Cardioprotective Effect Afforded by Transient Exposure to Phosphodiesterase III Inhibitors

Shoji, Shuichi; Kitakaze, Masafumi; Papst, Philip J.; Asanuma, Hiroshi; Node, Koichi; Takashima, Seiji; Asakura, Masanori; Ogita, Hisakazu; Liao, Yulin; Sakata, Yasuhiko; Ogai, Akiko; Fukushima, Tomi; Yamada, Jun; Shinozaki, Yoshiro; Kuzuya, Tsunehiko; Mori, Hiromu; Terada, Naohiro; Hori, Masatsugu

doi:10.1161/hc3201.092216

Cited by 97 publications

(88 citation statements)

References 44 publications

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“…[33] . However, when delivered at 1.35 μg/kg per minute in dogs or at 10 μmol/L in isolated rat hearts approximately 30 min before preconditioning, H-89 completely blunted the infarct-limitation effect of preconditioning [12,34] . Therefore, the partial inhibition of H-89 on SIM cardioprotection in our study most likely occurred because H-89 was delivered later than SIM, and the contradiction between these studies might be explained by the differences in H-89 dosage, experimental protocols, and animal species.…”

Section: Discussionmentioning

confidence: 94%

Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway

Yang

Geng³

et al. 2012

Acta Pharmacol Sin

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Aim: The cholesterol-lowering drugs statins could enhance the activities of endothelial nitric oxide synthase (eNOS) and protect myocardium during ischemia and reperfusion. The aim of this study was to examine whether protein kinase A (PKA) was involved in statinmediated eNOS phosphorylation and cardioprotection. Methods: 6-Month-old Chinese minipigs (20-30 kg) underwent a 1.5-h occlusion and 3-h reperfusion of the left anterior descending coronary artery (LAD). In the sham group, the LAD was encircled by a suture but not occluded. Hemodynamic and cardiac function was monitored using a polygraph. Plasma activity of creatine kinase and the tissue activities of PKA and NOS were measured spectrophotometrically. p-CREB, eNOS and p-eNOS levels were detected using Western blotting. Sizes of the area at risk, the area of no-reflow and the area of necrosis were measured morphologically. Results: Pretreatment of the animals with simvastatin (SIM, 2 mg/kg, po) before reperfusion significantly decreased the plasma activity of creatine kinase, an index of myocardial necrosis, and reduced the no-reflow size (from 50.4%±2.4% to 36.1%±2.1%, P<0.01) and the infarct size (from 79.0%±2.7% to 64.1%±4.5%, P<0.01). SIM significantly increased the activities of PKA and constitutive NOS, and increased Ser 133 p-CREB protein, Ser 1179 p-eNOS, and Ser 635 p-eNOS in ischemic myocardium. Intravenous infusion of the PKA inhibitor H-89 (1 μg·kg -1 ·min -1 ) partially abrogated the SIM-induced cardioprotection and eNOS phosphorylation. In contrast, intravenous infusion of the eNOS inhibitor L-NNA (10 mg·kg -1 ) completely abrogated the SIM-induced cardioprotection and eNOS phosphorylation during ischemia and reperfusion, but did not affect the activity of PKA. Conclusion: Pretreatment with a single dose of SIM 2.5 h before reperfusion attenuates myocardial no-reflow and infarction through increasing eNOS phosphorylation at Ser 1179 and Ser 635 that was partially mediated via the PKA signaling pathway.

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Section: Discussionmentioning

confidence: 94%

Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway

Yang

Geng³

et al. 2012

Acta Pharmacol Sin

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“…Amrinone also improved contractile recovery after ischemia-reperfusion (IR) in the isolated rat heart in an extracellular calcium dependent manner [93] . Furthermore, injection of milrinone or olprinone before IR reduced infarct size in dogs [94] . Further dissection of the signaling pathways involved in olprinone-mediated protection revealed that it induced cardioprotection through cAMP/PKA and p38-MAPK dependent, but not PKC dependent mechanisms [94] .…”

Section: Phosphodiesterasementioning

confidence: 89%

“…Furthermore, injection of milrinone or olprinone before IR reduced infarct size in dogs [94] . Further dissection of the signaling pathways involved in olprinone-mediated protection revealed that it induced cardioprotection through cAMP/PKA and p38-MAPK dependent, but not PKC dependent mechanisms [94] . The authors proposed that the end-effectors of p38-MAPK may include opening of the mitochondrial ATP-sensitive potassium channel (mitoKATP) channel or translocation of Hsp27 to the Z-disc to stabilize the myofibril and cytoskeleton.…”

Section: Phosphodiesterasementioning

confidence: 89%

Pivotal effects of phosphodiesterase inhibitors on myocyte contractility and viability in normal and ischemic hearts

Rao

2008

Acta Pharmacol Sin

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Phosphodiesterases (PDEs) are enzymes that degrade cellular cAMP and cGMP and are thus essential for regulating the cyclic nucleotides. At least 11 families of PDEs have been identified, each with a distinctive structure, activity, expression, and tissue distribution. The PDE type-3, -4, and -5 (PDE3, PDE4, PDE5) are localized to specific regions of the cardiomyocyte, such as the sarcoplasmic reticulum and Z-disc, where they are likely to influence cAMP/cGMP signaling to the end effectors of contractility. Several PDE inhibitors exhibit remarkable hemodynamic and inotropic properties that may be valuable to clinical practice. In particular, PDE3 inhibitors have potent cardiotonic effects that can be used for short-term inotropic support, especially in situations where adrenergic stimulation is insufficient. Most relevant to this review, PDE inhibitors have also been found to have cytoprotective effects in the heart. For example, PDE3 inhibitors have been shown to be cardioprotective when given before ischemic attack, whereas PDE5 inhibitors, which include three widely used erectile dysfunction drugs (sildenafil, vardenafil and tadalafil), can induce remarkable cardioprotection when administered either prior to ischemia or upon reperfusion. This article provides an overview of the current laboratory and clinical evidence, as well as the cellular mechanisms by which the inhibitors of PDE3, PDE4 and PDE5 exert their beneficial effects on normal and ischemic hearts. It seems that PDE inhibitors hold great promise as clinically applicable agents that can improve cardiac performance and cell survival under critical situations, such as ischemic heart attack, cardiopulmonary bypass surgery, and heart failure.

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“…Improvement of myocardial pump function and myocardial damage will be the important strategies in this situation. Recent studies demonstrated that PDE III inhibitors attenuate myocardial damage and pump function after ischemia-reperfusion injury [9,12,13]. PDE III inhibitors are the therapeutic agents for acute congestive heart failure and they possess positive inotropic and vasodilatory action.…”

mentioning

confidence: 99%

“…They speculate that the reduction of Ca 2+ overload in the myocyte due to amrinone induces the myocardial cardioprotection. Also, Sanada et al reported that the transient activation of p38 MAPK which induced by PDE III inhibitors elicit cardioprotection [13]. However, the mechanisms of myocardial protection from ischemiareperfusion injury by PDE III inhibitors are not clarified.…”

mentioning

confidence: 99%

Effects of Olprinone on Myocardial Ischemia-Reperfusion Injury in Dogs

Setoyama

Kamimura

Fujiki

et al. 2006

The Journal of Veterinary Medical Science

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ABSTRACT. We investigated the effect of olprinone on canine myocardial pump function and myocardial damage after ischemia-reperfusion injury. Three dogs of the experimental group were given olprinone (Olprinone group) and another 3 dogs were served as control (Intact group). All animals were occluded left anterior descending artery for 60 min, followed by 6 hr of reperfusion. In the experiment, hemodynamics, infarct area, creatine kinase and troponin-I were measured. Olprinone infusion induced significantly high cardiac output value and significantly low values in left ventricular end diastolic pressure and systemic vascular resistance index after reperfusion. Also, olprinone tend to attenuate the infarct area, creatine kinase and troponin-I. KEY WORDS: canine, ischemia-reperfusion injury, olprinone.J. Vet. Med. Sci. 68(8): 865-868, 2006 In the field of veterinary clinics, cardiovascular surgery using cardiopulmonary bypass has become one of the promising treatments in recent years. However, open heart surgery sometimes induces myocardial ischemia-reperfusion injury and leads to myocardial dysfunction as well as myocardial infarction [4]. To prevent myocardial dysfunction, various agents such as Na + /H + -exchange inhibitor, oxygenderived free radical scavenger and statins have been studied [10].Phosphodiesterase (PDE) III inhibitors, a therapeutic agent for acute congestive heart failure, have both inotropic and vasodilatory effects. The pharmacological effect of PDE III inhibitors have been shown to be due to an increase in intracellular cyclic-adenosine monophosphate (cAMP) without beta-adrenergic pathway [1-3, 6, 7, 11]. Recently, it has been demonstrated that amrinone and milrinone decreased infarct size in isolated rabbit heart with coronary artery occlusion [12]. Rechtman et al. also reported that amrinone suppressed creatine kinase and lactate dehydrogenase elevation, indicators of myocardial injury, in the isolated rat heart with ischemia-reperfusion injury [9]. In addition, our previous study showed milrinone increases myocardial blood flow in the hypoxic dogs [8]. From these results, we hypothesized that PDE III inhibitors may protect myocardial damage from ischemic or ischemia-reperfusion injury and it seems to have an interesting effect on treating myocardial dysfunction after cardiopulmonary bypass or myocardial infarction.However, few reports have evaluated the effect of PDE III inhibitors on canine myocardial pump function after ischemia-reperfusion injury. In this study, we investigated the effect of olprinone on canine myocardial function and damage after ischemia-reperfusion injury.The experiment was carried out after permission from the committee on Animal Experimentation, Kagoshima University.We used 6 beagle dogs (2 years old, male) weighing 9.2 ± 0.5 kg (mean ± standard error). The dogs were healthy, as determined by pre-operative examinations, including physical examination, clinical laboratory evaluation and radiography of the thorax.The dogs were premedicated with atropin sulfate (0...

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Cardioprotective Effect Afforded by Transient Exposure to Phosphodiesterase III Inhibitors

Cited by 97 publications

References 44 publications

Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway

Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway

Pivotal effects of phosphodiesterase inhibitors on myocyte contractility and viability in normal and ischemic hearts

Effects of Olprinone on Myocardial Ischemia-Reperfusion Injury in Dogs

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