Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amrinone, one of the phosphodiesterase III inhibitors, is clinically used for acute heart failure and possesses diuretic action, which is not observed in other phosphodiesterase III inhibitors. To clarify the mechanism of the diuretic action of amrinone, we investigated its effects on renal blood flow and some other hemodynamic parameters in comparison with the effects of milrinone and olprinone in anesthetized dogs. Amrinone increased both renal and femoral blood flow in a dose-dependent manner. On the other hand, milrinone and olprinone increased only femoral blood flow and had no effect on renal blood flow. Amrinone, milrinone and olprinone dose-dependently increased left ventricular max dp/dt, and the estimated slope of the dose-response curve for olprinone was significantly sharper than that of amrinone. Furthermore, these three drugs increased the cardiac index and decreased systemic vascular resistance (SVR) significantly. The action of amrinone on SVR was more potent than those of milrinone and olprinone. These results suggest that the diuretic action of amrinone is involved in augmentation of renal blood flow and may support useful effects on acute heart failure.
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PMID:[Effects of amrinone on renal blood flow and cardiac function, in comparison with those of milrinone and olprinone, in anesthetized dog]. 1020 62

To elucidate the physiological role of phosphodiesterase (PDE) in cardiac pacemaker cells, we studied the electrophysiological effects of amrinone, an inhibitor of PDE type III, on the spontaneous action potential (AP) and membrane currents, using small preparations (0.2 x 0.2 x 0.1 mm) of rabbit sinoatrial (SA) node cells. Amrinone (0.1-1.0 mM) progressively increased the AP amplitude, maximal rate of depolarization, and spontaneous firing frequency, shortened the AP duration, and made the threshold potential more negative. In voltage-clamp experiments using double microelectrode techniques, 0.1 mM amrinone increased the Ca2+ current (I(Ca)) obtained on step depolarization from -40 to -10 mV by 25.86% +/-4.6% (P < 0.05, n = 6), the delayed rectifier K+ current (I(K)) tail obtained on repolarization from 10 to -60 mV by 22.8%+/-4.7% (P < 0.05, n = 6), and the hyperpolarization-activated inward current (Ih) at -90 mV by 19.5%+/-7.3% (P < 0.05, n = 6), respectively. Amrinone did not affect the slope factors of either the inactivation curve for I(Ca) (finfinity curve) or the activation curve for the delayed rectifier I(K) (pinfinity curve). These results suggest that this PDE III inhibitor exerts a positive chronotropic action by enhancing the availability and the conductance of all the tested membrane currents in rabbit SA node cells.
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PMID:Electrophysiological effects of amrinone on the automaticity and membrane current system of the rabbit sinoatrial node cells. 1032 81

Acute increases in blood pressure (BP) increase myocardial tumor necrosis factor (TNF)-alpha production, but it is not known whether chronic hypertensive stress elevates myocardial TNF-alpha production, possibly contributing to cardiac remodeling, decreased cardiac function, and faster progression to heart failure. BP, cardiac function, and size were evaluated in normotensive [Sprague-Dawley (SD)], spontaneously hypertensive (SHR), and spontaneously hypertensive heart failure-prone (SHHF) rats at 6, 12, 15, and 18 mo of age and in failing SHHF. Left ventricular tissues were evaluated for secretion of bioactive TNF-alpha and inhibition of TNF-alpha secretion by phosphodiesterase inhibitors. All ventricles secreted bioactive and immunoreactive TNF-alpha, but secretion decreased with age. SHR and SHHF rats secreted more TNF-alpha than SD rats at 6 mo of age, but only failing SHHF rats secreted significantly more TNF-alpha at 18 mo. Amrinone inhibited TNF-alpha secretion in all rats and was less potent but more efficacious than RO-201724 in all strains. TNF-alpha secretion correlated with BP and left ventricular mass in 6-mo-old rats, but this relationship disappeared with age. Results suggest that hypertension and/or cardiac remodeling is associated with elevated myocardial TNF-alpha, and, although hypertension, per se, did not maintain elevated cardiac TNF-alpha levels, SHHF rats increase TNF-alpha production during the end stages of failure.
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PMID:Myocardial tumor necrosis factor-alpha secretion in hypertensive and heart failure-prone rats. 1044 79

The effects of phosphodiesterase III (PDE III) inhibitors administered after aortic declamping during cardiopulmonary bypass (CPB) for open heart surgery were investigated. Ten patients (group M) were administered milrinone (50 microg/kg) after aortic declamping during CPB, 10 patients were administered amrinone (1 mg/kg) at the same time during their surgery (group A), and 10 patients served as controls with no drug administered (group C). Soon after bolus infusion of the PDE III inhibitor, perfusion pressure dropped significantly in groups M and A. However, after release of CPB and at the end of surgery, there was no difference in aortic pressure between the 3 groups. There were also no differences between the groups in heart rate, pulmonary artery pressure, and pulmonary capillary wedge pressure. After weaning from CPB, the cardiac index was high and systemic vascular resistance index was low in groups M and A. There were no significant differences in the need for additional catecholamines and time for rewarming between groups. No adverse reactions were observed. A single administration of a PDE III inhibitor during CPB was useful for post-CPB management of patients undergoing open heart surgery. Amrinone reduced perfusion pressures more than milrinone, but cardiac indices and aortic pressures after weaning from CPB showed no differences between group M and group A patients.
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PMID:Effects of single administration of a phosphodiesterase III inhibitor during cardiopulmonary bypass: comparison of milrinone and amrinone. 1047 10

We investigated the effect of amrinone, a phosphodiesterase III inhibitor, on rat airway smooth muscle, and thereafter, compared its activity with aminophylline and diltiazem. Amrinone produced relaxation of the acetylcholine-induced airway contraction in a dose-related manner. This bronchodilatory activity of amrinone was similar to that of aminophylline, but smaller than that of diltiazem. The 50% relaxant effect (ED50) of amrinone, aminophylline and diltiazem were 3.6 x 10(-4) M, 1.4 x 10(-4) M and 1.4 x 10(-5) M, respectively. Diltiazem was the most potent airway relaxant, and amrinone was less potent in these experiments. Taken together in its positive inotropic and chronotropic effects and anti-inflammatory activity, however, amrinone could be beneficial for treatment of patients suffering from asthma or heart failure with cardiac asthma.
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PMID:Comparative effect of amrinone, aminophylline and diltiazem on rat airway smooth muscle. 1090 23

The effects of amrinone, a selective phosphodiesterase III inhibitor, on liver ischaemia reperfusion injury have not yet been clarified. Forty-five patients with hepatocellular carcinoma who underwent partial liver resection using Pringle's manoeuvre were studied. Patients were divided into three groups: those given amrinone, those given prostaglandin E1 (PGE1) and those not treated (controls). An indocyanine green (ICG) clearance test was performed before the operation and three times during surgery: just before induction of liver ischaemia, just after liver resection and 60 min after reperfusion. Blood lactate and base excess were measured at the same times. Systolic and diastolic arterial pressure, heart rate, cardiac index and oesophageal temperature were monitored. Aminotransferase levels were recorded the day before surgery, 1 h after operation and on the first and third postoperative days. These data were compared between groups. The ICG elimination rate, lactate and base excess in the amrinone group differed significantly from those in controls during the observation period (P = 0.03, P = 0.04 and P = 0.03, respectively). The differences between the PGE1 and control groups were not significant. There were no significant differences between the groups in perioperative vital signs, cardiac index or postoperative aminotransferase. Amrinone enhanced intraoperative ICG elimination in cirrhotic patients who underwent liver resection.
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PMID:Effects of amrinone on ischaemia-reperfusion injury in cirrhotic patients undergoing hepatectomy: a comparative study with prostaglandin E1. 1110 79

(1) The vasorelaxation produced by the phosphodiesterase 3 (PDE3) inhibitor, amrinone was investigated in isolated rat aorta denuded of endothelium. In the presence of extracellular Ca(2+), amrinone, milrinone and 3-isobutyl-1-methylxanthine (IBMX), relaxed endothelium-denuded rat aortic rings constricted with phenylephrine. While the actions of milrinone and IBMX were inhibited by the protein kinase G (PKG) inhibitor, Rp-8-Bromo guanosine-3',5' monophosphothioate (Rp-8-Br-cGMPS; 0.5 mM), that of amrinone was only slightly affected; whereas the protein kinase A (PKA) inhibitor, Rp-adenosine-3',5' cyclic monophosphothioate (Rp-cAMPS; 0.5 mM) had no effect on any agent. (2) Amrinone (100 microM) inhibited (45)Ca(2+) influx through receptor- or store-operated Ca(2+) channels following stimulation with phenylephrine (1 microM) or thapsigargin (1 microM). In contrast, amrinone had no effect on KCl (120 mM)-stimulated Ca(2+) influx. (3) In the absence of extracellular Ca(2+), amrinone (30 microM) inhibited the constriction produced by phenylephrine, 5-hydroxytryptamine (5HT) and U46619, and this effect was not affected by Rp-cAMPS or Rp-8-Br-cGMPS. (4) The intracellular mechanism of action of amrinone may involve the phospholipase C (PLC)-inositol 1,4,5 trisphosphate (IP(3))-intracellular Ca(2+) signal transduction pathway. However, amrinone (100 microM) had no effect on either basal- or noradrenaline (100 microM)-stimulated PLC activity. Similarly, IP(3) stimulated a concentration-dependent release of Ca(2+) from rat brain microsomes that was not affected by amrinone (30 and 100 microM). (5) In conclusion, the vasorelaxant action of amrinone does not involve adenosine 3',5' cyclic monophosphate (cAMP) or involve guanosine 3',5' cyclic monophosphate (cGMP) but may include an inhibition of Ca(2+) influx through receptor- or store-operated Ca(2+) channels, although it does not directly affect intracellular Ca(2+) release.
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PMID:The role of cyclic nucleotides and calcium in the relaxation produced by amrinone in rat aorta. 1128 18

Amrinone is a selective phosphodiesterase III inhibitor that increases cyclic adenosine monophosphate by preventing its breakdown. It is effective in the treatment of congestive heart failure because of its ability to increase myocardial contractility and vascular smooth muscle relaxation. This study was designed to clarify the potential efficacy of amrinone in plastic surgery by clinically assessing its ability to enhance flap blood flow after reconstructive surgery and relieve intraoperative vasospasm. Its effects were compared with those of prostaglandin E1 and lidocaine, which are widely approved agents for improving the hemodynamics of flaps. In the first clinical study, the effects on flap blood flow after flap transfers were investigated. Twenty-six patients underwent reconstructive surgery with vascularized free or pedicled flaps. Blood flow was measured before and 60 minutes after intravenous infusion of lactated Ringer solution (control), amrinone (10 microg/kg/min), or prostaglandin E1 (10 ng/kg/min) using a laser Doppler flowmeter. In the second study, the effects on relief of vasospasm during operation were evaluated. The blood flow of 28 island flaps was measured by laser Doppler flowmetry immediately after flap elevation and 10 minutes after topical application of saline (control), amrinone (5 mg/ml), or lidocaine (10%) to the pedicle in an attempt to resolve the vasospasm. In both clinical studies, the effects of amrinone were statistically no less than those of prostaglandin E1 and lidocaine. The results show that amrinone positively influences the microcirculatory blood flow of transferred flaps and relieves intraoperative vasospasm in clinical cases. The present study suggests that amrinone could be useful for postoperative and intraoperative care in reconstructive surgery.
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PMID:Clinical use of amrinone (a selective phosphodiesterase III inhibitor) in reconstructive surgery. 1174 79

Therapies that mitigate the fibrotic process may be able to slow progressive loss of function in many lung diseases. Because cyclic adenosine monophosphate is known to regulate fibroblasts, the current study was designed to evaluate the activity of selective phosphodiesterase (PDE) inhibitors on two in vitro fibroblast responses: chemotaxis and contraction of three-dimensional collagen gels. Selective PDE4 inhibitors, rolipram and cilomilast, each inhibited the chemotaxis of human fetal lung fibroblasts (HFL-1) toward fibronectin in the blindwell assay system (control: 100% versus cilomilast [10 microM]: 40.5 +/- 7.3% versus rolipram: [10 microM] 32.1 +/- 2.7% cells/5 high-power fields; P < 0.05, both comparisons). These PDE4 inhibitors also inhibited contraction of three-dimensional collagen gels (control: 100% versus cilomilast: 167.7 +/- 6.9% versus rolipram: 129.9 +/- 1.9% of initial size; P < 0.05, both comparisons). Amrinone, a PDE3 inhibitor, and zaprinast, a PDE5 inhibitor, had no effect in either system. Prostaglandin E(2) (PGE(2)) inhibited both chemotaxis and gel contraction, and the PDE4 inhibitors shifted the PGE(2) concentration-dependence curve to the left in both systems. The inhibition of endogenous PGE(2) production by indomethacin diminished the effects of the PDE4 inhibitors in both chemotaxis and gel contraction, consistent with the concept that the PDE4 inhibitory effects on fibroblasts are related to the presence of cyclic adenosine monophosphate in the cells. In summary, these in vitro results suggest that PDE4 inhibitors may be able to suppress fibroblast activity and, thus, have the potential to block the development of progressive fibrosis.
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PMID:PDE4 inhibitors attenuate fibroblast chemotaxis and contraction of native collagen gels. 1203 68

Tissue destruction, resulting in emphysema, can be a consequence of several pathologic processes. The current study evaluated the effects of the phosphodiesterase (PDE)4 inhibitor, cilomilast, and other PDE inhibitors on the ability of fibroblasts to degrade extracellular matrix. Using the three-dimensional collagen gel culture system, fibroblasts (HFL-1) were cultured with tumor necrosis factor (TNF)-alpha, known to induce matrix metalloproteinase (MMP) release, and/or neutrophil elastase (NE), which can induce MMP activation. On Day 4, gels containing TNF-alpha and NE were significantly degraded (20.8 +/- 2.9% of original collagen content). Cilomilast (10 micro M) inhibited this degradation (84.4 +/- 8.4%). Amrinone, a PDE3 inhibitor, and zaprinast, a PDE5 inhibitor, had no effect. Gelatin zymography and immunoblotting revealed that fibroblasts cultured with TNF-alpha released increased amounts of latent MMP-1 and -9. The addition of NE resulted in the conversion of MMP-1 and -9 to their active forms, indicative of collagen degradation. Cilomilast inhibited the release of MMP-1 and -9, as well as conversion of MMP-1 to its active form. Using real-time PCR analysis, cilomilast's effect on MMP-1 release was not associated with the proteinase's mRNA expression, suggesting that the inhibition of release is regulated at the post-transcriptional level. These results suggest that cilomilast may be a potentially effective therapeutic agent in diseases characterized by excessive tissue destruction, such as emphysema.
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PMID:Phosphodiesterase 4 inhibitor cilomilast inhibits fibroblast-mediated collagen gel degradation induced by tumor necrosis factor-alpha and neutrophil elastase. 1235 83


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