milrinone increases left ventricular dp/dt.…”

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confidence: 98%

Baroreflex Sensitivity Might Predict Responders to Milrinone in Patients With Heart Failure

Kishi

Sunagawa

2010

Int. Heart J.

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SummaryThe phosphodiesterase III inhibitor milrinone (MIL) is considered to be effective for "wet and cold" heart failure. In some cases, however, the inotropic effects of milrinone are insufficient. A previous study suggested that baroreflex sensitivity (BRS) predicts the cases in which MIL increases left ventricular dp/dt. The aim of this study was to determine whether BRS measured using the spontaneous sequence method predicts the MIL responders. Twenty-four patients with "wet and cold" heart failure whose systolic blood pressure > 100 mmHg were enrolled. At 2 hours MIL improved dyspnea, general fatigue, urine volume, and tricuspid regurgitant pressure gradient in 13 patients (responders; R group), whereas it failed to improve in 11 patients (nonresponders; NR group). BRS in the R group was significantly higher than that in the NR group prior to the MIL infusion. At 2 hours after the MIL infusion, BRS was further increased in the R group, but did not increase in the NR group. The sensitivity and specificity of BRS at a cut-off level of 5 ms/mmHg for the prediction of R group were 0.94 and 0.93, respectively. BRS might be useful for identifying potential responders to milrinone in patients with blood pressure-preserved "wet and cold" heart failure. (Int Heart J 2010; 51: 411-415)

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Effects Of Milrinone On Left Ventricular End‐Systolic Pressure–Volume Relationship Of Rat Hearts In Situ

Cited by 18 publications

References 36 publications

Isoproterenol-Induced Hypertrophied Rat Hearts: Does Short-Term Treatment Correspond to Long-Term Treatment?

Isoproterenol-Induced Hypertrophied Rat Hearts: Does Short-Term Treatment Correspond to Long-Term Treatment?

Identification of Interaction Sites of Cyclic Nucleotide Phosphodiesterase Type 3A with Milrinone and Cilostazol Using Molecular Modeling and Site-Directed Mutagenesis

Baroreflex Sensitivity Might Predict Responders to Milrinone in Patients With Heart Failure

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